Immuun nr 3 2014 by Lorient

IMMUUN Volume 3 - Issue 3 - December 2014 -

for every professional in the immunology chain

Van Loghem Laureate Yvette van Kooyk: “Join forces to target immune mediated diseases” Cure for diabetes within reach? One Health Congress: A plea for prevention at the source

Theme stem cell therapy

Jon van Rood the underrated potential of cord blood

Lustrum Lively debate at De Balie

Contains NVVI Anniversary Congress 2014 programme ’A Future Heritage’, p 36

Your Power for Health

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COLOPHON

contents IMMUUN December2014

Immuun is published by the NVVI and written and edited by Bureau Lorient Communicatie BV. In 2014, Immuun will have three issues. The target groups are NVVI members, relevant clinicians, suppliers and other partners of immunologists as well as policy makers. EDITORIAL BOARD Dr. Godelieve de Bree Prof.dr. Mieke Boots Dr. Hans Jacobs Dr. Edward Knol Prof.dr. Yvette van Kooyk (chair) Dr. Ingeborg Streng-Ouwehand Dr. Andrea Woltman recommendation committee Prof.dr. R.E. Bontrop Prof.dr. F. Claas Prof.dr. M.R. Daha Prof.dr. C.G.M. Kallenberg Prof.dr. G. Kraal Prof.dr. R.A.W. van Lier Prof.dr. C.J.M. Melief Prof.dr. D. Roos Prof.dr. J. van de Winkel editor in chief Drs. L. van der Ent PUBLISHER NVVI Contacts via Bureau Lorient Communicatie BV Hoofdstraat 98 - 100 2235 CK Valkenburg ZH T + 31 71 5890848 info@lorient.nl lay out & print Van der Weij BV Grafische Bedrijven, Hilversum PHoto front page Bureau Lorient Communicatie advertizing Congress Company Bruistensingel 250 5232 AD ’s-Hertogenbosch T +31 73 7003500 w.vandijk@congresscompany.com DISCLAIMER Immuun is made with the utmost care. NVVI nor Bureau Lorient Communicatie BV can be held responsible or liable for errors. Articles do not necessarily reflect the opinion of the editorial board, the publisher or the writer.

dutch society for immunology

7 17 18 21 30 24 31 32 34 4

News

Column

Agenda

News

Reinier de Graaf Immunology lab

NVVI 50th anniversary

Opinion

Debate at De Balie

Computer to replace animal models

Immuno Valley A to B Day

Inaugural lecture Joost van Neerven

Immune system of chick embryos

One Health Congress

NVVI 50th anniversary

Eight UMC immunology tour

Huib Ovaa

Ab Osterhaus

“Prevention at the source”

Theme Stem Cell Therapy

8 11 14 23 26 Bart Roep

Bob Löwenberg Progress in leukemia treatment

Sjef Copray

“Developments happen so fast, it’s almost scary”

Induced Pluripotent Stem cells against MS

Jaap Jan Zwaginga

Research

Hope and science or hype and fiction?

Jon van Rood The discovery of yang in medicine

Contains NVVI Anniversary Congress 2014 programme ’A Future Heritage’, p 36 December 2014

IMMUUN

Column

Double the speed Fifty years of immunology have brought us much progress. We’ve already witnessed wheelchairs disappear from rheumatology departments. We see a similar underlying immune mediated cause in diseases which seem at first sight unrelated, such as rheumatoid arthritis, psoriasis and inflammable bowel disease (IBD). This could also happen in other diseases. Many chronic diseases share the same mechanism: an immune system gone haywire. There are basically two physical processes that cause disease: uncontrolled

‘Chili pepper’ receptor discovered on T Cells Researchers at University of California, San Diego School of Medicine, have discovered that T-cells are activated by a pain receptor. The study, reported online Oct. 5 in Nature Immunology, shows that the receptor supports regulating intestinal inflammation in mice and that its activity can be manipulated, offering a potential new target for treating certain autoimmune disorders, such as Crohn’s disease and possibly multiple sclerosis. “We have a new way to regulate T-cell activation and potentially better control immune-mediated diseases,” said senior author Eyal Raz, MD, professor of medicine. The receptor, called a TRPV1 channel, has a wellrecognized role on nerve cells that help to regulate body temperature and alert the brain to heat and pain. It is also sometimes called the ‘capsaicin receptor’ because of its role in producing the sensation of heat from chili peppers.

cell growth, called cancer, and uncontrolled immune reactions, called, called.... Unlike cancer, immune mediated diseases lack a common denominator. We don’t say: ‘he or she has a chronic immune mediated disease.’ In cancer, a lot of progress is made by focusing on the general mechanism of uncontrolled cell growth. Likewise, research in inflammatory diseases such as rheumatoid arthritis, diabetes, MS and IBD should be aimed at the underlying process of immunologic disbalance. After the energising and inspiring debate at the Amsterdam grand café De Balie on November 20th, the disease-transcendent concept proposed by NVVI comes within grasp. An integrated, patientoriented research approach could double the speed of progress to the benefit of millions of chronic disease patients’ daily lives. A lot of practical challenges still lay ahead. We must formulate themes, set up collaborations between researchers and clinicians, find an ambassador for the field and give the patient a voice in the process. The willingness among stakeholders to allocate funds for our new approach and their readiness for hands-on practical action made me confident that all practicalities can be overcome. Valuable input was given as a solid base to move ahead. The board of NVVI together with the debate’s organising committee will discuss the next step during the NVVI annual conference. To be continued! Reina Mebius, Dutch Society for Immunology

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Dogma broken The study is the first to show that these channels are also present on T-cells, where they are involved in gating the influx of calcium ions into cells – a process that is required for T-cell activation. “Our study breaks current dogma in which certain ion channels called CRAC are the only players involved in calcium entry required for T-cell function,” said lead author Samuel Bertin, a postdoctoral researcher in the Raz laboratory. “Understanding the physical structures that enable calcium influx is critical to understanding the body’s immune response.” T-cells are targeted by the HIV virus and their destruction is why people with AIDS have compromised immune function. Certain vaccines also exploit T-cells by harnessing their ability to recognize antigens and trigger the production of antibodies, conferring disease resistance. Allergies, in contrast, may occur when T-cells recognize harmless substances as pathogenic.

Manipulate T cell response TRPV1 channels appear to offer a way to manipulate T-cell response as needed for health. Specifically, in in vitro experiments researchers showed that T-cell inflammatory response could be reduced by knocking down the gene that encodes for the protein that comprises the TRPV1 channel. Overexpression of this gene was shown to lead to a surge in T-cell activation, which in human health may contribute to autoimmune diseases. T-cells also responded to pharmaceutical agents that block or activate the TRPV1 channel. In experiments with mice models, researchers were able to reduce colitis with a TRPV1-blocker, initially developed as a new painkiller. One of the promising discoveries is that colitis in mice could be treated with much lower doses than what is needed to dull pain. “This suggests we could potentially treat some autoimmune diseases with doses that would not affect people’s protective pain response,” Raz said.

NEWS editorial

NVVI is much obliged to the many volunteers who made all lustrum activities into a success. Many thanks to all!

Highlights: Frits Gmelig-Meyling, Moh Daha, Bouke Hepkema, Georg Kraal, Jon Laman, Martijn Nolte, Dirk Roos, Marca Wauben App: Joris Sprokholt, Angelic van der Aar, Ger Rijkers, Babs Verstrepen, Carla Ribiero Debate: Mieke Boots, Bert ’t Hart, Irma Joosten, Frits Koning, Anje te Velde, Michiel van der Vlist, Lisa Vogelpoel Sponsoring: Leendert Trouw, Ellen van der Voort, Bing Thio, Jos van Strijp, Wouter de Jonge, Stefan Nierkens 8-UMCs tour: Wilfred Germeraad, Jasper Koning, Sonja Buschow, Andreea Ioan, Menno van Zelm, Ester van Leeuwen, Anne-Hilde Muris, Frans Kroese, Edward Knol, Virgil Dalm Congress: Esther de Jong, Hermelijn Smits, Ghaith Bakdash, Sandra van Vliet, Leonie van Duivenvoorde, Rogier Reijmers, Diahann Jansen Lustrum Commission: Esther de Jong, Mieke Boots, Wilfred Germeraad, Leendert Trouw

Reumafonds grant

Successful opposition against patent

Merus can coninue its cancer research In September 2014 intellectual property expert EP&C and life sciences intellectual property expert JPWaVe jointly succeeded in revoking a European patent on behalf of their Dutch customer Merus. This enables the company to continue its research into novel treatments for cancer. The revoked patent called ‘Methods of Modifying Eukaryotic Cells’ involves a method to make a transgene mouse that can be used for generation of therapeutic antibodies. The American biopharmaceutical company Regeneron Pharmaceuticals received this patent in 2012. It threatened the use of Merus’ own transgene mouse MeMo®, in turn hampering the development of therapeutic antibodies and with that treatment of cancer. That is why Merus in 2013 filed a complaint against the patent at the European Patent Office (EPO). Already in the first round, during the hearing, the patent was revoked on the grounds of ‘lack of inventiveness.’ “This verdict fully confirms our conviction that we have the freedom to develop therapeutic antibodies for the treatment of cancer patients with our MeMo® mice”, says Merus CEO Ton Logtenberg.

for Utrecht Sjögren and Lupus research The Laboratory for Translational Immunology within the spearhead Infection & Immunology at UMC Utrecht has received two Reumafonds grants for Sjögren and Lupus research. Joel van Roon PhD and Marzia Rossato PhD will target Sjögren. They will try to influence dendritic cells with microRNAs in order to inhibit the auto-immune reaction. Professor Linde Meyaard and Michiel van der Vlist PhD will study the disorder of the immune system by Lupus (SLE) which affects several organs. Both projects will be carries out in cooperation with reumatologists professor Timothy Radstake and Ruth Fritsch MD.

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Trained immunity in white blood cells is induced by monocyte glycolysis Cells undergoing trained immunity switch their internal metabolism. BLUEPRINT scientists of the team of prof. dr. Netea, Professor of Experimental Medicine at Radboud University Medical Center conclude this. They uncover epigenetic and metabolic programs that distinguish tolerant and trained macrophage phenotypes, providing invaluable resources to further understand and manipulate immune-mediated responses. This study is one of three BLUEPRINT papers published in the Science issue of September 26. The European Commission BLUEPRINT project aims at deciphering the epigenomes of more than a hundred different types of blood cells. It is one of the two first European high impact research initiatives Photo Radboud UMC

During an infection, monocytes from the blood infiltrate the infected tissue where they differentiate into macrophages to eliminate the invading pathogen. Both monocytes and macrophages are populations of cells belonging to the innate arm of the immune system. A Science paper by Cheng et al. describes a novel dimension of innate immune memory, namely that cells undergoing trained immunity switch their internal metabolism: the process that insures the energy needed for a proper function. Netea and his colleagues discovered that monocyte metabolism switches from the normal way of using glucose (by oxidative phosphorylation) towards glycolysis: a rapid shortcut for increasing energy production for the cell. This switch enables monocytes and macrophages to insure the energy necessary for an increased activity in the fight against pathogens. “The immune response of the host is much stronger regulated by environmental factors than we thought”, remarked Netea.

Epigenetics of blood After the human genome was deciphered, it became apparent that knowing the DNA code and how it is organised in chromosomes is insufficient to understand how the code is used to determine the identity of cells. There are lots of different cell types in the body and each cell has the same DNA content, yet cells differ greatly in their appearance and function. They change in response to outside signals and as a consequence of aging and their altered states underlie diseases. Thus, the way the genetic information is used differs between each type of cell and this difference is in part determined by how DNA is packed in chromosomes. Epigenetics aims at unravelling this packaging through structural adaptation of chromosomes which determines how DNA elements are regulated. The newly gained layers of information, which are unique to a particular type of cells, are placed on ‘top of the genome’ to form a master plan or blueprint of the cell.

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High Impact Project “The BLUEPRINT achievements make a significant contribution to the International Human Epigenome Consortium that joins up with other worldwide efforts to unravel ‘epigenomes’ of hundreds of different types of cells in the body”, said co-author Professor Hendrik Stunnenberg at the Radboud University. Stunnenberg coordinates the BLUEPRINT endeavor. Epigenetic profiling identifies mTOR/HIF1α-dependent induction of glycolysis as the cellular metabolic basis of trained immunity; Monocyte glycolysis induces trained immunity Cheng et all. Science, September 26 2014

NEWS

Robots take over your boredom The company Transcriptic, established by Max Hodak, an ex-biotechnology student at Duke University in Durham, North-Carolina, was born out of boredom. “I was endlessly busy starting cultures in petri dishes and pipetting liquids in flasks. More than half of my time was consumed by easy handwork. I felt like a robot.” Now his Transcriptic robots extract DNA, check for antibodies and grow cultures – on an hourly basis. Stanford, Harvard, Caltech en UC send in instructions and get results back. Hodak: „We wish to free scientists from boring, repetitive work, in order to give them more time for their real work: thinking, result interpretation and writing papers.” Source: NRC 28/10, Eva de Valk, pp 18,19

Antibodies into the brain Genentech in San Francisco has succeeded in introducing a therapeutic antibody into the brain. Normally the blood-brain barrier is closed for large molecules, which prevents antibodies in the blood to enter. By connecting an antibody that inhibits the Alzheimer protein bèta-amyloid to an antibody especially designed to open a transferrin receptor in the blood-brain barrier, the researchers managed to get the therapeutic antibody into monkey brains. Source: Science Translational Medicine, 5 november, Huup Dassen, NRC 15 November pp7.

AGENDA 17-19 december 2014 50th Anniversary Congress NVVI Efteling, Kaatsheuvel Informatie: www.dutchsocietyimmunology.nl

6 januari 2015 (startdatum) Statistiek voor laboratoriummedewerkers Hogeschool van Arnhem en Nijmegen Zes wekelijkse bijeenkomsten op dinsdag 18.00-21.00 uur Locatie: Amsterdam (Sanquin) Kosten € 776,00 Informatie en aanmelding: www.hanlifesciences.nl of E: info.lifesciences@han.nl 13 januari 2015 (startdatum) Immuunhematologie Hogeschool van Arnhem en Nijmegen Zestien wekelijkse bijeenkomsten op dinsdag 18.00-21.00 uur Locatie: Amsterdam (Sanquin) Kosten € 1.452,00 Informatie en aanmelding: www.hanlifesciences.nl of E: info.lifesciences@han.nl. 13 januari 2015 (startdatum) Klinische Cytologie Hogeschool van Arnhem en Nijmegen Tien tweewekelijkse bijeenkomsten op dinsdag 9.30-16.00 uur Locatie: Nijmegen Kosten € 1.929,00 Informatie en aanmelding: www.hanlifesciences.nl of E: info.lifesciences@han.nl. 23 januari, 13 februari, 6, 20, 27 maart en 10 april 2015 Immunohistocytochemie Cursusprijs € 2.000,-. Inschrijven tot 9 januari 2015 Hogeschool Leiden, CBD, website: cbd@hsleiden.nl 27 januari 2015 (startdatum) Research Immunologie Hogeschool van Arnhem en Nijmegen Zes bijeenkomsten op dinsdag 18.00-21.00 uur Locatie: Amsterdam (Sanquin) Kosten € 694,00 Informatie en aanmelding: www.hanlifesciences.nl of E: info.lifesciences@han.nl.

Galapagos presents favourable results with Rheumatoid Arthritis drug Galapagos presented data supporting the safe use and absence of drug-drug interactions of GLPG0634 (filgotinib) with drugs commonly prescribed for rheumatoid arthritis patients at the ACR/ ARHP Annual Meeting, November 14 - 19, in Boston, Massachusetts. In addition, Galapagos showed support for the dose selection in the Phase 2B DARWIN program and presented the reversals of rheumatoid arthritis gene expression in patients treated with filgotinib.

2, 3, 4 en 5 februari 2015 Introductie tot de real-time PCR (PH-3201) NIEUW Cursusprijs € 1460,- (inschrijven vóór 15 december 2014 € 1325,Hogeschool Leiden, CBD, website: cbd@hsleiden.nl 2 en 3 maart 2015 GMP basis Cursusprijs: € 525,- (er is geen kortingsregeling van toepassing) Hogeschool Leiden, CBD, website: cbd@hsleiden.nl 5 en 6 maart 2015 Workshop Genome browsing Cursusprijs € 740,- (inschrijven vóór 20 december 2014 € 675,-) Hogeschool Leiden, CBD, website: cbd@hsleiden.nl 15-18 maart 2015 3rd International One Health Congress Prevention at the source and Science Policy Interface Informatie: www.immunovalley.nl or www.IOHC2015.com 19 maart 2015 Workshop High Resolution Melting (HRM) analyse (PH-3206) Cursusprijs: € 520,- (inschrijven vóór 5 februari 2015 € 475,Hogeschool Leiden, CBD, website: cbd@hsleiden.nl 12 maart 2015 Alternatieven voor ELISA’s: Luminex, MSD assay en AlphaLISA (PH-3257) NIEUW Cursusprijs: € 480,- (inschrijven vóór 1 januari 2015 € 435,-) Hogeschool Leiden, CBD, website: cbd@hsleiden.nl 12 maart 2015 Immunologie voor microbiologisch analisten (PH-3237) Cursusprijs: € 430,- (inschrijven vóór 1 januari 2015 € 390,-) Hogeschool Leiden, CBD, website: cbd@hsleiden.nl 27 maart, 10, 17 en 24 april 2015 De PCR van A tot Z Cursusprijs € 2.190,- (inschrijven vóór 16 januari 2015 € 1.990,-) Hogeschool Leiden, CBD, website: cbd@hsleiden.nl 23 april 2015 Celkweek Hogeschool van Arnhem en Nijmegen 1 dag van 18.00-21.00 uur Locatie: Nijmegen Kosten € 537,00 Informatie en aanmelding: www.hanlifesciences.nl of E: info.lifesciences@han.nl.

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On the verge of a cure for diabetes In 2012 it was discovered that most type 1 diabetes patients still have insulin producing beta cells. Curing type 1 diabetes is therefore no longer the product of a vivid imagination. Cell therapy is under development for certain patient categories. “Things begin to fall into places, we are knocking on heaven’s door. Developments happen so fast, it’s almost scary”, says Bart Roep of the LUMC. Diabetes treatment is still symptom treatment. Despite the effort of patients and practitioners and despite advanced sensors and insulin pumps, effective glycemic control is not attained in more than 80% percent of the cases. As a consequence, diabetes can lead to complications such as blindness, kidney conditions and cardiovascular diseases. Diabetes*, which used to be an orphan disease, has now reached a still increasing incidence of a half percent in The Netherlands. This assassin has become the major cause of death in the western world, often via cardiovascular diseases.

“Even ten years after diagnosis there is still fertile ground for reactivation of beta cells by immunotherapy” Diabetes type 1 is an autoimmune response – a fact that could only quite recently be proven. The autoimmune response causes beta cells in the islets of Langerhans in the pancreas to stop producing insulin. “But until recently, it was an equation with two unknown variables: which T-cells act against what exactly?”, says professor Bart Roep Ph. D. of the LUMC, involved in an American, Italian and Dutch research collaboration. Twenty five years ago, transplantation of islets of Langerhans started. This works for some people, but in general it is like filling a bucket full of holes, because the immune memory is not changed and inflammation can recur. Recent careful study of pancreatic lesions uncovered the subtleties of the inflammation. In locations where T-cells where found, no insulin-producing beta cells were left in the islets of Langerhans. The surprising part was the patchiness: where no T-cells were found, there can still be beta cells present. Roep: “The assumption that all beta cells in type 1 diabetes patients were destroyed proved wrong. In 2012 we discovered that most patients sometimes still had even more than half of their beta cells. The autoimmune response has only driven these into inactivation, whereas 10% of beta-cell mass

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suffices to reach insulin independence in islet transplantation. Apparently, beta cell mass and function are disconnected.”

From dogma to dead dog The implication is immense. Roep: “The dogma that immunotherapy is only useful directly after diagnosis has turned into a dead dog. Even ten years after diagnosis there is still fertile ground for reactivation of beta cells by immunotherapy.” ...Provided this reactivation is possible, of course. Roep: “We already proved that it is. After a bone marrow transplant – an extreme kind of immunotherapy – a patient from Brazil was completely cured. One could regard such a measure as overshoot, but it depends on the situation. For a five year old child with type 1 diabetes the prognosis is just as bad as with leukemia – for which we see bone marrow transplantation as the way to go, just like we sometimes do that for juvenile arthritis. We can even predict whether a relapse or side effects will follow in individual patients. And even if relapse would eventually follow, if you are able to drag children through puberty before relapse, it would make a huge difference. Even a year of proper blood sugar regulation leads to a far better prognosis. But for most patients a bone marrow or a pancreas transplant will be a bridge too far.”

Who is Bart Roep? He studied at the University of Amsterdam and at Leiden University. He got his Ph. D. in Medicine cum laude for his research on the pathogenesis of type 1 diabetes in 1992. He finished his specialization in immunology at the LUMC in 1993 and now works there as professor in diabetology, immunoparthology and intervention of type 1 diabetes. Roep received several awards, such as the Minkowski Prize in 2002. In 2007 he received a VICI for innovative research into cell therapy for diabetes.

THEME: STEM cell therapy

Bart Roep: “We are knocking on heaven’s door” (Photo LUMC)

The recent discovery at least means that the dreary daily routine of measuring blood glucose and injecting insulin comes with a reward. “This helps beta cells to relax and survive”, says Roep. “These survivors open the perspective of curative immunotherapy: total insulin independence, without suppletion of beta cells, pure regenerative medicine. As long as there are beta cells and there is inflammation, there is a basis for inflammation-targeted immunotherapy. It would enable a cure for type 1 diabetes. ”

Soft touch How should immunotherapy be deployed to stop inflammation? Roep: “We don’t look for the ‘bombing into submission’ approach

of chemotherapy or a symptomatic and generic immune suppression. We need the soft touch in immune system activation.” To get there, Roep zooms out from diabetology and looks through a wide-angle of disease transcendent immunology. “It is much easier to recognize an elephant by looking from a distance than by feeling it with a blindfold. There are many examples with aspects to learn from, such as allergy desensibilization and the way in which parasite infections avoid and trick the immune system selectively. Lots of my eureka moments were spoiled by ancient allergy knowledge. Both allergy and parasite infections are all about knowing the target. With MS and rheumatoid arthritis the target is still a question mark, but with type 1 diabetes we now have the targets in view.

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That opens the way for tissue specific immune modulation.” Inspiration is also provided by virology, by the successful survival of the cytomegalo virus (CMV) and cancer, Roep explains. “The tumour micro environment which impairs the immune system to the tumour is exactly the environment you’d need in the islets of Langerhans to inhibit the autoimmune reaction. A failed attack in cancer research to affect this micro environment therefore means a promise for autoimmunity.”

Type 2 diabetes Since a couple of years, morbidly obese people, in almost all cases diabetes type 2 patients, are treated with gastric bypass. Roep: “After surgery, their beta-cells in the islets get back into action almost overnight, to the extent that they have to get a glucose drip.”

“Lots of my eureka moments were spoiled by old allergy knowledge” Brain-picking from other specializations in immunology is a second nature for Roep – always with a keen eye for the similarities as well as the differences. “Deployment will always occur mutatis mutandis. Take for instance allergy: the target is not a self protein as with diabetes. The mechanisms therefore must be different.”

Fifty shades In the hunt for a diabetes cure there is no heritage to work around. Roep: “We can start from a clean sheet because there was nothing except insulin replacement therapy. We have the lock – we know which cells get off track – and we found the key – we know against what they turn. We also learned that the problem is much more heterogeneous than was thought, which has its downside and its upside. There will not be a magic bullet to cure all cases, that is just wrong to expect. This explains why successful phase II trials were followed by failing phase III trials. In the latter, too many patients were lumped together. But we know that the type of successful phase II patients were also successful in phase III.” Differentiation and precision medicine are vital. “There are fifty shades of grey”, as Roep puts it. “This heterogeneity, which could be compared with the differences between allergens, opens opportunities for patients. Dedicated bullets can and will be found. I’m sure we can cure certain diabetes type 1 patients at some point – some, not all. We need tissue specific immune modulation for that: something that doesn’t work for one patient, could work for another. It comes down to the immunology question: against what is the derailed immune reaction targeted? We start to see the logic, things begin to fall into place, we are knocking on heaven’s door. Developments happen so fast, it’s almost scary.”

Cell therapy All these developments culminate in the outlines of a bench to bedside approach: cell therapy vaccination against derailed T-cells. In 2007 Roep received a VICI to study the feasibility of such a cell therapy. Five years later his conclusion was that it would indeed be feasible. “The way to go is intradermal micro-needle injection, which promotes homing. For the personalized vaccine itself monocytes will be grown in vitro into

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tolerogenic dendritic cells (DC) in the presence of vitamin D3 and dexamethasone. The tolerogenic DCs will be combined with a tissue specific proinsulin peptide which can be produced at the Leiden GMP facility. The result would be the induction of targettissue specific suppressive regulatory T-cells (Tregs).” The first in-man study to establish whether it all works as planned is about to start, thus skipping the animal model phase. “We cannot test or prove it in mice first, as it is impossible to prove personalized medicine in mice. For one, we use the human proinsulin peptide and HLA DR4 which mice lack. I am delighted that the CCMO ethical commission recognized this fact.”

Embryonic stem cells There are several alternatives to the vaccine approach described above. One alternative in the pipeline, is based on an observation by Van Rood: to use mesenchymal stem cells (MSCs) from blood as an alternative source of tolerogenic adjuvants. Roep: “Green light to pursue a third exciting road came very recently from the American Food and Drug Administration (FDA). In a multinational study we are allowed to grow embryonic stem cells into beta-cell progenitors using a special protocol. We culture these in vitro to the point where they can be implanted in capsules into the body; the body can take it from there to turn them into actual insulinproducing beta cells.”

“I’m sure we can cure certain diabetes type 1 patients” Careful systematic monitoring is vital in this study – one of the first ever trials with embryonic stem cells in man. Roep: “Embryonic stem cells can in theory develop into unwanted cells. This risk is contained by growing them in a capsule. The patients are Americans; at the Leiden LUMC we will analyze their blood to establish the safety and the immune reactions taking place. We’ve discovered bio-markers of disease progression and therapeutic intervention. The same immune correlates can now tell us whether the therapy works.” Leendert van der Ent *type 1 and 2 together, the bulk coming from type 2. Type 1 alone was an orphan disease incidence wise (number of new cases per 100,000), not prevalence wise (total number of patients per 100,000).

THEME: STEM cell therapy

Induced Pluripotent Stem cells for MS:

Potential tool for a new therapeutic approach Patient-derived skin cells can be reprogrammed into Sjef Copray: “We

Induced Pluripotent Stem cells (IPCs). These can in turn

see the solution

be differentiated into oligodendrocytes. When these

for myelin repair

autologous oligodendrocytes are introduced to the brain,

oligodendro-

in IPS-derived cyte implantation”

they might be able to restore myelin formation and thus

(Bureau Lorient Communicatie)

reduce the neurological deficits characteristic for Multiple Sclerosis. With animal studies almost concluded, there are strong indications that it will work like this. Sjef Copray, Neurosciences researcher at the University Medical Center Groningen, hopes that it might lead to a clinical trial to establish this. Medical textbooks describe Multiple Sclerosis (MS) as an autoimmune disease. Fast conduction of electric signals along the networks of nerve fibers (axons) in the brain is enabled by myelin, the substance that isolates axons in the way copper electric wiring is isolated. Oligodendrocytes produce this vital myelin. Although the primary cause of MS is still unknown, the theory is that wrongly instructed T-cells turn against myelin and oligodendrocytes and start breaking them down. One of the theories as to the ‘why?’ is that these T-cells erroneously recognize myelin fragments as virus membrane components.

“IPS reprogramming efficiency has now improved to almost one percent” Where the immune cells invade the brain, a lesion will develop, characterized by massive cell accumulation and myelin degeneration. Loss of myelin in the lesion leads to signal transduction loss in the local axons and eventually to injury and loss of the axon itself. This can in turn lead to specific neurological functional deficits, such as paralysis, dependent on the location of the lesion. “Recently the primary role of the immune system has been debated and shifted towards a more secondary role, in response to some degenerative events that originate in the brain”, says

Copray from the UMCG and the MS center for the NorthNetherlands. “One of the arguments for that was provided some years ago by an Australian MS patient, who had the misfortune of dying in an early stage of the disease, because her lesions were located in the respiratory center in her brain. Her sad fate offered unique research material for post-mortem analysis. Aggressive T-cells were not found in the affected part of the brain, whereas myelin breakdown was undeniable. This strongly suggested that the T-cell response is secondary. It is now concluded that MS shows similarities with other neurodegenerative diseases, like Alzheimer’s and Parkinson’s. In research focus, MS has shifted from immunology more towards the neurobiology field.”

MS types and treatment The immune system still plays a vital role in the disease process, especially in Relapsing Remitting MS (RR-MS), the most common MS type. In this form of MS, the immune cell invasion and inflammation of the brain comes as an acute attack – relapse accompanied by neurological symptoms affecting sight, posture,

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The (distant) future Development has been fast since 2006. More far reaching possibilities are under consideration. Taking cells from a patient and turning them into any desired other cell type may have a big drawback: they will always still contain the patient’s DNA – including the mutation related to the disease. Spectacular developments in ‘genome editing’ will allow repair of mutations before implanting the cells into the patient in the near future. The application of IPS cells combined with gene mutation repair has already been proven to cure mice with sickle-cell anemia. Another promise for the future is a shortcut. Why convert cells first into IPS and then into the desired cell type? Direct conversion of fibroblasts into for instance neural cells, induced by special transcription factors, is now possible. Admittedly, it is a one-to-one conversion with an as yet very low efficiency, but it seems way faster, less complicated and riskyful and holds new promises for direct local cell replacement strategies.

muscle force and other body functions. During recovery after a relapse - the remitting period - the plasticity of the brain restores most of the injury. Oligodendrocyte precursor cells can be recruited for new myelin formation. In the benign form of RR-MS, recovery after relapse is almost always complete. In most RR-MS patients, however, recovery after relapse is only partially due to inadequate brain plasticity and/or insufficient oligodendrocyte precursor cells. A large percentage of these MS patients gradually develop secondary chronic progressive MS (SP-MS), in which gradual neurological deterioration evolves linear without overt relapses. Ten to twenty percent of MS patients have the most severe primary progressive type of MS (PP-MS), characterized by gradual neurological deterioration from diagnosis onward, without clear relapses. Present RR-MS therapy suppresses the number and gravity of relapses, thus delaying deterioration. Older drugs like interferon prove their value alongside novel drugs such as natalizumab*, which consists of humanized antibodies targeted at T-cell membrane components. It thereby prevents or inhibits T-cells to cross the blood-brain-barrier into the brain.

Schwann cells Although present RR-MS treatment can often enable decades of a reasonably normal life with MS, there is no therapy to prevent myelin loss or to restore it in the progressive chronic MS types. Axon and eventually neuron loss will become inevitable. Copray: “We see the solution for myelin recovery and the rescue of axons and neurons in the implantation of exogenous myelinproducing cells.” But where do you get new, preferably autologous, myelinforming cells from? How can you introduce these into the brain? Copray: “Schwann cells, the myelin-forming cells of the peripheral nervous system, have been considered as candidates

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since they can be collected in small quantities from the patient’s own sensory nerve. In monkeys this approach appeared to work rather well, but in pilot studies in three MS patients intracerebrally implanted Schwann cells proved ineffective. Copray: “The Schwann cell is a different kind of myelin-forming cell than the one you need in the brain. It forms a different type of myelin and can only myelinate one axon, whereas one oligodendrocyte might myelinate hundreds.”

Stem cells Copray is sure that stem cells could provide the solution. Stem cell research started in hematology. After the nuclear explosions of Hiroshima and Nagasaki with its many leukemia victims, a vivid interest in hematopoietic (blood-forming) stem cells came up. “So much basic knowledge of stem cells and cell differentiation was gathered, that other fields could build on that during the last two or three decades. Lately, neural stem cell research is catching up in knowledge on the regulation of neural stem cell maintenance and differentiation”, says Copray. Neural stem cells can be differentiated into myelin-forming oligodendrocytes in a culture dish via a complex process. If neural stem cells could provide a source for myelin-forming cells, where should they come from? “Autologous neural stem cells can be endoscopically collected from two small loci in the adult brain. But their number is way too limited to become useful for clinical application. That option is out”, Copray concludes. This is where Shinya Yamanaka comes in with his 2012 Nobel Prize winning research, partially based on the 1962 discovery of his cowinner John Gurdon. Gurdon established that each ordinary body cell contains exactly the same genetic information encoded in DNA as embryonic stem cells. In principle, each body cell therefore contains the appropriate genetic information to build a complete embryo. In 2006, Yamanaka showed that any normal body cell can indeed be genetically reprogrammed into a pluripotent embryonic stem cell by forcing the expression of the four ‘Yamanaka factors’. These four factors are genes that play a central role in maintaining pluripotency in a cell. Yamanaka called the reprogrammed cells induced pluripotent stem cells (IPS). They can multiply indefinitely and can be differentiated into any cell type. The implications for regenerative medicine are huge. It means that everybody has an unlimited source for any type of cell for cell transplantation or cell replacement therapy”, says Copray. The reprogramming process, however, is in practice complex and demands meticulous control over cell growth and differentiation. “Moreover, before actual clinical application of IPS-derived cells, stringent purification steps are crucial to prevent contamination of the IPS-derived cell graft with undifferentiated IPS cells, since these are pluripotent and can form teratomas, a tumor type with a broad variety of proliferating cell types.”

Towards a human trial The Groningen researchers were among the first in the Netherlands that mastered the technology to produce IPS cells. They are well aware of the drawbacks and safety concerns

THEME: STEM cell therapy

regarding IPS cell clinical application. Copray: “But luckily, progress has been swift. Yamanaka used virally transfected cells - unacceptable in clinical application. New safe, nonviral ways have been developed to force expression of the four factors. In his Nobel Prize research, Yamanaka only managed to reprogram one in ten thousand cells. Reprogramming efficiency has now improved to almost one percent. Good specific membrane markers are available and fluorescence activated cell sorting with proper antibodies directed against them has become a standard purification method. Finally, IPS cells can now be generated under strict GMP conditions. Application of the IPS technology is growing and we’ve helped a number of research groups to start mastering this technology.” The Groningen group has proven the efficacy of IPS-derived oligodendrocyte precursor cells and oligodendrocytes in mouse models that mimicked MS. “We have differentiated human IPS cells into oligodendrocytes and have shown that they produce myelin in vivo.” Next step was to choose an animal model resembling human MS. A trial with marmosets at the Biomedical Primate Research Centre in Rijswijk has been concluded and the results are currently analyzed. “Their immune system comes close to that of man”, says Copray. “We induced Experimental Autoimmune Encephalomyelitis (EAE) in them, which appears to come with the same symptoms and course of disease as MS. We presently investigate the survival of the grafted cells, their migration and their myelin production at the sites of lesion. We hope that the final results are encouraging enough to prepare a first clinical trial.”

A wider scope Apart from its huge potential for cell transplantation therapy in regenerative medicine, IPS cells present an unprecedented tool for detailed studies of cellpathogenic processes. Copray: “IPS cells from a patient with a specific mutated gene that leads to the degeneration of a particular neuron type, can be differentiated into this affected neuron type. This enables researchers to study why the mutation leads to the degeneration of that neuron. Examples for this type of IPS application are for instance familiar Parkinson’s disease, Huntington’s disease and familiar ALS.” Not only neurological, but also genetic disorders affecting for instance liver or heart functioning and even some types of cancer already benefit from the IPS technology. Not only does this so called ‘disease in a dish’ application of IPS cells provide unique detailed insight in the cellpathogenic processes, it also allows development and testing of new powerful drugs. “Presently we are also applying this approach of IPS cells for PP-MS patients and are trying to elucidate whether there may be some intrinsic differences between oligodendrocyte precursor cells of a healthy person and those of a PP-MS patient, for instance in the way they react to small local stress events in the brain.” Leendert van der Ent *Monoclonal antibody directed against the α-4 integrin. This drug in rare cases is reported to coincide with often fatal Progressive Multifocal Leucoencephalopathy.

Sjef Copray: “We have differentiated human IPS cells into oligodendrocytes and have shown that they can produce myelin in vivo” (Bureau Lorient Communicatie)

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Prof. Bob Löwenberg, MD, PhD

“Let’s make hematopoietic stem Bob Löwenberg is Professor of Hematology at Erasmus University in Rotterdam. His research activities are in the treatment and the pathobiology of leukemia. “I take my inspiration from biology and molecular research, but my motivation from the patients”, he says. The treatment of leukemia has progressed significantly in the past decades, he adds. “But wouldn’t it be great if we could make hematopoietic stem cell transplantation redundant?” An overview of developments.

Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. Its incidence increases with age. Each year, in Holland around 700 new patients are diagnosed with AML. Several risk factors and a dazzling variety of genomic abnormalities have been identified, but the specific cause is not clear. AML progresses rapidly and is typically fatal within weeks or months if left untreated.

better understanding about how to use classical chemotherapy optimally as well as by enhancing the utility of stem cell transplantation. But we also have still a long way to go”

Match He worked with Dick van Bekkum at TNO in Rijswijk, at that time the world leading center of Dutch research on experimental stem cell transplantation. “Van Bekkum was a pioneer in the early development of hematopoietic stem cell transplants in experimental animals”, he says. “I can still recall the thrill of the first achievements in stem cell transplantation in pediatric infants in Leiden.” In patients with AML, the first step in treatment is chemotherapy. Unfortunately, even when remission through the microscope ‘at the outside’ seems complete, there are often hidden cancer cells left. Therefore, doctors opt for additional chemotherapy or a stem cell transplant. This choice requires insight into the many factors involved: the type of leukemia, the age of the patient and various other clinical features, for instance. “We have to carefully balance the risks, make sure the potential benefits outweigh the possible risks in terms of excess morbidity and mortality that are added by the transplantation”,

HOVON Professor Löwenberg, Professor of Hematology, is one of the driving forces in Dutch leukemia research and treatment. At the Erasmus University Medical Center his colleagues and he see up to a hundred newly diagnosed AML patients per year. They inspire him to do the best he can, he says. “In 1984 we treated a 40 year old mother of three children with our first autologous stem cell transplantation, which at the time had no precedent. I was so nervous, I just couldn’t sleep.” The woman was cured, the leukemia never recurred. “Wouldn’t it be great if we could say that of all our patients?”, says Löwenberg. This requires continuous research and, at the age of 68, Löwenberg doesn’t waste time thinking about retirement. He is for instance the principal investigator for AML patients in the large HOVON trial, a Dutch-Belgian cooperative consortium with the major Swiss, Norwegian, Swedish and Finnish institutions that aims at advancing the treatment outcome for patients with leukemia. “We have come far in four decades of research and treatment”, he says. “We have learned a lot about the different types of leukemia, requiring different treatments. And we have been able to improve treatment outcome by developing new drugs, by a

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Bob Löwenberg: • •

• • • • •

• •

Started his education in UMC Groningen; Did his PhD at TNO in Rijswijk in experimental bone marrow transplantation, then pursued his career at UCLA (Los Angeles), Daniel den Hoed and ErasmusMC; Has held various leading positions in international scientific organisations; Research interest in the treatment and the pathobiology of leukemia; Has extensively published in leading scientific journals (>700 publications, 17,000 citations); Is the first non-American Editor in Chief of the weekly ‘Blood’; Is founding president of the Dutch-Belgian HOVON Cooperative Group for Hemato-Oncology and current chair of the HOVON leukemia trial group; Is an elected member of the Royal Academy of Sciences and Arts; Has received various prizes and awards.

THEME: STEM cell THERAPY

cell transplantation redundant” says Löwenberg. “In some cases the advantages of stem cell transplantation will outweigh the risks, in other cases it may not.” Löwenberg’s own research has been involved with understanding the fascinating diverse biology of AML in man and it has focused on matching the patients’ type of leukemia and the best possible treatment. Stem cell transplantation today has become safer than before, says Löwenberg. “A well-known complication of stem cell transplantation is the Graft-Versus-Host reaction, where immune cells of the donor attack the patient, which may result in the patient’s death. Thanks to improved pre- and post-operative treatment, the introduction of new methods of immunosuppression, we have become better at controlling Graft-Versus-Host reaction. This has enabled us today to treat patients of up to 70 years of age, whereas previously we would only consider donor stem cell transplantation for patients less than 40 years of age. In terms of clinical practice this marks a genuine breakthrough.” At Erasmus MC, Professor Jan Cornelissen, MD, PhD, supervises a large international programme that aims at further improving immune recovery and battling Graft-Versus-Host complications after transplantation.

Umbilical cord blood Thanks to the introduction of volunteer blood banks and the fact that molecular techniques allow for a much more accurate donor typing, the possibilities for a good match between a donor and a patient have grown enormously. “First we still look at a patient’s nearest family for a perfect match, but we can also use stem cells from unrelated donors”, says Löwenberg. Also, it has become much easier to harvest stem cells: instead of having to harvest them from the bone marrow under general anesthesia, today growth factors help to drive stem cells into the blood, which makes harvesting a lot easier. Still, there is always a chance that there is no good donor match. In those cases, doctors can now resort to umbilical cord blood. Dutch hospitals are leading in this treatment option, says Löwenberg: “Cord blood is rich in stem cells and if a good match cannot be found, a cord blood transplant may offer an attractive therapeutic option. It’s a type of transplant that does not require a separate donation procedure and is associated with a reduced risk of Graft-Versus-Host disease. Cord blood doesn’t have to be as closely matched as bone marrow or peripheral blood.” Since cord blood cells are readily available in internationally coordinated cord blood banks where they are stored, it is the

Bob Löwenberg: “A cord blood transplant may offer an attractive therapeutic option” (Photo Löwenberg, Erasmus UMC)

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fasted option for patients who urgently need a transplantation and do not have a family donor at hand.” There also is a disadvantage, says Löwenberg: “The total amount of stem cells in the limited portions of cord blood is comparatively small and we may have to combine two portions from two donors. Researchers are now trying to expand these blood cells in culture, but as yet results leave to be desired.”

Haploidentical donors and autologous transplants A fourth and final option is to use blood from a haploidentical donor. These donors have half of the white blood cell antigens matched with those of the patient. “In Holland, the application of this treatment is not yet common, since the risks are relatively high but here also steps forward are being made. “

Discussion When Löwenberg applied for a position at TNO in Rijswijk, he was interviewed by Dick van Bekkum, for whom he had and still has high regard. “We got into a vehement discussion, so when I closed the door behind me I thought that this would be for good. I was wrong: by the time I got home, Van Bekkum had decided to hire me for the job.”

Besides these donor transplants, today there is also the option of an autologous stem cell transplant: stem cells of the patient are collected in order to be re-administered after intensive chemotherapy. Löwenberg: “The advantage is that the GraftVersus-Host reaction does not present itself as a medical complication. An autologous stem cell transplant helps to prevent the recurrence of leukemia – but it is less powerful than an allogeneic stem cell transplant. Again it depends on the type of leukemia for whom and when this is considered the preferred option. In case of an aggressive type of leukemia, we generally prefer the allogeneic transplant.”

A thing of the past?

Löwenberg: “An autologous stem cell transplant helps to prevent the recurrence of leukemia – but it is less powerful than an allogeneic stem cell transplant” (Photo Erasmus UMC)

Participate in research Löwenberg has always had the desire to work with patients. Het also thinks it’s important to convince patients to participate in research. “It’s not so difficult. If you explain to them that their participation may lead to better treatments in the future, whilst they themselves take advantage of the results of prior clinical research and thus can get the best treatment available, they rarely object to participate.”

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Researchers are working hard to make transplantation safer and more effective, and are making steady progress at that. Still, Löwenberg hopes that one day stem cell transplantation will have become a thing of the past. “You would prefer medicines over transplantation to battle leukemia. And there are various developments in this area, for instance an improved understanding of the critical genetic pathways in leukemia and the identification of novel targets for drug development. Also recent research into the genetics of AML has for instance resulted in the availability of tests that can predict which drug or drugs may work best for a particular patient, as well as how long that patient is likely to survive. The fact that new treatment drugs are being developed that target the leukemia via entirely novel mechanisms, is an exciting development with significant promise. This has already become reality in the case of acute promyelocytic leukemia, an aggressive type of leukemia that usually presents itself in young people. If we treat a patient with a combination of arsenic trioxide and retinoic acid (a vitamin A analogue) the leukemia is eliminated in over 90% of the cases. Here we do not need classical chemotherapy any more. It is remarkable to witness these breakthroughs of chemotherapyfree treatment of an aggressive form of disseminated cancer.” Another example is chronic myeloid leukemia, that today can be treated with a specific drug, a kinase inhibitor, that targets the basic molecular perturbation in this disease which has made transplantation largely redundant. Various forms of antibodymediated and cellular immunotherapy offer other particularly promising perspectives, Löwenberg says. “Developments like these furnish hope for a better perspective for an increasing proportion of leukemia patients in the near future.” Alinda Wolthuis

Frans Blijleven: “There were hardly commercial tests available, so we developed them by ourselves” (photo Bureau Lorient Communicatie)

The immunology lab of the Reinier de Graaf Group, a top clinical hospital in Delft, was among the pioneers in the field of immunology diagnostics. Today, it is one of the largest immunology labs in the Netherlands. Customers are not only the hospital itself and regional general practitioners; other (hostipal) laboratories also call upon the Delft immunology lab. They do that among other things because it has interesting in-house developed ELISA tests, for instance for Campylobacter antibodies (Guillain-Barré), Legionella antibodies and rheuma testing.

Immunology lab Reinier de Graaf Group:

A pioneer still going strong The laboratories at Reinier de Graaf Group handle some 100,000 orders monthly. The immunology lab is, as part of it, among the largest in the Netherland and has a relatively long history. Team leader Frans Blijleven recalls: “When immunology diagnostics came up around 1980, we were among the pioneers. A specialist from the CLB, now Sanquin, came over to Delft and we started T cell and B cell determination, alongside for instance HLA B27 determination related to Bechterew’s disease. Another thing we did and still do is nuclear antibody determination, to establish antibody activity against proteins in cell nuclei, related to systemic auto-immune diseases.”

Own ELISA tests During the eighties period there were hardly any commercial tests available. “So we developed them by ourselves”, Blijleven explains. Since then, more and more commercial tests have entered the market. “We replaced a number of our own tests by commercial tests. It even occurred that employees started their own company to commercialise in-house developed tests. In other cases there are still no – or no satisfactory – commercial tests available. In these cases we hold on to our own ELISA tests, which are still very costeffective.”

Guillain-Barré This goes for instance for a test on an auto-immune reaction after Campylobacter infection, related to the Guillain-Barré syndrom. “As far as I know we are the only lab in the Netherlands which does such testing by ELISA. There was until recently no sufficient commercial test available”, Blijleven comments. A speciality worth mentioning is the Haemophilis influenza type B (HIB) antibody test, mostly performed to define the working of the immune system in young children shortly after vaccination. Another own ELISA test regards Legionella antibody testing and

Your Power for Health

“As far as I know we are the only lab in the Netherlands for Guillain-Barré testing by ELISA” a third regards rheumafactor Immunoglobulin M (IgM) testing in Rheumatoid arthritis. Blijleven: “Remarkably, such a test isn’t easily attainable either. Often still quite outdated agglutination tests are performed. These don’t distinguish between IgG, IgM and IgA, as an ELISA test does.”

Plates from one tested batch The immunology laboratory at the Reinier de Graaf Group in Delft uses about 2,500 microtiter plates per year, all 96 wells plates. The immunology lab has a long cooperation history with Greiner. Team leader Frans Blijleven explains: “We order our ELISA plates only once every 2.5 of 3 years. We do that because we like to use the same batch, which we test and approve beforehand, for a long time. With ELISA you coat antigens to the plates. Every antigen has different binding characteristics. Because you only wish to have known variables in your process, the binding behaviour of the plates should be right as well as predictable. As plates from different batches might differ somewhat, it’s important to work with stable quality plates from the same batch.” This article was made possible by the kind support of Greiner Bio-One, www.gbo.com.

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science across borders

De Balie debate

Sharing knowledge for the patient’s sake Zooming out from particular diseases and concentration on underlying mechanisms might solve structural problems for chronic disease patients. NVVI is convinced that such an approach in immunology research can accelerate research results: better treatments, cure of diseases which gravely affect millions of people’s lives and future budget savings. This concept fuels a lively discussion with stakeholders in Amsterdam. Parties involved mainly focused on rounding up practical problems - as all embraced the concept. The approach should be patient-oriented, all agree. In her opening words of the NVVI Lustrum debate at the Amsterdam grand café De Balie on November 20th, moderator Inge Diepman hopes for a “memorable evening that may change the quality of life of chronic disease patients.” Most of these diseases share the same underlying mechanism: an immune system gone haywire. NVVI Chairwoman Reina Mebius announces to the some 125 attendants: “Now is the time to join forces in research to double the speed of progress. We’ve seen wheelchairs disappear from rheumatology waiting rooms. We see knowledge on rheumatoid arthritis be applied to psoriasis and inflammatory bowel disease (IBD) and vice-versa.” This could also happen for other diseases, when dispersed funds can be combined, she argues. “It could be the dawn of a revolution”, says rheumatologist/ paediatrician Berent Prakken in his introduction to the basics of immunology: “Immunology plays a central role in almost all diseases, but patients seldom see an immunologist.

Gijs van den Brink: “The more knowledge we share, the quicker progress in the interest of the patient will be.”

Ben Crul

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We lack a common denomination such as ‘infectiologist’ or ‘inflammologist’. Immunology achievements disappear into the compartments of medical specialisations.” Achievements are major and abundant: “Biologicals against rheumatoid arthritis for instance work like Lourdes water.” But Prakken admits that recent breakthroughs in systematic insight, in many diseases have not yet boosted the patient’s quality of life. “We need a paradigm shift towards disease transcendent research with the patient involved, a chain of patient, doctor and researcher.”

Overwhelming fatigue Colitis ulcerosa patient Esther Kievit, mid-twenty, and nine years chronic disease patient, shares how three years ago she had to give up working. Five months ago, she and her specialist Gijs van den Brink from AMC saw no other option left but a stoma. “There isn’t a lot of attention for chronic disease patients. People

“It could be the dawn of a revolution”, according to Berent Prakken

“You cannot see a chronic disease from the outside”, says Esther Kievit

don’t understand the impact on daily life, especially fatigue. You get wary of people saying, ‘come on, you’re young, take up sports’. Problem is, you cannot see a chronic disease from the outside. You cannot imagine what it is to go to the toilet twenty times a day. But the fatigue is the worst of all.” Van den Brink: “At a certain point, the effect of biological drugs can wear off. There are however tricks to postpone that moment as long as possible. You see that with IBD, psoriasis as well as rheumatoid arthritis. There are similarities and differences to learn from; the more knowledge we share, the quicker progress will be.” Centre piece of the evening is a panel discussion between stakeholders. These are immunologist Frits Koning and rheumatologist/paediatrician Berent Prakken, Hannie Bonink from ZonMw, Ben Crul from Achmea, Barend van der Meulen from Rathenau Institute, Hans Kuijpens from VGZ, Aletta Kraneveld for the Federation for Innovative Drug Research Netherlands (FIGON), Michael Rutgers for Longfonds and Hans van Laarhoven from patient association Hart&Vaatgroep. All embrace the ‘disease transcendent’ concept in their opening statements – some with reservation. Van der Meulen: “A new approach in medical research is necessary, but don’t expect extra budget. The concept convinces me, but it will be difficult to organise.” Or Kuijpens: “Immunology research is worth the investment – also for healthcare insurance companies. Twenty to twenty-five percent of some hospital’s budget is now spent on oncology and rheumatoid arthritis medication. After a huge cost bulge for ‘the costly drugs’ the next decennium, immunology research can lead to long term savings. But we never meet immunologists at the negotiation table.” Kraneveld: “It is hard to get biologicals to the part of the body where they should work – a common theme between diseases. Costly clinical trials now have to be carried out per disease and not for several diseases combined. Through collaboration we can improve and save a lot.”

Frits Koning: “Translation alone will not bring a big bang in prevention or early cure”

Break down walls Rutgers remarks that Longfonds and ZonMw already have some history in disease-transcending projects: “There is a lot to gain.” Van Laarhoven sees difficulties in joining all funds in this mission, but he fully supports the approach: “Hartstichting has made major steps by setting up a top five research agenda in collaboration with patients and researchers. In this way, the public can understand and support disease transcendent research.” Rutgers: “We could start by making an inventory of disease transcendent opportunities.” Jannie Borst, head of immunology at NKI comments from the public: “We already know that they are in fundamental research, where underlying knowledge comes together.” Many examples, however, illustrate how difficult it is to break down the traditional walls between diseases. Koning: “Yet that is what we’d like to accomplish together with all parties present.”

Flywheel Immunologist Erik Hack in the public agrees: “Oncology provides the example for an underlying mechanism approach. Just like cancer, we need a word to find connecting elements. Terminology is important.” Immunologist Mieke Boots, also in the public, agrees: “As Prakken indicates, we need ‘inflammologists’.” Rutgers: “It is a matter of marketing. We could make a plan to tackle that issue.” Crul: “Or look at oncology, where for each patient’s night in hospital a small sum is reserved for KWF Kankerbestrijding. This could be done for chronic diseases as well. Health insurance companies are keen to find solutions that combine patient benefit with cost savings.” Kuijpens adds: “As for instance optimised drug dosage research. What I hear confirms my image of immunology: we have top

Hans Kuijpens: “Immunology research can lead to long term savings”

“We are all forced to label ourselves”, says Michael Rutgers

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Aletta Kraneveld: “Progress can be much accelerated if we start connecting diseases to underlying mechanisms, instead of inventing the wheel in each disease”

“Future research could be funded by research-earned savings, thus creating a flywheel effect”, says Hannie Bonink

Inge Diepman and Reina Mebius

basic research, but we need to focus more on diminishing fragmentation in patient care and on clever immunologicepidemiology.” Koning returns that it would be a mistake to solely focus on translation. “Only fundamental research can bring the big bang in prevention or early cure.” Kraneveld agrees: “Progress can be accelerated if we start connecting diseases to underlying mechanisms, instead of inventing the wheel in each disease. It should be possible to attract private funding, as the immune system is difficult to unravel, but contains vital knowledge important to many parties.” Bonink adds that funding shouldn’t be the spoiler, as the return of investment in good research is three euros annually to each initially invested euro: “That’s profit for society. Future research could be funded by research-earned savings, thus creating a flywheel effect.”

Barend van der Meulen

ZonMw can bring the flywheel into motion.

Practical action Mebius draws some end of the debate conclusions. “I’ve enjoyed an energising and inspiring evening. I’m happy the concept is received well, this provides us with a solid base to move ahead. Solutions for the patient’s problems must come from an integrated research approach, bridging disciplines and diseases. But how do you get this message across to patients and public?” Will November 20th later be recognised as a memorable date for the quality of life of millions of Dutch chronic disease patients? It could well be. As Mebius says, much depends on the aftermath. The goodwill amongst stakeholders to allocate funds for a disease transcendent approach, and even more importantly, to turn good intentions into practical action, is a positive thing indeed.

Proposal and reactions Then it is time for Frits Koning to present his plan for research on chronic diseases. It should begin and end with patients, focus on more years of good health. It should be multidisciplinary and disease transcendent. The fund would need a time horizon of five to ten years, under the wings of ZonMW. As to funding, a million could come from ZonMW, a million from health insurers and half a million from health funds to involve societal stakeholders. Kraneveld thinks this is a great plan, but regrets that the private sector is left out, because there is willingness to invest. Rutgers: “This field needs an ambassador. Immunologists are smart but modest. You need a ‘champion’ who’s able to present the story to the general public.” He thinks the proposed budget is small compared to the magnitude of the challenge. Van Laarhoven agrees. He likes the proposed ‘shared savings’ mechanism and sees a task for government to organise that

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Text: Leendert van der Ent Photos: Jesse Klaver and Bureau Lorient Communicatie

The debate was organised by Mieke Boots, Bert ‘t Hart, Irma Joosten, Frits Koning, Anje te Velde, Michiel van der Vlist en Lisa Vogelpoel.

Translational neuroscientist and KNAW Young Academy chairman professor Jeroen Geurts works on guidelines for interdisciplinary research. In a video address he contributes: “Building bridges is vital. In our work on MS, the interesting similarities and crucial differences with Alzheimer’s and Parkinson’s teaches us the most.”

OPINION

Computer modeling replaces animal models Animal testing is an ethical issue. It is often also difficult to translate results to humans. Computer models comprising all processes of the human body are a possible alternative for the future. The first steps in this area of systems biology have been made. More and more countries comply with the so called 3R principle. They strive for replacement, reduction and refinement of animal testing. The Netherlands contribute to this. A lot of effort is put into developing alternatives, such as the use of human cell lines and of stem cells. Hans Westerhoff, professor in Microbial Physiology at the Vrije Universiteit and professor in System Biology at the University of Amsterdam and at the University of Manchester, regards these alternative as useful, yet restricted. “A human being is more complex than a single cell line. Stem cells bring you a lot further. These enable to grow parts of tissue as a basis for all kinds of experiments. But they still don’t offer the complexity of complete tissues of organs.”

In silico Westerhoff himself is active in system biology, the study of biological systems as a whole of, among other things, gene and protein networks and metabolic systems. New research areas such as genomics, proteomics and metabolomics chart these processes in animal and human bodies. System biologists integrate this knowledge. “We translate all relevant processes into a mathematical model. Eventually, you simulate the integral behaviour of these processes in silico”, says Westerhoff.

Drug distribution “A complete, working model is still a future ideal”, he admits. “But we succeed in constructing metabolic road maps that provide insight into the metabolic system – and into deviations in it – on the cellular level. We can find the pathways and calculate how individuals differ in this regard. At the total body level we sometimes succeed in showing how a drug is distributed over the body. The industry already uses computer models to chart this so called pharmacokinetics.” What still is missing in all the models, is the role of normal cells with cancer. On a dynamic cellular level the complexity makes it a lot more difficult to simulate, Westerhoff knows. He explains that human cell interaction is about approximately seven thousand chemical reactions and three thousand substances. He acknowledges that test animals will still be necessary for quite some time. “Not only to study drugs, but also to validate computer models and stem cell tests.”

Cancer cells A field where computer- and stem cell models still have a long way ahead is oncology. Jos Jonkers, head of the Molecular Pathology

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department at the Netherlands Cancer Institute and professor in Experimental Oncogenetics at Leiden University, underlines again that cancer development is a complex process. “Still lacking in all these models is the role of normal cells in the origination and the metastasis of cancer. Take for instance the immune system. On the one hand this systems deals with aberrant cells such as cancer cells. On the other hand certain immune cells, such as macrophages and T-cells, have a stimulating side effect on tumor growth and metastasis. The creation of new blood vessels is also important for cancer development. All these processes are hard to simulate in a tissue growth model as well as a computer model.” What makes it still more complex is the wide variety of tumor subtypes. Jonkers: “What formerly was simply covered under the umbrella of cancer, is now distinguished as many different types and subtypes of tumors, all with their own characteristics, demanding made to measure treatment. Try to put this in a generic model. If you ask me, that cannot be done.”

Genetic modification Jonkers therefore thinks that cancer research will still depend on animal research for a long time. Animal testing will become more and more refined, which automatically leads to diminished use of test animals. ‘Take for instance breast cancer, with all kinds of subtypes with different mutation combinations. These combinations in humans are simulated in mice. This was

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December 2014

formerly done through breeding of mice with single mutations, which demanded a lot of mice. Now we are able to get the right mutation combinations directly in embryonic stem cells, which we subsequently turn into mice from which we can get the information we want at once.”

Mathematical rat model Jonkers as well as Westerhoff plead for further development of the in vitro and in silico models. They are glad that ZonMw stimulates this with the ‘More Knowledge with Less Animals’ programme. Westerhoff has a proposal: “Let’s make a mathematical rat model. Subsequently we could test whether this model is better than the experimental model of the live mouse as predictor of the effect of substances in the rat. The rat thus plays for once the role of man. Once this works, you can try to design mathematical models to predict the effect of substances in man. When these mathematical models also work satisfactorily, they could in the long run lead to replacement or reduction of animal testing. It would take a considerable investment, but this could make the Netherlands stand out in the world.” John Ekkelboom This article was earlier published in Dutch on: http://mediator.zonmw.nl/mediator-7-augustus-2014/computermaakt-dierproeven-overbodig/

THEME: STEM cell THERAPY

Novel therapies:

Hope and science or hype and fiction? In 2013 internist and haematologist Jaap Jan Zwaginga was appointed professor of Clinical Transfusion Medicine. Apart from classic blood transfusion, he focuses on novel cell therapies. “That is costly high risk research. It is important to distinguish hope and science from hype and fiction.”

Jaap Jan Zwaginga (Photo Pieter van der Linden)

Do we know all there is to know about blood transfusion?

With ‘healing blood’ you mean blood transfusion?

“Far from it! Luckily transfusions are almost always successful, but sometimes things go wrong due to rare and grave side effects. Think for instance of immune reactions against new blood. Patients who start to produce antibodies can ultimately only tolerate blood from carefully matched donors. Especially in acute situations this is not yet feasible. Together with epidemiologist professor Anske van der Bom we try to unravel risk factors for this type of problems by investigating people who underwent side effects in their past. By now a file with transfusion data of tens of thousands of patients from many hospitals is built up. It enables us to compare people with immune reactions with a comparable group of blood recipients without these reactions.”

“Not just classic blood transfusion products such as red blood cells, blood platelets and plasma. We also set up the same chain of care for regenerative medicine: blood cells grown in the lab which we use to try to replace or improve damaged, aged or renegade tissues. It can involve stem cells or immune cells. In cancer or virus infections the immune system can be insufficiently active, in auto-immune reactions or organ rejection just the opposite. Classic blood transfusion is like a popular wine from a reputable vineyard, made by a master winemaker. It tastes great and the bottle seldom has cork taste. The novel blood cell products are more like exclusive young wines, produced by the bottle for one person only. We don’t know about aftertaste nor whether it ever will be paid for!”

Can more go wrong? “Yes, other side effects are overfilling and transfusion induced acute lung damage. In the LUMC we look into this in relation to patients receiving blood during heart surgery. Someone with a bad heart is overfilled much quicker and shows lung damage much faster. We also identify risk patients and risky circumstances. My valued colleague and predecessor Anneke Brand always said: ‘Transfusion is custom fit’.

What do you mean by the title ‘Links to healing blood’ “It refers to the chain of transfusion: donor selection, blood donation, establishment of need for transfusion, finding matching blood, transport and conservation matters, and so on. In any of these links things can go wrong, but the weakest link is identification during blood donation and during blood transfusion. My deepest wish is therefore an electronic identification system.”

Jan Hein van Dierendonck for Cicero nr. 4, August 26th, 2014, translated by Leendert van der Ent

Who is Jaap Jan Zwaginga? Jaap Jan Zwaginga studied Medicine in Utrecht. In 1989 he got his PhD with Jan Sixma on the causes of blooding with uremia, high concentrations of waste material in the blood caused by kidney failure. During his specialisation to become internist and haematologist he also worked at the Utrecht UMC as researcher and blood transfusion consultant. Since 2001 he divided his activities between the AMC and Sanquin. In 2005 he came to Leiden to become head of the Blood Transfusion Department, of the Center for Stem Cell Therapy and clinical manager at the Sanquin-LUMC Jon van Rood Research Center for Clinical Transfusion Medicine.

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First AtoB day:

New consortium on immune system ‘How do we effectively enhance the development of chick embryos – including their immune system?’ This was the question animal health company Zoetis submitted for the first AtoBday, organized by Immuno Valley in June 2014. Christine Jansen PhD of Utrecht University and Annemarie Rebel PhD of the Central Veterinary Institute at Lelystad, together formulated an answer. Encouraged by a fourty thousand euro grant and additional cofounding from Zoetis, it resulted in a consortium that will soon kick-off and aims to identify whether Natural Killer (NK) cells can serve as biomarkers for the development of the innate immune system in chickens. “As a leading animal health company we need to understand the fundamentals in strategic interest areas. Food security is a major topic in intensive farming, which is vital to keep on feeding the world. This explains our vivid interest in pro-active collaboration with academia in pre-competitive research.”, Theo Kanellos, director of strategic alliances at Zoetis states. “We have a long history of cooperation with the Dutch knowledge institutes involved in Immuno Valley; therefore it’s important for us to be part of it”, he explains. He is pleased with the outcome of AtoBday and the thorough and constructive two-step sparring process. “This approach is completely different from traditional procedures. We were able to explain our interest and the challenges we face. The academic partners were both responsive and creative, so I enjoyed the constructive discussion. I hope the project will expand our

scientific knowledge and that we can apply solutions to the benefit of the poultry farmer”, says Kanellos. “To improve the immune system of the chickens the innate or the adaptive immune system should be targeted. When NK cells are targeted during an intervention in the embryo stage, we could stimulate the immune development in the young chickens. But this is only the initial angle for our cooperation”, Rebel explains. “We might change the angle on the basis of growing insight during the project, if it proves that other targets can be used to strengthen the chicken immune system.”

“It is important to have shared goals and expectations” An important aspect of the project will be that the intervention to be developed should be implemented in the existing practice of in-ovo vaccination. Kanellos: “In-ovo technologies to inject millions of egg yokes with millimeter precision quickly are quite revolutionary. We exactly target the location that is important to the immune system. Improved in-ovo vaccines can revolutionize the way the industry is working; egg stage interventions might prevent vaccination in later stages. I hope the project contributes to future development of interventions to both enhance productivity and reduce the burden of disease. We still face lots of challenges and therefore need in-depth study of the chick’s immune system in the early embryonic stage.”

New markers

Is it technically feasible to boost the immune system in-ovo to strengthen the chicken during its lifecycle? (Photo Wikipedia)

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“We’ll start out by identifying and characterizing NK cells in the chick’s embryos and young chickens. We will determine whether it is possible to intervene in order to stimulate the development of the innate and adaptive immune system”, Rebel looks ahead. “We know that NK cells are important for the first immune reactions and we are going to find out if we can modulate the activation and development of NK cells in chickens. We are able to do so thanks to Christine Jansen’s research. She recently

Annemarie Rebel, photo WUR

of chick embryos developed a method to measure NK cell activity and killing in chickens.” New markers for determining different populations of NK cells could be used to investigate NK development. “It was therefore obvious to join forces when a proposal to answer the question brought in by Zoetis came our way”, Rebel states. “Before, Christine and I already collaborated in a project on chicken immune reaction in airways after influenza infection. That taught us how complementary our competences are. We will now combine Chistine’s expertise with NK cells with our immuno-chemical and gene expression related knowledge. Additionally we will look at other markers related to the overall question: ‘can the chicken’s immune system been stimulated by modulation at embryo level in the egg in the same procedure as in ovo vaccination?’ Our combined expertise makes us perfectly equipped to answer that question.”

Same focus Before AtoBday, Christine Jansen and Annemarie Rebel obviously did know Zoetis, but hadn’t worked for the company nor did they know Theo Kanellos. “We didn’t even know which company had posted the research question when we jointly worked at answering it. Once we met Theo, we formulated an more tangible research question than was posted beforehand. We discussed each other’s roles in the project and also the potential deliverables. It is important to have shared goals and expectations, to have the same focus. It is quite exploratory research, which we hope to bring to a proof of concept for technical feasibility. Economic feasibility is a subject for later

research.” Kanellos agrees: “If the project proves to be successful, we’ll continue with our present partners into a proof-of-concept study.” Leendert van der Ent

A to B day AtoB day® is based on a proven concept for matching science and business. AtoB day® can be organized around a single issue or multiple topics, featuring multidisciplinary expert teams. The unique format one question, one hour, one team of experts has proven to be successful in making useful contacts, starting new collaborations, and developing new paths to find solutions to business questions. If questions and scientific solutions match, a joint research proposal will be written. The best proposal resulting from each AtoB day®, will be rewarded with the AtoB day® Grant. Immuno Valley has initiated AtoB day® to accelerate R&D processes of companies that operate at the interface of human and animal health, leading to the development of novel technologies, new vaccines, immuno-modulatory products, and novel therapies. AtoB day® will be organized again in 2015. Immuno Valley is a business driven public-private consortium at the interface of human and animal health. Immuno Valley’s scientific and business partners collaborate in order to translate R&D expertise into products that combat infectious diseases. More information: www. immunovalley.nl

Arno Vermeulen and Christine Jansen, photo Immuno Valley

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Potential of cord blood underestimated:

The Ying Yang of Cord Blood Stem “Nowadays what happens immunologically during pregnancy and its consequences after birth is ignored in the clinic”, says Professor Jon van Rood, senior consultant at Europdonor in Leiden. Indications of its relevance increase. Recent studies for instance show a significant difference in survival between acute leukemia patients having two HLA mismatches with the blood cord donor. Van Rood: “Patients with one of these mismatches, compensated by a Non Inherited Maternal Antigen (NIMA) match, a ‘virtual’ match so to speak, have a higher chance of survival. Apart from genetic factors, the immune memories of both mother and child are a highly relevant feature.” Already at the discovery of the Human Leukocyte Antigen (HLA) groups or ‘white blood groups’ in 1967, it was clear that these were vital for successful transplantation. The better the similarity in HLA profile between donor and recipient, the larger the chance of success. Unfortunately, HLA matching proves very complicated. In a study with two million stem cell donors, no less than 500,000 different HLA groups or phenotypes were found, 13% of which were unique, as they occurred in one donor only. “Especially in hematological stem cell transplantation, as for instance carried out in patients with acute leukemia, the HLAmatch is pivotal for survival”, says Van Rood. If patients have no HLA identical sibling donor they have to rely on searching one in Bone Marrow Donors Worldwide, a compilation of all volunteer donors globally available. The importance of a worldwide approach is adequately shown by the fact that of the five hundred bone marrow transplants in the Netherlands, only 5% receive a transplant from a Dutch donor. Van Rood: “This lack of Dutch donors is a shame. Rich countries are expected to recruit sufficient stem cell donors and cord blood units to provide a suitable donor for at least 50% of their patients. For that reason I appeal to the readers to visit the Europdonor website and sign up as a stem cell donor.”

Life-long memory

“This insight adds a new paradigm to medicine”, says Van Rood. (Photo Bureau Lorient Communicatie)

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Procreation is a highly interesting process in general and certainly with regard to HLA. A fetus receives hereditary information from both the mother and the father, the Inherited Maternal Antigens (IMA) and the Inherited Paternal Antigens (IPA). Half of the hereditary information is not inherited from the parents and is therefore called Non Inherited Maternal Antigens (NIMA) and Non Inherited Paternal Antigens (NIPA) respectively. The umbilical cord enables two way traffic, an immunologic dialogue between mother and child during pregnancy. Fetal cells

Jon van Rood: “An HLA mismatch compensated by a NIMA match is an acceptable mismatch” (Photo Bureau Lorient Communicatie)

Cell Transplantation migrate via the cord to the mother. Van Rood: “This implicates that the mother will encounter IPA, which she will recognize as ‘not self ’. She will therefore normally develop immunity against it, with a potential fatal effect on the fetus. This is in fact what actually happens in about 80% of conceptions, which do not continue into pregnancy. In 20% of cases, however, the contradiction of pregnancy resolves itself: regulatory T-cells (T reg) create an immunologic balance, controlling these anti IPA cells in such a way that they accept these ‘not self ’ cells with IPA as ‘self ’. This enables the fetus to develop into a baby, despite the ‘time bomb’ of anti-IPA immune cells formed by the mother. The mother’s cells also reach the fetus and can still be detected decades after birth.” It was only recently discovered that the fetus already in the third or fourth month after conception recognizes the NIMA, which migrate on maternal cells into the fetus, who likewise develops regulatory T cells. Van Rood: “This regulation prevents that the fetus attempts to reject the mother. Both mother and child recognize the ‘non-self ’ of each other and are able to regulate this recognition in such a way that rejection does not occur.” The consequences are, that there remains a life-long chimerism

Who is Jon van Rood? Immuno-haematologist professor Johannes J. van Rood (1926) studied medicine in Leiden from 1944 onward. He got his PhD in 1962. From the beginning he is intrigued by the immune reactions and mechanisms at work in transplantation and procreation, with a central role for the HLA system. This system is also vital in prevention and suppression of diseases like cancer. Van Rood discovered how the complexity of this system with more than a hundred million combinations could be unraveled. He established Eurotransplant for donor organs in 1967 and a stem cell donor bank in 1988, presently called Europdonor after a non-incorporated initiative in 1970. Van Rood was three times recommended for the Nobel Prize and received the Wolf Price (Israel), The Heineken Price (The Netherlands), the Baillot-Latour Price (Belgium) and many other awards. The European Blood and Bone Marrow Transplant Group founded the Jon J. van Rood Award for the best paper in the Immunology of Allogeneic Hematopoietic Transplantation. The Leiden LUMC named its Center for Clinical Transfusion Research after Jon J. van Rood.

of maternal and fetal cells in both mother and child with a lifelong memory of their mutual immunological recognition and its regulation. “The memory of this mutually maintained balanced recognition for instance explains why a stem cell transplantation from mother to child is much more effective against leukemia than a stem cell transplantation from father to child”, says Van Rood.

Yin and Yang “One could compare this mechanism with the complementary situation of yin and yang”, he continues explaining: “You have the unchangeable genetic data, the yin. Closely attached to that is the flexible yang, the immune construction which both mother and child, or patient and donor, have built up in their past. This immune memory has until now only been charted in part. This yang part still needs to be further investigated. Especially the context of the memory of the pregnancy of the cord blood donor and probably also the recipient seem to be relevant.”

“Mother’s anti-IPA immune cells reach the fetus and can still be detected decades after birth” In transplantation immunology, there have recently been some noteworthy studies regarding the relevance of immune memory at the New York Blood Center and the LUMC. Van Rood: “845 cases of acute leukemia treated with cord blood transplantation were included in a study. The maternal typing of the transplant was known and hence the IMA was known and the IPA could be deduced. There were 45 grafts in which none of the Cord Blood’s IPA were shared by the recipient. The outcome of these grafts was compared with the outcome of grafts with shared IPA.” Van Rood: “More than twice as many leukemic patients relapsed when there was no shared IPA antigen in the patient receiving the Cord Blood stem cell transplant. This offers significant (indirect) evidence that micro-chimeric elements in the cord blood unit, most likely maternal T-cells with anti IPA immunity, reduce relapse in acute leukemia patients.” This anti IPA immunity might play a more general role in controlling malignancy, Van Rood speculates: “Potentially malignant DNA mutations already occur in newborns. It is therefore not odd that people get cancer. It is far more surprising that almost all of us survive the age of ten without getting cancer. This anti IPA immunity from pregnancy probably pops up

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Further research needed: T-cell immunity in mother’s blood Already during the sixties it was noticed that one third of mother blood samples contained antibodies for B-cell immunity against their husband. Probably an even larger percentage of mothers had developed T-cell immunity against the IPA, but this has not yet been inventarised properly. Probably the number of pregnancies and the time-lapse after pregnancy are relevant factors. It is quite probable that this T-cell immunity is as least as relevant as the B-cell immunity. again when a cell becomes malignant. This could help explain why cancer is luckily so rare in younger people.”

Acceptable mismatch The role of anti NIMA immunity was also investigated, this time among 1,121 acute leukemia patients. 62 had zero HLA mismatches, 25 had one HLA mismatch and 54 had two HLA mismatches, but all had one NIMA match. Such a NIMA match means that for instance the phenotype A2 is not present in the cord blood unit, while it is in the patient. However because the fetus was confronted with an A2 during pregnancy, as the NIMA was an A2, the fetus learned to accept A2 as self. “It is ‘virtually present’: it isn’t there, but the fetus reacts is as if it were”, Van Rood indicates.

as they are also relevant beyond the transplantation field, for instance in auto-immune diseases like rheumatoid arthritis or other types of cancer besides leukemia. The field of application of this insight could be fairly wide. When there is a challenge, the immune system comes to the aid – including the immune memory, we can now conclude. It is a sort of life insurance every child gets from his mother.” The full meaning of the ‘why’ and the ‘how’ of this memory function has to be further investigated. Van Rood: “Also under investigation is whether this IPA an NIMA not only works with cord bloods but also with adult bone marrow donors, as can be expected since we know that this immune memory of mother and her child has a life-long validity. Furthermore, we try to isolate regulator T cells and anti IPA cell from cord bloods in vitro.” Besides everything that is possible and ongoing, it is beyond doubt that in transplantation it is important to know the parent’s typing and to add this to the child’s typing data. Van Rood: “Unfortunately, as more often with a new paradigm, there is resistance and reluctance to change and the red tape that comes with it. It seems that something unchangeable such as genetics is easier to accept than something variable such as the immune system. At Europdonor we have developed a program for NIMA matching. If we would be facilitated to define the NIMA typing of all 1,500 cord bloods within our Dutch stem cell bank, we would be able to help as many patients as well as the largest stem cell bank in the world. It would mean an enormous enlargement of our donor potential.” Leendert van der Ent

www.europdonor.nl

“It seems that something unchangeable such as genetics is easier to accept than something variable as the immune system” The 79 NIMA match grafts were compared with grafts lacking this match. The study showed that patients receiving a cord blood stem cell transplant with one HLA mismatch plus one NIMA match had a five year survival of 72%, which is comparable to patients with zero mismatches. Survival of patients with one or two HLA mismatches plus one NIMA match was 55%. Survival of patients with two HLA mismatches without NIMA match was only 40%. This is very welcome information given the difficulty to find cord blood units with zero mismatches. An HLA mismatch compensated by a NIMA match is an acceptable mismatch. The introduction of ‘virtual’ phenotypes enable many more optimal matches.”

New paradigm Before these studies took place, fetal-maternal chimerism and its immune memory was only occasionally taken into account. Van Rood: “The findings have equal significance in organ transplantation. They add a new paradigm to medicine,

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HLA and sexuality HLA acts as ‘traffic tower’ of immune response, by presenting peptides of microbial invaders to B-cells and T-cells. The variability of the HLA system, with in theory more phenotypes than humans, serves the survival of the species. It sees to it that almost always part of the population will be immunologically equipped to survive a devastating disease. Procreation is aimed at stimulating polymorphism. Links between the HLA system and sexuality have been uncovered (Wedekind and Füri, Proceedings of the Royal Society Biology 1997, Robert, Gosling, Carter and Petrie, Proceedings of the Royal Society Biology 2008). The more HLA groups are shared between sex partners, the more sexual responsiveness decreases over time and the more adultery takes place. Women with many HLA groups similar to those of their partner were more attracted to other men, especially during their fertile phase. On the other hand, male pheromones particularly attract women with a differing HLA profile. A little warning here: the pill messes up this process.

The Sanquin Laboratory for Cell Therapy specializes in Advanced Therapy Medicinal Products (ATMPs). The laboratory is licensed to produce tumour infiltrating lymphocytes (TILs) and Mesenchymal Stromal Cells (MSCs). A third application is currently being assessed. Sanquin’s services are very relevant for University Medical Centers or cancer hospitals in the Netherlands, explains project leader Daphne Thijssen-Timmer. “We have the facilities, the knowledge, the license and the capacity to help them produce innovative medications.”

Daphne Thijssen-Timmer. Photo Ineke Oostveen, for Sanquin

Sanquin Laboratory for Cell Therapy

Partner for ATMP production Growing TILs The Laboratory for Cell Therapy joins forces with medical doctors in clinical trials. Currently, Sanquin is involved in a European study, supervised by John Haanen, PhD, professor at the Netherlands Cancer Institute/ Antoni van Leeuwenhoek hospital. “We are producing TILs for patients with melanoma”, Daphne Thijssen-Timmer says. “T-cells from the tumor are cultured and grown in the presence of feeder cells to very large numbers. Patients are then infused with the TILs in combination with interleukin 2. So far, the study has been conducted with ten patients at the NKI. The outcomes are highly promising: in several patients, complete remission has been achieved. And even though this is an experimental and advanced therapy, it is relatively affordable.” Now, it’s time to scale up to thirty patients. Half of the TILs will be produced at Sanquin. “We have the facilities, the knowledge and the license for this. We are highly experienced in the production of TILs in accordance with good manufacturing practices. In this way, our clinical partners can spread risks, scale up and save capacity for other activities.”

Growing MSCs The laboratory also contributes to the HOVON 113 study, led by the Leiden University Medical Center. “We grow MSCs from bone marrow of healthy donors for patients suffering from GraftVersus-Host disease, a common complication following an allogeneic hematopoietic stemcell transplant. In the case of this disease, the transplanted immune cells recognise the recipient as foreign and attack the host’s body cells. Researchers now assume that the MSCs can regulate the activity of the immune system.”

The Free University Amsterdam and the University of Amsterdam participate in this study and requested Sanquin to grow their MSCs. “Previous studies have been executed with MSCs, demonstrating a immuno-modulatory effect, but this is the first randomized study to do so”, Thijssen says. “All over the world researchers are anticipating the outcomes.”

There is a need for tailor made in vitro grown red blood cells that are compatible for alloimmunized patients

Red blood cells Currently, the Laboratory for Cell Therapy is also preparing the growth of red blood cells for patients suffering from, for instance, sickle cell anemia. “These patients have had so many blood transfusions that they have developed antibodies against many bloodgroup antigens making them depend on a small group of donors with the correct blood group. There is a need for in vitro grown tailor made red blood cells that are compatible for these alloimmunized patients.” Sanquin researchers have developed a protocol which is currently being translated into a clinical grade product by the LCT. In addition several in vitro safety assays are being developed. “We hope to submit for a production license within two years, in order to be able to obtain proof of principle in healthy volunteers.”

This article was made possible by Sanquin: www.sanquin.nl.

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inaugural lecture

Can targeted nutrition prevent respiratory tract infections, allergies and inflammation? Targeted nutrition and additional micronutrients can increase resistance against respiratory tract infections, allergies and inflammation. That is vitally important for children under the age of five years and people aged sixty-five and over. Resistance in tissues covered with a mucous membrane in mouth, throat, and nose has scarcely been investigated. Such research could, however, yield important results, says Professor Joost van Neerven. On Thursday 2 October 2014 he became Professor in Mucosal Immunity (endowed chair) at Wageningen University. Until now, research into the resistance in tissues with a mucous membrane, so-called mucosal immunity, has mainly focused on the gastrointestinal tract. Subsequently it was investigated how diarrhoea or chronic inflammation of the gastrointestinal tract could be combatted along this route, for example with food, explains Joost van Neerven in his inaugural lecture Mucosal Immunity: Barriers, Bugs and Balance. Van Neerven (Heerlen, 1966) is senior researcher at the FrieslandCampina Innovation Centre in Wageningen; his chair is funded by FrieslandCampina. Recently it became known that certain nutritional components, including (raw) milk, clearly have a positive influence on the immunity in the upper respiratory tract. With this knowledge the chances of small children developing an allergy or infection can be reduced. It might be possible to prevent respiratory tract infections and chronic inflammations in the elderly as well. “The mucous membrane has a complex role in the immune system”, explains Joost van Neerven. “First of all it forms a barrier against pathogens and if they still get inside, then a balanced reaction – ‘not too little, but also not too vehement’ – is vitally important.”

Allergies Van Neerven: “It is already known that the mucosal system in the upper respiratory tract also facilitates immunity against infections and the development of allergies. But how this works and which mechanisms are involved is still largely unknown. We suspect that lymphoid tissue at the back of the throat plays a role. More research is required, especially to see how nutrition can positively affect this. With the knowledge that emerges from this research we can develop targeted strategies to help prevent these conditions, not only via the diet but also via mucosal vaccinations in the mucous membrane.” In his inaugural lecture, Professor Van Neerven explains that immune-related diseases and conditions via the mucous membranes mainly occur in children under five years old and in people aged sixty-five years and over. The world population is growing rapidly and, on average, is also becoming older. It is expected that in 2050, 16% of the world’s population – more than 1.5 billion people – will be older than sixty-five. Elderly are susceptible to both non-allergic inflammatory diseases and to infections. With an ageing population a strong increase in inflammatory and infectious diseases can therefore be expected, he says.

Societal costs Besides infections, children under five are also susceptible to the development of allergies. In the rich West, the number of allergies has increased markedly in recent decades and currently about 25 to 30% of young children develop an allergy; a considerable proportion of these children develop asthma. In developing countries the figures are still lower at present, but recent studies have shown that in Asia the number of children with an allergy is rising rapidly. Van Neerven: “Societal costs arising from direct and indirect medical costs and sick leave are high. If prevention via the diet is possible then the same treatment level can be achieved against far lower costs. Further research into this is therefore definitely worthwhile.”

Reduced antibiotics use “This knowledge is not only important for human health but can also be used for agricultural animals”, says Professor Van Neerven: “The prevention of respiratory tract infections in animals by means of targeted nutrition will not just result in higher production but also in reduced antibiotics use.”

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Photo Joost van Neerven

Eight UMCs tour

Very interested audiences learn about immunology

When it’s your birthday, there is cake for the guests

On October 11, the UMCs tour was held in seven out of eight University Medical Centres in the Netherlands. Each centre presented another topic. The AMC Amsterdam focused on HIV and AIDS. This meeting was dedicated to Joep Lange who tragically passed away in the MH17 plane crash. The other topics included healthy aging with a systemic autoimmune disease (UMCG), arthritis (LUMC), organ-specific autoimmune disease and tumour immunology (MUMC), Lyme’s disease (Radboud UMC), humoral immune deficiencies (ErasmusMC) and (food) allergy (UMCU). Unfortunately, in the VUMC the meeting was cancelled. The meetings drew audiences varying from 40 to 130 very interested people. In all places, lectures were presented to explain immunology in laymen’s terms, alternated with a poster session. Various posters were on display and were ground for lively discussions among presentors and participants. Several attendees were patients themselves. Although they came in already well informed through internet, they had many remaining questions. The experts willingly answered these. Both attendees and presentors look back on a successful day. From this place I would like to thank all the local organizing committees for their effort to make it happen. Without financial support by the NVVI and several companies, the day could not have been organised. We therefore greatly appreciate their contributions. The day made clear that there surely is need to inform the general public on immunology. More of these meetings should be organised in the future! Wilfred Germeraad Photos NVVI

Maastricht

Leiden

Not only theory, but also practice

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eSS

Professor Albert Osterhaus

“Prevention at the source is key” The eradication of smallpox virus allowed scientists and policymakers to dream of a world without infectious diseases. Since then, however, the world has seen the spread of devastating

ourne, Australia infectious diseases

manyTuberculosis,

like AIDS, Avian flu, Ebola, SARS, MERS,

Q-fever and Lyme disease affecting both men and

animals. “It is crucial to identify the predisposing factors for the

rlands occurrence of newly emerging infectious diseases”, says virologist Ab Osterhaus. The 3rd International One Health Congress focuses

Netherlands on prevention at the source. ‘One Health’ is largely inspired by the notion that animal and human health as well as their environments are closely interconnected. Better cooperation between several disciplines, including human and veterinary medicine, biology and ecology, will contribute to the prevention or solution of serious global health problems. Indeed the third factor in the triangle, the environment, is a crucial element of One Health, says Ab Osterhaus, Scientific Chair of the 3rd International One Health Congress in March 2015 in Amsterdam. “Take for instance organochlorines like PCBs that pollute the marine food chain.

eld , United Kingdom

ure, Morogoro, Tanzania

15-18 March 2015, 3d International One Health Congress – Abstracts welcome! Prevention at the source is key in controlling disease outbreaks that have a growing impact on humans, animals and their ecosystems. The 3rd International One Health Congress in Amsterdam will focus on how science can help in preventing disease outbreaks. Nobel Laureate Professor Peter Doherty of the University of Melbourne, Australia, will give the opening lecture. The congress in Amsterdam will be of special interest to infectious disease specialists, immunologists, biologists and ecologists. They are invited to submit late breaker abstracts targeting for instance topics like vaccine development, treatment, antibiotics resistance or newly emerging diseases and their predisposing factors.

ses that have a growing

rnational One Health nting emerging and

Policy Interface policy

Www.IOHC2015.com st scientific advancements

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December 2014

Bird flu Recently, an outbreak of the H5N8 subtype of bird flu has emerged in Asia and Europe, a highly lethal infectious viral disease of birds. This highly pathogenic avian influenza is extremely dangerous to poultry and can seriously impact local and global economies and international trades. Whether it might eventually also constitute a zoonotic risk cannot be ruled out at present. “Previous outbreaks of bird flu have taught us how to control the disease and measures have been taken at once”, says Osterhaus. “Still, ideally we should have been able to prevent such an outbreak. The fact that we have not been able to do this, despite the fact that we already know a lot about the mechanisms involved in the spread of bird flu, illustrates the challenges we are facing and the importance of One Health.”

They accumulate in this food chain by entering via plankton, that is being eaten by fish which are the main diet of seals and to a lesser extent of humans. This eventually affects the seals’ and possibly also the humans’ immune system. Man, animal and environment are part of the same ecosystem and many diseases spread from animal reservoirs to men and vice versa. One Health studies the factors that determine or threaten health within this triangle as well as their complex interrelationship.”

Urbanisation and globalisation take their toll Agents that cause emerging infectious diseases in humans like AIDS, SARS, and Ebola have been present in animals for ages. “For as long as these animals had only limited contacts with men living in relative isolation, these infections did not cause a major problem. And when they did spread to humans, in these isolated areas limited human-to-human spread would take place. But the world has changed. Urbanisation and globalisation are taking their toll: newly introduced viruses, antibiotic-resistant bacteria and parasites are being spread to much more densely populated areas and travel the world like wildfires. They may cause epidemics or even pandemics, affecting or killing thousands, tens of thousands or even millions of human beings and animals alike.” There are many other factors that may contribute to the spreading of diseases. Besides poverty, one of them is wealth. “In 2003, the coronavirus that caused the SARS epidemic was traced to carnivores like masked palm civets that had been

Ab Osterhaus

infected with the SARS-

Prof. Dr. Albert Osterhaus is the CEO of Artemis One Health Research Foundation. He is Professor of Virology at the Department of Viroscience of Erasmus Medical Center in Rotterdam and Professor of wildlife virology and virus discovery at the Utrecht University. He is Director of the Research Center for Emerging Infections and Zoonoses Research and guest Professor at the Tierärztliche Hochschule Hannover in Germany.

food contaminated with the central nervous system (brain, spinal cord, ganglia) or digestive tract of infected animals. In humans it manifested itself as a new form of Creutzfeldt-Jakob disease, taking the lives of hundreds of people. Maybe we could have prevented this epidemic among cows and humans if we had refrained from turning herbivores into carnivores – or even cannibals.”

Prevention at the source

Photo Erasmus UMC

coronavirus from bats. These civets that are considered a delicacy are trapped or farm raised in, for instance, China. The local growth of wealth, allowing many people to treat themselves to this delicacy, appears to have been a factor in the transmission of SARS-coronavirus to humans. A rather similar story now goes for camels in relation to the new MERScoronavirus in the Middle East.”

Food production methods Osterhaus also points at changing mores and taboos, like intravenous drug abuse, changing sexual practices and the fact that we are constantly introducing new food products or changing our food production methods. “An interesting example is bovine spongiform encephalopathy (BSE), also known as ‘mad cow disease’. At some point livestock producers thought that it would be a good idea to feed slaughter offals of cattle in the form of meat and bone meal to cows. It could serve as a protein rich feed component for lactating cattle, which was considered an ecologically sound practice by recirculating locally produced materials. This however allowed a not previously known infectious agent to spread, and made it necessary to cull millions of cattle. The agent was transmitted to human beings eating

Of course, these chains of events were never expected to happen. “Every time we are surprised by them, mourning harm to the environment or the loss of animal and human life. We jump at them and do our best to control them. That is of course indispensable, but at the same time it’s a case of selling refrigerators to Eskimos. We should be starting at the other side, at the source. We must try to prevent these incidents from happening. It is therefore crucial to identify the predisposing factors that allow for the introduction of diseases. We must learn what mechanisms are involved in their occurrence and spread. All around the world scientists are aware of this challenge. They investigate the subject and try to understand the underlying causes and mechanisms that allow an emerging virus, a bacterium or other parasite to cause a devastating epidemic. The bonus would be subsequent progress in prevention. This is the focus of the 3d International One Health Congress 2015 in Amsterdam. We invite everybody who is interested in health issues related to the interaction of humans, animals and the environment to join us.” By Alinda Wolthuis

Ebola An outbreak of Ebola is currently ongoing. Thousands of people have now died in west Africa from this infectious disease that has its origin in eating bush meat. Could it have been prevented? Why don’t we have effective vaccines or medicines? Will this result in a true pandemic? Can we prevent such disasters at the source? All questions that will be addressed in a special Ebola session at the 3d International One Health Congress in Amsterdam.

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science across borders

‘Screening of T-cells by applying biocatalytic synthesis’: Biocatalysis, organic synthesis and immunology all came together in a project aimed at developing novel immune-technological reagents. Such reagents – basically peptides – play a key role in characterising and purifying T-cell populations with desirable characteristics for both diagnostics and therapeutic immunological applications. The peptides themselves can also be of therapeutic value, for instance in the treatment of autoimmune disease.

Huib Ovaa:

Developing novel reagents Photo NKI

The very multidisciplinary project was part of the NWO public-private-partnerschip programme known as ‘Integration of Biosynthesis and Organic Synthesis’. Chemical biologist Professor Huib Ovaa, chemical biology group leader at the Netherlands Cancer Institute in Amsterdam, worked together with his immunology colleagues as well as with researchers from MSD Pharmaceutics, Sanquin Blood Supply and the chemical start-up Chiralix. The project comprised the utilisation of a short chemo-enzymatic ‘green chemistry’ route in the synthesis of specific building blocks for the peptides. An exciting result was that the group was able to develop novel reagents that were more dedicated and more potent than their predecessors. It’s now up to the industrial partners to bring this technology to the market.

Satisfying project Ovaa: “It has always been our dream to do research that will lead to actual applications. This has been a very satisfying research project. We have not only been able to significantly improve the immunological technology, but – which is equally important – it has resulted in a valuable addition to our laboratory toolbox. The biocatalytic approach has really expanded the number of possible chemical transformations that we now are able to perform on a routine basis. To a chemist like me, that is very worthwhile.” This article is published with kind permission of NWO Elements, annual magazine NWO chemical sciences 2014-2015, where it was published earlier under another title.

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December 2014

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Welcome to the NVVI Anniversary Congress 2014 ‘A Future Heritage’ Full Program Poster Walks

Interviews LISET WESTERA YVETTE VAN KOOYK

December 2014

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Prof.dr. R. Mebius, chair

Welcome to the NVVI Anniversary Congress 2014

VU Medical Center, Amsterdam

Dear Friends Colleagues,

Organisation Members of the NVvI Board

Prof.dr. R. Toes, treasurer LUMC, Leiden

A warm welcome to the NVVI Anniversary Congress 2014. This year we are celebrating the founding of

Prof.dr. L. Meyaard, secretary general

the NVVI, which took place on November 20, 1964. The lustrum committee, directed by Esther de Jong,

UMC Utrecht

Mieke Boots, Wilfred Germeraad, and Leendert Trouw, has been extremely active to memorise this an-

Prof.dr. P. van Hagen, member

niversary year by a variety of activities, which were organized by a total of 43 enthusiastic sub-committee

Erasmus MC, Rotterdam

members. This Anniversary Congress can be seen as the celebratory closing party of NVVI 50th birthday.

Prof.dr. M. Boots, member

Unlike other years, this year we will have a three day meeting, which will allow for a fantastic scientific

UMC Groningen

program with an outstanding list of (inter)national speakers. The program has been put together by

Dr. A. Langerak, member

the program committee, chaired by Janneke Samsom, together by the lustrum committee guided by

Erasmus MC, Rotterdam

Esther de Jong. The result is fantastic with Marcel van den Brink, Miriam Merad and Frederica Sallusto as keynote speakers, and 21 additional plenary lectures by outstanding invited speakers.

Scientiﬁc Committee Dr. J. Samsom, Erasmus MC, Rotterdam

On Wednesday evening the Van Loghem lecture 2014 will be delivered by Professor Yvette van Kooyk,

Prof.dr. L. Meyaard, UMC Utrecht

principal investigator at the Dept. Molecular Cell Biology and Immunology, VUMC, Amsterdam, studying

Prof.dr. T. Geijtenbeek, AMC Amsterdam

the functional consequences, of the interaction between pathogen derived glycolipids/proteins and host

Dr. A. Lankester, LUMC, Leiden

immune cells, for the resulting immune response. Her work on the interaction of HIV with the c-type lec-

Dr. M. Heemskerk, LUMC, Leiden

tin DC-Sign, expressed on dendritic cells, evolved towards the identification of glycans which can be used to tweak the immune responses, initiated by dendritic cells. She views the glycan binding receptors on

Dr. K. Tesselaar, UMC Utrecht

dendritic cells as remarkable tuning switches to modulate the immune response towards the response

Prof.dr. R. Toes , LUMC, Leiden

that is needed, being either improving anti tumor responses or dampening auto-immune or allergy

Prof.dr. J. de Vries, UMC St. Radboud, Nijmegen

responses. I can highly recommend reading about her research in the interview with Yvette in Immuun.

Dr. M. Schreurs, Erasmus MC, Rotterdam

This year’s winner of the NVVI thesis award is Liset Westera, who was selected as winner of 9 candida-

Prof.dr. N. Bos, UMC Groningen

tes. She performed her PhD work at the UMC Utrecht, LTI, under the supervision of Dr. José Borghans and Dr. Kiki Tesselaar, and reported her findings in her thesis entitled “Quantification of Lymphocyte

Anniversary Committee

Dynamics”.

Prof.dr. E. de Jong, AMC Amsterdam

This year 363 abstracts covering 20 different themes have been submitted of which 80 will be presented

Prof.dr. M. Boots, UMC Groningen

in the regular workshops. We have an additional session, covering the topic Chemical Immunology,

Dr. W. Germeraad, UMC Maastricht

organized by the Institute of Chemical Immunology, with Hidde Ploegh and Ton Schumacher and two

Dr. L. Trouw, LUMC Leiden

additional invited speakers. This session is especially set up to familiarize the NVVI members with this new research area, which was funded last year by the Gravity fund from NWO. For the Bright Sparks

Anniversary Sub-Committees

session we received 74 abstracts. All these abstracts were judged by a regular as well as a separate jury,

Highlights-committee: Dr. F. Gmelig Meyling; Prof.dr. M.

and they selected the best 5 abstracts. These will be presented in the Bright Spark session on Friday as a

Daha; Dr. B. Hepkema; Prof.dr. G. Kraal; Prof.dr. J. Laman; Dr. M.

plenary session right before the last keynote speaker, Frederica Sallusto, and the poster award ceremony.

Nolte; Prof.dr. D. Roos & Prof.dr. M. Wauben

The ‘brightest‘spark 2014 will be announced at the end of the meeting. The other abstracts will be pre-

App-committee: Drs. J. Sprokholt; Dr. A. van der Aar; Prof.dr.

sented in poster format and following the successes of previous years, poster walks will be organized on

G. Rijkers; Drs. B. Verstrepen & Dr. C. Ribeiro.

Wednesday, Thursday, and Friday in 3 different sessions around lunch time. Abstracts can be found online

Debate-committee: Prof.dr. M. Boots; Prof.dr. B. ’t Hart; Prof.

at the following url:

dr. I. Joosten; Prof.dr. F. Koning; Dr. A. te Velde; Dr. M. van der

https://www.eventure-online.com/eventure/welcome.do?type=public&congress=133_1446

Vlist & Drs. L. Vogelpoel

On Thursday afternoon we will have the opportunity to visit the Efteling, while both evenings hold a

Sponsor-committee: Dr. L. Trouw & E. van der Voort

‘surprise’ for all 600 participants, all allowing for enough social interactions in addition to the scientific

Dr. B. Thio, Prof.dr. J. van Strijp; Prof.dr. W. de Jonge & Dr. S.

encounters.

Nierkens 8 UMC Toer-committee: Dr. W. Germeraad; Dr. J. Koning; Dr.

Please note that the European Congress of Immunology will be held in Vienna, from Sept 6-9 2015, with a

S. Buschow; Dr. A. Ioan-Facsinary; Dr. V. Dalm; Dr. M. van Zelm;

very inviting and challenging program. I would like encourage everyone to have a look at it (http://www.

Dr. E. van Leeuwen; Dr. A. Muris; Prof.dr. F. Kroese & Dr. E. Knol

eci-vienna2015.org/).

Anniversary Congres-committee: Prof.dr. E. de Jong; Dr. H. Smits; Dr. G. Bakdash; Dr. S. van Vliet; Drs. D. Jansen, Dr. L. van

I wish you all an inspiring meeting!

Duivenvoorde & Dr. R. Reijmers

Reina Mebius President of the NVVI board ORGANISATION

Secretarial Oﬃce NVvI Saskia ter Braak | +31 (0)88 755 4306 | nvvi@umcutrecht.nl

Members of the NVvI Board

A FUTURE HERITAGE

Partners: Partners: Platinum Partner:

Gold Partners:

Silver Partners:

Sponsors & Exhibitors:

Sponsors and exhibitors

Bio-‐Connect Diagnostics Bio-‐Techne eBioscience Eppendorf Nederland Greiner Bio-‐One Bio-Connect Diagnostics

IBL International / Sanquin InvivoGen Libra Diagnostica Mediphos Medical Supplies merck Millipore IBL International / Sanquin

Meso Scale Discovery Miltenyi Biotec Phadia Sony Europe Limited Stemcell Technologies Meso Scale Discovery

Bio-Techne

InvivoGen

Miltenyi Biotec

EBioscience

Libra Diagnostica

Phadia

Eppendorf Nederland

Mediphos Medical Supplies

Sony Europe Limited

Greiner Bio-One

Merck Millipore

Stemcell Technologies

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December 2014

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A FUTURE HERITAGE

GENERAL INFORMATION Venue Efteling Europalaan 1 5171 KW Kaatsheuvel

registration. You are kindly requested to wear your name badge during the whole meeting.

Registration

Abstracts For the abstracts of the Bright Spark, Parallel and Poster Walk sessions, please check www.dutchsocietyimmunology.nl

Accreditation

Registration is possible till Monday 15 December 2014 via www.dutchsocietyimmunology.nl or www.congresscompany.com. It is also possible to register on site at the registration desk.

Cancellation

The 50th Anniversary Congress of the Dutch Society for Immunology is accredited by the Nederlandse Internisten Vereniging (NIV) and the Nederlandse Vereniging voor Reumatologie (NVR).

All cancellations must be sent to the congress secretariat by e-mail. Payments will be reimbursed, minus Euro 25 to cover administration costs, if the cancellation is received before 24 November 2014. No reimbursement will be given if the cancellation is received after 24 November 2014.

Cottages

Liability and Insurance

Check-in is possible at the desk in the Efteling Theater on Wednesday in the afternoon and should be done by the person who has booked the cottage. For every cottage there will be in total two keys.

The organisation of the NVvI 50th Anniversary Congress accepts no liability for any personal injury, loss or damage of property belonging or additional expenses incurred to conference participants either during the meeting or as result of delays, strikes or any circumstances. Participants are requested to make their own arrangements with respect to health and travel insurance.

Parking Delegates who stay at a cottage in Bosrijk, please leave your car on the parking of Bosrijk. Delegates who stay in the Efteling Hotel and the NH Waalwijk, please park at the main parking of the Efteling. Please leave your luggage in your car (except valuables). After parking we kindly ask you to come to entrance 19 of the Efteling, you can find this entrance at the right side of the main entrance of the Efteling.

All participants will receive a personal badge upon

Congress secretariat P.O. Box 2428 5202 CK ’s-Hertogenbosch The Netherlands Tel: +31 (0)73 700 35 01 Fax: +31 (0)73 700 35 05 E-mail: info@congresscompany.com www.congresscompany.com

Before the deadline 13 December 2014: NVvI member - 3 Days Non-member - 3 Days NVvI member - 1 day Non-member - 1 Day

From 13 December 2014 and on site: NVvI member - 3 Days Non-member - 3 Days NVvI member - 1 day Non-member - 1 Day

Meeting language The meeting language will be English. No simultaneous translation will be available.

Name badge

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December 2014

€ 345 € 425 € 150 € 195

€ 395 € 475 € 150 € 195

Program-at-a-glance Wednesday, December 17 09.00-10.00 Registration 10.00-10.15 Opening 10.15-11.15 Keynote Lecture 11.15-12.45 Parallel sessions* Invited speaker and selected oral presentations 12.45-14.15 13.00-14.00 13.00-14.00 14.15-15.45

Lunch General Assembly NVVI (with lunch) Poster Walk Session* 1 Parallel sessions* Invited speaker and selected oral presentations

15.45-16.15 16.15-17.45

Break Parallel sessions* Invited speaker and selected oral presentations

17.45-18.45 18.45-20.15 20.30-21.00 21.00-22.00 22.00-22.45 22.45-00.00 23.00-00.00

Drinks Dinner Thesis Award winner Van Loghem Lecture Drinks NVVI Cabaret Drinks

Thursday, December 18 08.00-09.00 Registration 08.00-09.00 Breakfast 08.00-09.00 Meet the Expert Breakfast 09.00-10.30 Parallel sessions* Invited speaker and selected oral presentations 10.30-11.00 11.00-12.30

Break Parallel sessions* Invited speaker and selected oral presentations

12.30-14.00 12.45-13.45 14.00-15.00 15.00-18.00 18.15-18.30 18.30-00.30

Lunch Poster Walk Session* 2 Keynote lecture Visit the Efteling Aquanura, light and water show Anniversary Party with NVvI Open Stage

Friday, December 19 08.00-09.00 Registration 08.00-09.00 Breakfast 08.00-09.00 Meet the Expert Breakfast 09.00-10.30 Parallel sessions* Invited speaker and selected oral presentations 10.30-11.00 11.00-12.30

Break Parallel sessions* Invited speaker and selected oral presentations

12.30-14.00 12.45-13.45 14.00-15.00 15.00-16.00 16.00-16.15 16.15-16.30

Lunch Efteling theater Poster Walk Session* 3 Bright Sparks* Keynote lecture Poster and bright spark award ceremony Closing

Marcel van den Brink Autoimmunity and allergy - Marsha Wills-Karp Infection and inﬂammation -Tom van der Poll Mucosal immunology - Bana Jabri

Adaptive immunity - Marc Veldhoen Tumor immunology - Katarina Wolf Infection and inﬂammation - Veit Hornung Adaptive immunity - Facundo Batista Mucosal immunology - Ben Marsland Tumor immunology - Tanja de Gruijl

Liset Westera Yvette van Kooyk Ernst van der Pasch

Chemical immunology - Hidde Ploegh Autoimmunity and allergy - Catharien Hilkens Innate immunity - Aljay Chawla Adaptive immunity - Muzlifah Haniﬀa Innate immunity - Leo Koenderman Tumor immunology - Jerome Galon

Miriam Merad

Adaptive immunity - Georg Hollander Clinical immunology - Yehuda Schoenfeld Autoimmunity and allergy - Leonie Taams Adaptive immunity - Francesco Annuziato Medical immunology - Xavier Bossuyt Innate immunity - Sergei Nedospasov

Federica Sallusto Reina Mebius

Efteling theater Theaterzaal Theaterzaal Theaterzaal Applaus r NVvI Paviljoen Efteling theate NVvI Paviljoen Upper Foyer Theaterzaal Applaus NVvI Paviljoen Efteling theater Theaterzaal Applaus NVvI Paviljoen Efteling theater Efteling theater Theaterzaal Theaterzaal Efteling theater Theaterzaal Efteling theater

Efteling theater Efteling theater Applaus Theaterzaal Applaus NVvI Paviljoen Efteling theater Theaterzaal Applaus NVvI Paviljoen Efteling theater Upper Foyer Theaterzaal Efteling Efteling Fata Morgana Palace

Efteling theater Efteling theater Applaus Theaterzaal Applaus NVvI Paviljoen Efteling theater Theaterzaal Applaus NVvI Paviljoen Upper Foyer Theaterzaal Theaterzaal Theaterzaal Theaterzaal

*For the abstracts of the Bright Spark, Parallel and Poster Walk sessions, please check www.dutchsocietyimmunology.nl

December 2014

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A FUTURE HERITAGE

Wednesday,

10.00-10.15 Opening - Theaterzaal Theaterzaal - Keynote lecture 1 0 .1 5 -1 1 .1 5 Marcel van den Brink Novel Approaches to Graft-versus-host disease Chair Kiki Tesselaar

Wednesday, December 17

Session 1 Location Chair 11.15-11.45

Session 2 Location Chair 11.15-11.45

Session 3 Location Chair 11.15-11.45

11.45-12.00

12.00-12.15

12.15-12.30

12.30-12.45

Autoimmunity & Allergy Theaterzaal Marsha Wills-Karp & Hermelijn Smits Marsha Wills-Karp Innate and Adaptive Immune Responses in Asthma Baarsen, L.G.M. van CD4 T-Helper Cell Subsets in Lymphoid Tissue and Peripheral Blood during the Earliest Phases of Rheumatoid Arthritis Rogier, R.L. Immunomodulatory effects of dietary non-digestible oligosaccharides in T cell-mediated autoimmune arthritis Willemsen, L.E.M. Dietary galacto-oligosaccharides reduce airway eosinophilia and enhance the Th2 suppressive effect of budesonide in house dust miteinduced asthma in mice Li, B.W.S. Role of T cell activation in the induction of group 2 innate lymphoid cells in allergic asthma

Wednesday, December 17 Session 4 Location Chair 14.15-14.45 14.45-15.00

Adaptive Immunity Theaterzaal Marc Veldhoen & Willemijn Hobo Marc Veldhoen From dichotomy to a free for all Aalderen, M.C. van Infection history determines the differentiation state of human CD8 T-cells 15.00-15.15 Salerno, F. Innate reactivation through TLR triggering relieves the translational block for IFN-γ in memory CD8 T cells 15.15-15.30 Vieira Braga, F.A. Hobit is a transcription factor involved in metabolic regulation and survival of human CD8 T cells

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December 2014

11.45-12.00

12.00-12.15

12.15-12.30

12.30-12.45

Infection & Inflammation Applaus Tom van der Poll & Carla Ribeiro Tom van der Poll Cell specific innate immune sensing in host defense against bacterial infection Geerdink, R.J. Inhibitory collagen receptor LAIR-1 limits neutrophil-induced lung pathology Porto, A.P.N.A. de Susceptibility for S.pneumoniaeevoked pneumonia in Bruton’s tyrosine kinase deficient mice is not antibody dependent Does, A.M. van der Phenylbutyrate acts as a proresolving mediator during Pseudomonas aeruginosa-induced lung inflammation Steen-Louws, C. IL4-10 Synerkine as a novel immunoregulatory drug in osteoarthritis

11.45-12.00

12.00-12.15

12.15-12.30

12.30-12.45

Wednesday, December 17 Session 5 Location Chair 14.15-14.45

Tumor Immunology Applaus Katarina Wolf & Zsolt Sebestyen Katarina Wolf Niches of cancer invasion and immune effector function 14.45-15.00 Buuren, M.M. van High sensitivity of cancer exomebased CD8 T cell neo-antigen identification 15.00-15.15 Bruin, R.C.G. de Specific tumor targeting and activation of Vγ9Vd2 T cells for cancer immunotherapy 15.15-15.30 Kvistborg, P. Effect of T cell checkpoint targeting on neo-antigen-specific T cell reactivity in melanoma and NSCLC

Mucosal Immunology NVvI Paviljoen Bana Jabri & Serge van de Pavert Bana Jabri Virus-mediated intestinal immunopathology: a story of the virus and the host Menckeberg, C.L. Secretory leukocyte protease inhibitor (SLPI) is crucial for maintenance of a hyporesponsive intestinal epithelium Hansen, I.S. Fc alpha receptor I co-stimulation promotes inflammatory cytokine response by human CD103 mucosal dendritic cells Veenbergen, S. Tolerance in the large intestine to protein antigen is induced in the iliac lymph nodes independent of CD103 migratory DC Gisbergen, K.P.J.M. van The transcriptional regulator Hobit and its homologue Blimp-1 cooperatively establish tissueresidency of lymphocytes

Wednesday, December 17 Session 6 Location Chair 14.15-14.45 14.45-15.00

Infection & Inflammation NVvI Paviljoen Veit Hornung & Sandra Van Vliet Veit Hornung Innate sensing of cytosolic DNA Teijlingen, N.H. van Activation of vaginal Langerhans cells increases HIV-1 susceptibility: a role for the vaginal microbiome 15.00-15.15 Ribeiro, C.M.S. Human Trim5a restricts HIV-1 infection of Langerhans cells by autophagy 15.15-15.30 Montfoort, N. van Low soluble CD14 in neonates prevents efficient activation of dendritic cells by Hepatitis B virus surface antigen

, December 17 15.30-15.45 Windt, G.J.W. van der Bio-energetics regulate CD8 memory T cell formation and function

15.30-15.45 Bossche, W.B.L. van den Minimally invasive diagnostics for cancer using circulating tissue macrophages

15.30-15.45 Vogelpoel, L.T.C. FcÎłRIIa co-ligation orchestrates pathogen and cell-type specific immunity by human myeloid cells

Wednesday, December 17

Session 7 Location Chair 16.15-16.45

Session 8 Location Chair 16.15-16.45

Session 9 Location Chair 16.15-16.45

Adaptive Immunity Theaterzaal Facundo Batista & Menno van Zelm Facundo Batista to be announced 16.45-17.00 Lighaam, L.C. IgG4 B cells: lessons learned from a small population of B cells 17.00-17.15 Stark, R. CD40L expression marks CD8 T cells with helper functions and is induced by strong T-cell-receptor signals and IL-12-mediated STAT4 signaling 17.15-17.30 Mesman , A.W. Profiling influenza virus A specific memory B cells via a novel protein microarray tool 17.30-17.45 Szilagyi, K. The inhibitory receptor SIRPa on B1 cells is restricting production of atheroprotective IgM antibodies and mediating development of atherosclerosis

Mucosal Immunology Applaus Ben Marsland & Isme de Kleer Ben Marsland Host-microbe interactions in lung diseases 16.45-17.00 Boks, M.A. Human glycoprotein Salivary Agglutinin affects DC-SIGN and Langerin interaction with oral pathogens and modulates the immune response via IL-10 induction 17.00-17.15 Aparicio-Domingo, P. NKp46-mediated activation of ILC3 regulates the intestinal epithelial response to tissue damage 17.15-17.30 Kuipers, Kirsten Cholera toxin subunit B confers antigen-independent protection against bacterial colonization 17.30-17.45 Unen, V. van Mass cytometry reveals extensive diversity of innate intraepithelial lymphocytes

Tumor Immunology NVvI Paviljoen Tanya de Gruijl & Reno Debets Tanja de Gruijl Break - Lower and Upper Foyering the immune suppressive status quo in solid tumors and their draining lymph nodes 16.45-17.00 Vliet, S.J. van Tumor-associated glycans trigger the C-type lectin MGL on dendritic cells to dampen anti-tumor immunity 17.00-17.15 Unger, W.W.J. Antigen targeting to dendritic cells combined with transient regulatory T cell inhibition results in long-term tumor regression 17.15-17.30 Gielen, P.R. Increased granulocytic myeloid derived suppressor cells in blood and tumor of patients with glioblastoma 17.30-17.45 Berg, J.H. van den Adoptive cell transfer in melanoma patients at the NKI-AVL; update on current and future clinical trials

Wednesday, December 17 Theaterzaal 20.30-21.00 Thesis Award Winner - Liset Westera Quantification of lymphocyte dynamics 21.00-22.00 Van Loghem Lecture by Yvette van Kooyk The Good and the Bad of glycans that control immunity Chair Reina Mebius

December 2014

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A FUTURE HERITAGE

Thursday, December 18 Thursday, December 18

Thursday, December 18

Session 10 Chemical Immunology Location Theaterzaal Chair Hidde Ploegh & Ton Schumacher 09.00-09.30 Hidde Ploegh New ways of visualizing the immune system 09.40 Celia Berkers Class and Specificity of the Human T Cell Response to Pathogens and Vaccines 10.05 Alan Rowan Stiff Polymer Worms: a novel approach to synthetic Dendritic Cells

Session 11 Location Chair

Autoimmunity & Allergy Applaus Catharien Hilkens & Niels van der Geest 09.00-09.30 Catharien Hilkens Inflammatory and tolerogenic dendritic cells in rheumatoid arthritis 09.30-09.45 Jansen, D.T.S.L. Abatacept decreases disease activity in the absence of CD4 T-cells in the collagen induced arthritis model 09.45-10.00 Das, T. A20 In dendritic cells as the controller of b cell driven autoimmune diseases 10.00-10.15 Levels, M.J. Bob1 expression by B cells is required for germinal center formation and development of collagen-induced arthritis 10.15-10.30 Kerkman, P.F. Phenotyping and characterisation of freshly isolated anti-citrullinated protein antibody specific B cells from peripheral blood of patients with rheumatoid arthritis

Session 12 Innate Immunity Location NVvI Paviljoen Chair Ajay Chawla & Michiel van der Vlist 09.00-09.30 Ajay Chawla Innate Immunity and Metabolic Homeostasis 09.30-09.45 Everts, B. TLR-driven early glycolytic reprogramming via the kinases TBK1-IKK supports the anabolic demands of dendritic cell activation 09.45-10.00 Wensveen, F.M. NK cells link obesity-induced adipose stress to inflammation and insulin resistance 10.00-10.15 Veninga, H. Functional CD169 is important for collaboration between CD8 DCs and CD169 macrophages in the induction of T cell responses 10.15-10.30 Drewniak, A. Type I Interferon (IFN-I) responses regulate innate and adaptive immunity during fungal infection

Thursday, December 18 Session 14 Innate Immunity Location Applaus Chair Leo Koenderman & Joris Vanderlogt 11.00-11.30 Leo Koenderman Functional compartmentalization of neutrophils: occurrence of killing deficient neutrophils during acute inflammation. 11.30-11.45 Brandsma, A.M. Super-resolution imaging reveals increased clustering of FcγRI in the plasma membrane induced by inside-out signaling 11.45-12.00 Rijn, A. van Semaphorin 7A is Essential for Chemokine-driven Dendritic Cell Migration 12.00-12.15 Linden, M. van der Signal Inhibitory Receptor on Leukocytes-1 inhibits early release of neutrophil extracellular traps, without affecting intracellular bactericidal activity 12.15-12.30 Noordenbos, T. Human mast cells engulf and store exogenous IL-17A

Thursday, December 18 Session 15 Tumor Immunology Location NVvI Paviljoen Chair Jerome Galon & Gertie Schreibelt 11.00-11.30 Jerome Galon to be announced 11.30-11.45 Wimmers, F. The induction of multifunctional T cells is key to long-term tumor control in metastatic melanoma 11.45-12.00 Jahn, L. T-Cell Receptors (TCRs) Specific for the Intracellular Transcription Factor Bob1 Allow Efficient Targeting of Human B-cell Leukemia and Multiple Myeloma 12.00-12.15 Buschow, S.I. Extraction of a prognostic mRNA based blood biomarker for cancer immunotherapy: a proof of principle study in metastatic melanoma 12.15-12.30 Heeren, A.M. Immunosuppressive Microenvironment in Metastatic Cervical Cancer Lymph Nodes

Thursday, December 18 Session 13 Adaptive Immunity Location Theaterzaal Chair Muzlifah Haniffa & Yuri Souwer 11.00-11.30 Muzlifah Haniffa Human tissue mononuclear phagocyte system revisited 11.30-11.45 Spaapen , R.M. Intramembrane cleavage is necessary for proper MHC class I folding 11.45-12.00 Zuidscherwoude, M.C.M. Nanoscale organization of MHC class II in the plasma membrane of antigen-presenting cells by tetraspanin CD53 12.00-12.15 Hall, T. van Classification of a CD8 T cell subset that recognizes hidden selfantigens TEIPP 12.15-12.30 Oth, T. Recognition of viral pathogenassociated molecular pattern by natural killer cells enhances dendritic cell responsiveness to the same pathogenic stimuli Thursday, December 18 Theaterzaal - Keynote lecture 14.00-15.00 Miriam Merad The Dendritic & Macrophage Lineage Chair Janneke Samsom

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Friday, December 19 Friday, December 19

Friday, December 19

Session 16 Location Chair 09.00-09.30

Adaptive Immunity Theaterzaal Georg Hollander & Arjan Lankester Georg Hollander Cellular and Molecular Aspects of Thymic Development and Function 09.30-09.45 Van Baarle, D. T cell receptor bias is a common feature of HIV-specific T cells restricted through protective HLAalleles 09.45-10.00 Vrisekoop, N. T Cell Positive Selection Uses Self-Ligand Binding Strength to Optimize Repertoire Recognition of Foreign Antigens 10.00-10.15 Broek, Th. van den Rejuvenation and restoration of the T-and B-cell compartment after neonatal thymectomy 10.15-10.30 Jong, S.E. de Immunological differences between European and African new-borns and young adults

Session 17 Location Chair 09.00-09.30

Clinical Immunology Applaus Yehuda Shoenfeld & Virgil Dalm Yehuda Shoenfeld Autoimmune diseases induced by adjuvants( ASIA syndrome)-The role of environmental adjuvants, vaccines and silicones implants 09.30-09.45 Schreibelt, G. Natural human BDCA1 myeloid dendritic cells induce immunological and clinical antitumor responses in metastatic melanoma patients 09.45-10.00 Budding, K. Soluble CD59 is a Novel Biomarker for the Prediction of the Bronchiolitis Obliterans Syndrome After Lung Transplantation 10.00-10.15 Bloem, K. Measuring anti-drug antibodies 10.15-10.30 Heuvel, H. van den Novel Public Alloreactivities Mediated by CMV- and FLUDirected CD8 T Cells

Session 18 Location Chair 09.00-09.30

Friday, December 19 Session 19 Adaptive Immunity Location Theaterzaal Chair Francesco Annunziato & Felix Wensveen 11.00-11.30 Francesco Annunziato Th17 and non-classic Th1 cells in human chronic inflammatory disorders: two faces of the same coin 11.30-11.45 Kallemeijn, M.J. TCRγδ T-LGL cells are effector TCRγδ T-cells with disturbed proliferation and apoptosis 11.45-12.00 Helbig, C. A central role for Notch in effector CD8 T cell differentiation 12.00-12.15 Roock, S. de Impaired neonatal Th17 development is abrogated within the first 3 months of life 12.15-12.30 Souwer, Y. Elastase from pathogen-activated neutrophils is essential for the initiation of human Th17 responses

Friday, December 19 Session 20 Medical Immunology Location Applaus Chair Xavier Bossuyt & Kyra Gelderman 11.00-11.30 Xavier Bossuyt ANA: novel developments 11.30-11.45 Bie, M. de New cellular markers at diagnosis predict central nervous system relapse in childhood acute lymphoblastic leukemia 11.45-12.00 Beurskens, F.J.M. Enhanced IgG hexamerization mediates efficient C1q docking and more rapid and substantial complement-dependent cytotoxicity (CDC); preclinical proof of concept. 12.00-12.15 Sonderen, A. van Clinical relevance of antibodies directed to the voltage-gated potassium channel (VGKC) complex 12.15-12.30 Jacobs, J.F.M. Serum free light chain assays in patients with renal impairment

Friday, December 19 Session 21 Innate Immunity Location NVvI Paviljoen Chair Sergei Nedospasov & Tom Cupedo 11.00-11.30 Sergei Nedospasov Induction of IL-10 expression in pro-inflammatory CD4+ T cells in humans 11.30-11.45 Drylewicz, J. NK-cell memory: long-term memory maintained by short-lived cells 11.45-12.00 Costes, L.M.M. Macrophages favor differentiation of IL-10 secreting Tr1 cells driving oral tolerance to gliadin via an IL-27 dependent mechanism 12.00-12.15 Helden, M.J.G. Van A T-bet to Zeb2 transcriptional circuit controls Natural Killer cell maturation 12.15-12.30 Aa, E. van der IFNγ is mainly produced by BDCA3expressing myeloid dendritic cells and regulated by the NFkB and PI3K-PKB-mTOR pathway

Autoimmunity & Allergy NVvI Paviljoen Leonie Taams & Jeroen den Dunnen Leonie Taams Regulating inflammation in rheumatoid arthritis 09.30-09.45 Peeters, J.G.C. Autophagy: maintaining immune homeostasis by controlling regulatory T cell function 09.45-10.00 Koenders, M.I. IL-22 Plays a Significant Role in the Initiation and Augmentation of Th17-dependent Experimental Arthritis 10.00-10.15 Maria, N.I Nucleic-acid sensing receptors TLR7, RIG-I and MDA5 collaborate in driving the systemic IFNsignature and amplify the pathogenic loop in pSS 10.15-10.30 Vlist, M. van der Deregulated control of sex-biased TLR7 responses by CD200-Receptor in SLE patients.

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A FUTURE HERITAGE Friday, December 19 Session Location Chair 14.00-14.12 14.12-14.24 14.24-14.36 14.36-14.48 14.48-15.00

Bright Sparks Theaterzaal Annelies Mesman & René van Lier Romera Hernandez, M. IL-22 controls fitness of the intestinal epithelial stem cell niche Winde, C.M. de Deficiency of tetraspanin CD37 induces development of IgA B cell lymphoma through the IL-6 pathway Zoete, M.R. de Immunoglobulin A coating identifies colitogenic bacteria in inflammatory bowel disease Dr. Lindemans, C.A. IL-22 is an Intestinal Stem Cell Growth Factor Protecting Epithelium from Graft versus Host Disease Bies, L. Intratumoral CD4 T cell reactivity against mutated antigens is commonly observed in human melanoma

15.00-16.00 Chair

Theaterzaal - Keynote Lecture Federica Sallusto Class and Specificity of the Human T Cell Response to Pathogens and Vaccines Esther de Jong

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‘Quantification of lymphocyte dynamics’ by Liset Westera PhD wins this year’s NVVI thesis award. How long does a naive T cell or memory T cell actually live? And how many of these are produced by the thymus every day? These are apparently simple, basic textbook questions, but amazingly the answers were largely unknown. This is largely due to difficulties to experimentally address such questions, particularly in humans. Moreover, the translation of data into a lifespan or turnover rate is not straightforward. As a result, there is little consensus. Westera now figured out how to most reliably quantify lymphocyte dynamics in humans, and thus obtained a number of important biological insights into the maintenance of lymphocyte populations.

Liset Westera NVVI 2014 thesis award winner

The importance of cell population quantiﬁcation Simple questions are no guarantee for simple methods. Large part of Westera’s thesis investigates methodological aspects of in vivo deuterium-labelling techniques. With this method, a stable isotope of hydrogen, deuterium, is administered in the form of heavy water (2H2O). Due to the presence of an additional neutron in the atom core, deuterium is twice as heavy as normal hydrogen. When cell division occurs in the presence of deuterium, newly synthesized DNA will incorporate deuterium. This can be measured and indicates cell lifespan. “However”, says Westera, “even with this technique there was still a tenfold variation between laboratories. A comparison of lifespans in literature revealed a curious pattern: the longer the period of deuterium labelling, the longer the estimated lifespan. We investigated this problem in mice and found that it was caused by the mathematical model used in our field: it could not correctly describe cell populations that contain multiple sub-populations with distinct turnover rates. An alternative model brought the solution. Not only does this finding explain controversy in literature; from now on this multi-exponential model can also be used to reliably quantify cell turnover from deuterium-labelling experiments.”

Biological outcomes The work is not merely about calculation; these numbers actually tell us a lot about immune function. Hence the statement in the thesis: ‘Quantification of biological processes often leads to important qualitative insights’. Westera mentions a few: “The main source of new naive T cells in mice and men is qualitatively different: while in mice the thymus is the major source of new T cells, in humans most naive T cells are produced by cell division in lymph nodes and spleen. Even though the human thymus shrinks with age and its output declines tenfold during adulthood, this has little impact on total production of naive T cells

Liset Westera: “Quantiﬁcation of biological processes often leads to important qualitative insights” (photo Liset Westera)

during aging, as the contribution of thymic output is already small in young adults.” This also explains why Westera found that T cells in elderly people do not divide more than T cells in young adults – there is no need for ‘compensation’. As the source of naive T cells is fundamentally different in mice and men, it is not advisable to use a mouse model for human conditions where T-cell dynamics are disturbed. Quantification of lymphocyte dynamics is also clinically relevant, says Westera: “To understand clinical conditions with disturbed lymphocyte dynamics, we need quantitative information from healthy people. This learns how lymphocyte dynamics is altered after stem cell transplantation, or establishes the effect of drugs on cell turnover.

IBD Westera now works as a post-doc in the group of professor Gijs van den Brink at the Amsterdam AMC Tytgat Institute, where she studies Inflammatory Bowel Diseases (IBD). “This research is closer to the clinic and I like this translational angle. I use fresh human intestinal tissues to study the clonality of T cells in IBD. I do not exclude that, in the future, I will take the chance to apply deuterium labelling in this line of research.”

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A FUTURE HERITAGE What if Yvette van Kooyk’s wish to become an intern at Piet Borst’s lab at the Netherlands Cancer Institute Antoni van Leeuwenhoek had come true? Would she have seen her career skyrocket in the same way it has over the past decades? “I couldn’t possibly say, but what I do know is that I never regretted my decision to switch to Immunology. It’s such an important and rich branch of biomedical science”, says Van Loghem’s Laureate 2015.

Prof. Dr. Yvette van Kooyk Van Logh DC-SIGN, companion for life Yvette van Kooyk (Amsterdam, 1961) is Professor of Molecular Immunology at VUmc in Amsterdam. She studied Medical Biology because she was fascinated by the human body on a molecular level. She applied for an internship at the Molecular Biology department of the NKI, headed by Piet Borst, but found that there were no vacancies. She then decided to target the department of Immunology, where some molecular projects were available. “Cees Melief was growing dendritic cells in hanging drop cultures, that was all new and inspiring.” Her internship was the start of her interest in the complexity of the immune system. She became a PhD student at the NKI, where she worked with Carl Figdor to study communication and adhesion regulation of immune cells. “I then realized that I was in the perfect spot. I loved to do research on things that no one had mapped out before. To investigate subjects without knowing where you’re headed for. That’s where you make real discoveries. Immunology is the perfect branch for these fundamental discoveries.” She discovered that the process of cell adhesion was more ingenuous than scientists had thought until then. “The adhesion molecules have to change in order to bind counter-structures on target cells.” It is a regulated process that can be switched on or off, depending on the recognition of antigens.” She got her PhD cum laude for these findings.

DC-SIGN After she got her PhD, Van Kooyk joined Figdor in his move to Radboud UMC Nijmegen, where she became an assistant professor and continued her line of research. There, with her team, she made a breakthrough discovery. “I was looking into adhesion molecules and found a new receptor on dendritic cells. The receptor proved to have an important task in the immune system: it enabled binding of dendritic cells to T-cells, stimulating the immune system. The next thing we found, rather unexpectedly, was that this receptor could bind HIV. When HIV is transmitted sexually, the virus enters the mucus where there are no T-cells. There are, however, dendritic cells present. We’ve shown that with our receptor these dendritic cells can trap the

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virus and transport it to the lymph nodes, where they infect the T-cells. So, instead of what a dendritic cell normally does, which is to stimulate the immune response, it serves as a Trojan horse, transporting the virus.” The receptor was named ‘DC-SIGN’, which stands for Dendritic Cell-Specific HIV-1-Binding Non-integrin, a protein that enhances trans-infection of T cells.

“Immunology is the perfect branch for fundamental discoveries” Thus Van Kooyk entered the world of virology with a bang. “Newspapers headlined that thanks to this discovery HIV would be battled in a few years time. We persisted in saying this claim was unrealistic and would created false hope. Still, it was an important discovery.”

Glyco-immunology By 2001 she moved to VUmc Amsterdam, where she became a Professor and formed her own research group. “We discovered that DC-SIGN could also bind other pathogens, such as Mycobacerteria tuberculosis. This was due to sugar structures, that covered these pathogens: DC-SIGN would recognise these structures, bring the pathogens inside the dendritic cell, present them to T-cells and induce an immune response. This then made us wonder whether we could ‘artificially’ cover tumor antigens with such a sugar structure, in order to bind dendrititc cells through DC-SIGN and present it to T-cells to fight the tumour. With the help of VUmc colleagues specialised in sugar chemistry, we found out that indeed it worked out as we initially thought.” It made Van Kooyk’s group one of the world’s first group to study glyco-immunology. “The combination of immunology and sugar chemistry/biology is rare. It requires in-depth knowledge of both disciplines as well as expensive equipment. Also, implementing this kind of research on immune cells (such as dendritic cells) started to be very popular. It made this work interesting for

Yvette van Kooyk: “We’re not a bunch of nerds stuck in our laboratories, we are doing work that’s highly societally relevant” (Photo Bureau Lorient Communicatie)

hem Laureate 2015 many people; it’s not very appealing to be unique in a field that no one is interested in.” Luckily, though, the group made more important discoveries: “Sugar structures can carefully regulate the function of immune cells. We found that some sugar structures stimulate the immune system, while other sugar structures inhibit the immune system. In the case of a tumour, we want to use sugars that stimulate the immune system to fight harder. In the case of an auto-immune disease like rheumatic arthritis, or multiple sclerosis, we want to calm down the immune response. This opens the road to design new vaccines for tumours or auto-immune diseases based on the use of sugars. It is highly fascinating and promising.”

Advocate After thirty years of research, Van Kooyk is still enthusiastic about her work. “The human body is incredibly ingenious in organising its own defense mechanisms, it keeps me fascinated. It’s this respect for the human body which I try to convey to my graduate students when I explain the wonders of the immune system to them. It’s always a joy when I see it dawn in their eyes, when they start to understand the basics of immunology.” But it’s not just students who get energized by Van Kooyk. She is an impassioned advocate for the sake of immunology. “During the past decades, immunology research has contributed a lot to better treatments for patients suffering from many diseases, among other rheumatoid arthritis or cancer. Immunologists should get the word out, should be organized as immunologist in academia, and talk about these achievements, be proud of them. We’re not a bunch of nerds stuck in our laboratories, we are doing work that’s highly societally relevant.” The fact that she is this year’s Van Loghem’s Laureate makes her even more aware of her position as an ambassador for immunology. Is she proud of her election? “Yes, of course. I follow in the footsteps of globally respected predecessors. I’m all the more honoured since I’m the first ‘mother laureate’. It’s not always easy to combine a life in science with a family, but for me it worked out well. I’m aware of my blessings.” Alinda Wolthuis

December 2014

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A FUTURE HERITAGE

Poster Walk Session 1 A Wednesday, December 17 time 13:00 Topic Moderator Fehres, C.M. Sköld, A.E. Hutten, T.J.A. Bakdash, Ghaith Boks, M.A. Kuntal, Worah V. Halteren, A.G.S. van

Tumor Immunology Gerty Schreibelt C-type lectin mediated uptake of glycan-modified antigens by human skin DC subsets results in cross presentation to CD8 T cells Protamine-stabilized ssRNA as an ex-vivo stimulant of primary DC subsets Targeting CLEC12A leads to efficient antigen uptake and (cross-) presentation by human myeloid and plasmacytoid dendritic cells Synergistic activation of Mouse and human DC subsets by TLR agonists Targeting tumour antigen and adjuvant to human DC-SIGN dermal dendritic cells via glycan-modified liposomes as immunotherapy against cancer Proteomics and Transcriptomics interrogation of human blood DCs subsets uncovers overlapping and cell specific functions The presence of CXCR4 CD1a cells at onset of Langerhans Cell Histiocytosis is associated with a less favorable outcome

Wednesday, December 17 time 13:00

Topic Moderator Meyer, S. Matlung, H.L. Verheijden, G.F.M. Meesters, J.I. Singh, S.P. Simar Pal

Tumor Immunology Jeanette Leusen Molecular determinants dictating Type I & Type II classification of CD20 antibodies Neutrophils kill antibody-opsonized cancer cells by trogoptosis Toward clinical development of the novel HER2-targeting Antibody-Drug Conjugate SYD985 Effective Tumor Killing by Bispecific IgG1-Her2XCD3 Antibodies Generated by Controlled Fab-Arm Exchange Characterization of novel mouse cell lines to study the role of B-cell receptor signaling in development of Chronic Lymphocytic Leukemia

Topic Moderator De Mare-Bredemeijer, E.L.D. Litjens, N.H.R. Meinderts, S.M. Dalm, V.A.S.H. Roex, M.C.J. Markusse, I.M. Admiraal, Rick Vazirpanah, N. Timmermans , W.M.C. Bergen, C.A.M. van Schaarenburg, R.A. van De Mare-Bredemeijer, E.L.D.

Topic Moderator Hombrink , P. Broos, C.E. Habets, M.N. Amatngalim, G.D. Brugman, S. Jong, A.J. de Canbaz, D. Splunter, M.E. van

Topic Moderator Corneth, O.B.J. Trouw, L.A. Kempers, A. C. Falkenburg, W.J.J. Schaper, F. Land, J. Huizinga, H.G. Hafkenscheid, L. Aleyd, E. Hoelen , H.M.

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Wednesday, December 17 time 13:00

Clinical Immunology Ruth Fritsch CD8 CD244 T cells generated after liver transplantation are hyporesponsive to donor allo-antigen Allogeneic mature human monocyte-derived dendritic cells generate superior alloantigen-specific regulatory T cells in an IL-2-independent manner Phagocytosis and trogocytosis of red blood cells by human neutrophils Common variable immunodeficiency phenotype in Dutch patients with partial deletion of the long arm of chromosome 11 (Jacobsen syndrome) Streptamer Isolated Multi-Antigen Specific T Cells Contain Tumor Associated Antigen Reactive Donor T Cells as Elementary Component The additive value of nailfold videocapillaroscopy to disease-specific autoantibodies in organ screening in patients with systemic sclerosis Towards individualized dosing of Thymoglobulin® to optimize CD4 immune reconstitution, thereby improving survival in pediatric hematopoietic cell transplantation Short telomeres and mTORC1 pathway induction are an early feature of Gout and related to inflammatory, cardiovascular and renal morbidities B cell analysis reveals local and systemic B cell abnormalities in patients with Crohn’s disease Graft-versus-host disease separates from graft-versus-leukemia reactivity by magnitude, diversity and specificity of the CD8 T cell response C1q deficient individuals have a wide variety of clinical presentation, quality of life and life expectancy Human graft-derived mesenchymal stromal cells potently suppress allo-reactive t-cell responses

Wednesday, December 17 time 13:00

Mucosal Immunology Bart Everts The transcriptional profile of human CD8 lung resident memory T-cells Increased proportions of Th17 and non-classical Th1 cells in sarcoidosis lymph nodes Suppression of the Th17 response to S. pneumoniae by immunoglobulins Differences in innate immune function of bronchial epithelial cells from patients with chronic obstructive pulmonary disease (COPD) and non-COPD smokers T lymphocyte-dependent and independent regulation of Cxcl8 expression in zebrafish intestines T cells in the infrapatellar fat pad of osteoarthritis patients as a source of IL-6 in the joint Innate cytokine IL-33 has a role in induction of immunoglobulin production after inhalation of HDM in mice Characterization of tissue-specific homing marker expression on human lymphocytes

Wednesday, December 17 time 13:00

Autoimmunity Jantine Bakema Dysregulated BTK expression in peripheral blood B lymphocytes in systemic lupus erythematosus patients The Specificity of Anti-Carbamylated Protein Antibodies for Rheumatoid Arthritis in a Setting of Early Arthritis Anti-citrullinated protein antibody binding profile to fc gamma receptors Testing for Rheumatoid Factor reactivity against the four IgG subclasses reveals distinct patterns and fine-specificity Autoantibodies against high mobility group box 1 (HMGB1) in patients with SLE and incomplete lupus Predicting relapse in patients with Granulomatosis with Polyangiitis - the potential use of monitoring in vitro ANCA production A simplified protocol for the generation of anti-glycolipid antibodies in mice using liposomes Hyperglycosylation of ACPA-IgG variable domain modulates osteoclastogenesis in rheumatoid arthritis IgA and FcaRI induced tissue damage: mouse model for Linear IgA Bullous Disease Proinsulin degradation via the ERAD pathway; the production of auto-antigens in type 1 diabetes

December 2014

Topic Moderator Coorens, M. Brummelman, J. EIjk, M. van Zaal, A.

Wednesday, December 17 time 13:00

Hoonakker, M.E. Verhagen, L.M. Kraaij, M.D. Hartog, G. den Rijs, W. van Groot, A.M. de Altena, S.E.C. van

Innate Immunology Leendert Trouw Chicken Cathelicidin-2 (CATH-2) amplifies CpG-DNA-induced macrophage activation Immune modulation of neutrophil function by Bordetella pertussis Glycoprotein Nonmetastatic Melanoma protein B is a sensitive marker for lysosomal lipid overload in macrophages The anaphylatoxin C5a affects the pro-inflammatory potential of dendritic cells through alteration of TLR-induced p38/ ERK-CREB signaling Changes in Bvg status affect LPS structure and TLR4 signalling capacity of whole cell Bordetella pertussis vaccines Toward in vitro testing of whole-cell Bordetella pertussis vaccine quality Immunomodulatory effects of chicken cathelicidin in ovo and in vitro IgG from bovine milk may protect against RSV infection Polymorphisms in LPS-binding protein in relation to the susceptibility and clinical course of the Guillain-Barré syndrome Immunogenicity assessment in vitro of drug delivery systems Identification of putative B1 B-cells in cows

Wednesday, December 17 time 13:00

Topic Moderator Salerno, F. Heuvel, D. van den

Beek, J. van Westen , E. van Schellens, I.M.M. Jonge, J.M. de Rosendahl Huber, S.K.

Adaptive Immunology Ramon Arens Post-transcriptional regulation precludes aberrant cytokine production in memory T cells CMV- and EBV-associated CD8 T-cell expansions in young children do not impair naive T-cell subsets nor adaptive immune responses Dynamics of KLRG1 and IL-7Ra expression on virus-specific CD8 T cells during primary hCMV and EBV infections TCR priming drives IL-2 dependent post-thymic maintenance of naive CD4 T cells in aged humans Predicted Indirectly ReCognizable HLA Epitopes presented by HLA-DRB1 (PIRCHE-II) are related to HLA-antibody formation during pregnancy Cellular immune responses to pandemic influenza vaccination in a Dutch cohort of healthy individuals Characterization of T cell immunogenicity of pneumolysoid PlyD1 in mice Protective CTL do not shorten the lifespan of productively infected cells in HIV-1 infected individuals Pre-clinical evaluation of two live attenuated influenza vaccine strains against potentially pandemic H2N2 influenza virus Increased influenza-specific CD8 T cell immunity induced by non-natural modified T cell peptides

Wednesday, December 17 time 13:00

Remmerswaal, E.B.M. Van der Geest, K.S.M. Geneugelijk, C.C.A.

Topic Moderator Wentink, M.W.J. IJspeert, H. Koning, M.T. Slot, L.M. Muggen, A.F. Bovenkamp, F.S. van de Berkowska, M.A. Beek, A.A. van

Adaptive Immunology Annemiek van Spriel CD21 deficiency and CD19 deficiency: two defects in the same complex lead to different disease modalities DNA repair defects give new insights in antigen receptor repertoire formation Massive Parallel Sequencing of Full-Length B-Cell Receptor Sequences Reveals HLA-Dependent Shaping of the B-Cell Immune Repertoire Genome-wide analysis of somatic mutations in human B memory clones after successive tetanus toxoid immunizations Dynamics in B cell subset and B cell repertoire distribution during aging The development of IgG Fab glycosylation during antigen-specific immune responses Broad repertoire of antigen-specific IgM and IgG B cells is generated in response to RhD immunization Long-term probiotic intervention affects B cell differentiation in bone marrow of fast ageing Ercc1-/Δ7 mice

Wednesday, December 17 time 13:00

Topic Moderator Gram, A.M. Goedhart, M.J. Luk, F. Witte , S.F.H. de Angiolilli, C. Jong, S.E. de Zarcone, M.C.Z. Brouwers, H. Aalst, S. van Hoogduijn, M.J.

Infection & Inﬂammation Jorg van Loosdregt A novel EBV-encoded immune evasion molecule interferes with antigen presentation during the late phase of EBV infection The vascular bone marrow niche as immunological and hematopoietic hotspot Living and dead mesenchymal stem cells induce an immunosuppressive effect in an experimental sepsis model Persistent inflammatory phenotype of mesenchymal stromal cells, after removal of inflammatory stimulation Class I and class II HDACs differently contribute to the inflammatory status of rheumatoid arthritis fibroblast-like synoviocytes IgG galactosylation as a marker for inflammation and antigenic exposure of human populations Effect of rhinovirus on differentiated primary bronchial epithelial cells exposed to cigarette smoke A role for Adrenic Acid in the resolution phase of inflammation Adjuvants in vaccine-formulations change the influx of immune cells at the injection site Single cell analysis of the distribution of intravenously infused mesenchymal stem cells

Poster Walk Session 2 B Thursday, December 18 time 12.45 Topic Moderator Goeje, P.L. de Thijssen, R. Vasaturo, A. Poot, S.A.H. de Di Blasio, S.

Tumor Immunology Robbert Spaapen Prognostic value of myeloid-derived suppressor cells in non-small cell lung cancer Targeting BCR-independent proliferation of CLL cells Immune infiltrates impact on the prediction of prognosis and response to immunotherapy of melanoma patients A bioluminescent reporter to monitor killer cell-mediated delivery of granzymes inside tumor cells Taking the tumor micro-environment to the third dimension: a novel 3D immuno-competent human skin model of melanoma

December 2014

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A FUTURE HERITAGE Pont, M.J. Berrevoets, C.A. Vigneron, Nathalie Punt , S. Verdoes, M.

An alternative ITGB2 splice variant encodes a novel hematopoietic restricted minor histocompatibility antigen with therapeutic relevance Recurrence of melanoma following T cell treatment: continued antigen expression in a tumor that evades T cell recruitment Study of the unconventional processing of a MAGE-A4 peptide Galectin-1, -3 and -9 expression and clinical significance in squamous cervical cancer Highlighting Cathepsin S: A complementary toolkit for cathepsin labeling

Thursday, December 18 time 12.45

Topic Moderator Cornelissen, L.A.M. Kunert, Andre Waart, A.B. van der Sittig, S.P. Brakel, M. van Huijskens, M.J.A.J. Sebestyen, Z.S. Norde, W.J. Lamers , C.H.J Lamers , C.H.J

Tumor Immunology Pia Kvistborg Tumor sialylation negatively instructs T cell mediated anti-tumor responses while promoting tumor associated-Tregs Identification and optimization of patient-derived TCRs directed against MAGE-C2 positive melanoma and non-melanoma tumors Inhibition of Akt-signalling promotes the generation superior tumour-reactive T cells for adoptive immunotherapy A comparative analysis of T cell stimulatory and polarizing capacity of human primary blood dendritic cell subsets T-cell receptors coupled to CD28 and CD3e do not mis-pair with endogenous TCR-chains and mediate enhanced persistence and anti-melanoma activity Ascorbic acid induces proliferation and maturation of progenitor and mature T and NK cells in vitro Tumor cell recognition of g9d2TCR T cells is dictated via Rho GTPase by linking mevalonate pathway to BTN3A1 (CD277) Distinct patterns of co-inhibitory molecules co-expression and altered expression of signaling molecules in alloreactive CD8 T-cells in transplanted patients Gene-engineering and processing of human T-cells: GMP recommendations with focus on medium and large-scale culture Accumulation of immune effector cells in CSF following loco-regional oncolytic adenoviral therapy for glioblastoma in a clinical phase I/II trial

Thursday, December 18 time 12.45

Topic Moderator Lintermans, L.L. Scherpenisse, M. Koopman, G. Graav, G.N. de Van der Zee, M. Karahan , G.E Els, C.A.C.M. van Han, W.G.H. Heukels, P. Shi, X.L. Kemna, M.J. Keizer, M.P.

Clinical Immunology Virgil Dalm Decreased frequency of circulating CXCR3 CCR4-CCR6 CD4 effector memory T-cells in patients with Granulomatosis with polyangiitis Immunological biomarkers determining immune failure in HIV-infected individuals on ART Biomarkers of microbial translocation/immune activation are increased in HCV infected patients with liver fibrosis, but not in HCV infected chimpanzees CD28null effector-memory T cells: the Achilles’ heel of belatacept Transgenerational T cells: maternal care after birth with therapeutic potential in stem cell therapy Quantification of HLA class II-specific memory B cells in HLA-sensitized individuals Waning and ageing of pertussis specific humoral responses after symptomatic whooping cough Development of an IFNγ ELISPOT for the analysis of human T cell response against mumps Increased Bruton’s tyrosine kinase (BTK) -protein expression in B cells in patients with idiopathic pulmonary arterial hypertension CMV primary infection is associated with donor-specific T-cell hyporesponsiveness and fewer late acute rejections after liver transplantation Risk factors for a relapse at a rise of anti-neutrophil cytoplasmic antibodies Chemotherapeutic agent Asparaginase inhibits functionality of the complement system

Topic Moderator Emmens, R.W. Zonneveld, M.I. Jong, B.G. de Beek, L. van Luijn, M.M. van Bol-Schoenmakers , M.W.H.C. Willemsen, L.E.M. Beek, A.A. van Boerhout, E.M.

Topic Moderator Stoop, J.N. Wienke, J. Maria, N.I. Paulissen, S.M.J. Fleskens, V. Graeff, N. de Wolf, A.C.M.T. de

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Thursday, December 18 time 12.45

Mucosal Immunology Esther Nolte-Hoen C1-esterase inhibitor colocalizes with C3d and C4d and is produced locally in the myocardium after acute myocardial infarction Human breast milk contains various Extracellular Vesicle subpopulations with immune modulatory properties Dissecting abnormal immunoglobulin responses in destructive periodontal disease Obesity related IgG antibodies do play a role in the development of insulin resistance, however not via the Fcγ-receptor pathway Cerebrospinal fluid markers chromogranin A and clusterin are key components of white matter inflammation in multiple sclerosis brain Interaction between intestinal epithelial cells and intraepithelial lymphocytes in relation to food allergic sensitization Apical exposure to dietary non-digestible oligosaccharides and bacterial CpG DNA suppresses Th2 type chemokine release by activated intestinal epithelial cells Ercc1-/Δ7 mice are a suitable model for ageing of mucosal immunity and microbiota Effects of administration routes of a subunit vaccine on the quantity and quality of antibody responses in bovine

Thursday, December 18 time 12.45

Autoimmunity Sytze de Roock Carbamylation of self-proteins facilitates the break of tolerance at a T-cell level Mesenchymal stromal cells suppress synovial fluid-derived T cells from Juvenile Idiopathic Arthritis patients in vitro Elevated IDO-activity and KMO-expression in Interferon positive Primary Sjögren’s syndrome patients is associated with increased CD25hiFoxP3 Tregs: a skew towards neurotoxicity? Prominent role of pathogenic CCR6 Th17 cell populations in the pathogenesis of ACPA patients with RA Phenotypic, functional and molecular characterization of CD4 CD45RO CD25highCD127low regulatory T cells from patients with rheumatoid arthritis Understanding the role of autophagy in T cells in Juvenile Idiopathic Arthritis Immunomodulatory CD4 T cell epitope in murine experimental arthritis is cross-responsive and functional in the context of human MHC

December 2014

Sorvillo, N. Kraaijvanger, I. Nierop , G.P. van Hähnlein, J.S Blokland, S.L.M.

Topic Moderator Hsiao, C. Burm, S.M. Pinelli, E.

Restricted HLA-DRB1*11 dependent peptide presentation of ADAMTS13 by antigen presenting cells provides novel insight into the etiology of acquired TTP Influence of S100 proteins on T cell differentiation in systemic juvenile idiopathic arthritis (sJIA) No evidence for CNS specific T-cells in cerebrospinal fluid of multiple sclerosis patients Distinct expression of T-cell homing molecules in human autoimmune lymph node stromal cells upon TLR-3 triggering Increased serum IgG levels in Sjögren’s Syndrome patients are associated with downregulation of the MTORC1 pathway in B-cells Thursday, December 18 time 12.45

Haar, N.M. ter Heeres, M. Groot Kormelink, T. Hartkamp, L.M. Golbach, L.A. Thielen, A.J.

Innate Immunology Garcia Vallejo The adhesion-G protein-coupled receptor GPR56 inhibits human natural killer cell cytotoxicity Key differences in inflammasome-mediated activation between tissue-resident and peripheral innate immune cells Naturally occurring Bordetella pertussis isolates with altered lipooligosaccharide structure fail to fully mature human dendritic cells Combining IL-12 with IL-15 drives the generation of NK cells with superior maturation potential and anti-leukemic activity Potentiating complement factor H surface regulation with a monoclonal antibody NK Cell Dynamics in Chronic Hepatitis B Patients Associated with HBsAg Clearance after Combination Treatment with Peginterferon alfa-2a and Adefovir Interleukin-18 production upon S100 stimulation is reduced in systemic onset Juvenile Idiopathic Arthritis Neutrophil kinetics after major trauma Analysis of release and composition of extracellular vesicles derived from unstimulated or IgE-activated mast cells Bruton’s tyrosine kinase (Btk) drives IL6 production in human macrophages and this is independent of its catalytic activity Low-frequency electromagnetic field exposure enhances in vitro neutrophil extracellular trap formation In vitro complement activation on the membrane of stored red blood cells

Thursday, December 18 time 12.45

Cany, J. Pouw, R.B. Stelma, F.

Topic Moderator Lighaam, L.C. Dankers, W. Muris, A.

Vroman, H. Kragten, N. A. M. Nanlohy, N.M. De Groot, N.G.

Adaptive Immunology Yuri Souwer In vitro IL-10 induction is a transient trait of human activated B cells and does not define regulatory B cells Molecular mechanisms underlying 1,25(OH)2D3 mediated suppression of Th17 cell activity The relation between vitamin D and regulatory lymphocytes in multiple sclerosis patients; preliminary data on baseline measurements from the SOLARIUM-study Human bone marrow mesenchymal stromal cells display immunomodulatory properties and can be licensed by IFN-γ stimulation Activated dendritic cells and IL-17Ra signaling are crucial for the presence of RORγT IL-17A-producing γδ T cells in lungs Expression regulation of Hobit as a tool to study the formation of quiescent effector CD8 T-cells TCRzeta expression on T cells: a novel marker for T-cell effector function Functional plasticity of the MHC class I region: Duplicated B-locus compensates for the loss of C

Thursday, December 18 time 12.45

Cornelissen, A.S.M.

Topic Moderator Dekkers, G. Grosserichter-Wagener, C. Bartol, S.J.W. Unger, P.A. Bahjat, M. Sonneveld, M.E. Herwijnen, M.J.C. van

Topic Moderator Garde, M.D..B van de La Distia Nora, Rina Verreck , F.A.W. Nothelfer, K. Scholzen, A. Hovingh, E.S. Riet, E. van

Adaptive Immunology Hanna IJspeert Dissection of IgG effector functions by glycoengineering Defective molecular maturation of IgA but not of IgG in patients with IgA deficiency Extensive somatic hypermutation in patients with chronic autoinflammatory disease IL-4, an essential component for IgG4 B cell switching but not for IgG4 memory reactivation NF-kB signaling prevents DNA damage in pre-B cells by suppressing RAG1/2 expression and activity Glycosylation patterns of antibodies against platelets in different phases of pregnancy In-depth proteomic analysis of human breast milk reveals a specific association of immuno-modulatory proteins to distinct macromolecular structures in milk Infection & Inﬂammation Cécile van Els Kupffer cells and inflammatory monocytes are the central players during early virus-induced liver inflammation Clinical manifestations of patients with intraocular inflammation and positive QuantiFERON-TB gold in-tube test in a country nonendemic for tuberculosis Pulmonary BCG provides local protective effect in rhesus macaques that are not protected by standard intra-dermal BCG vaccination B lymphocytes undergo TLR2-dependent apoptosis upon Shigella infection Humoral and cellular immune responses in Dutch and Tanzanian volunteers after intradermal administration of aseptic, purified, cryopreserved Plasmodium falciparum sporozoites Circulating microRNAs as potential biomarkers associated with protection against pertussis Molecular Signatures of the Evolving Immune Response in Mice following a Bordetella pertussis Infection

Poster Walk Session 3 C Friday, December 18 time 12.45 Topic Moderator Horrevorts, S.K. Zhou, G. Plantinga, M.C.

Tumor Immunology Wilfred Germeraad Skin-resident antigen-presenting cell targeting for the treatment of cancer Combined treatment with soluble GITR-ligand and anti-CTLA-4 antibody completelyabrogates immunosuppression mediated by human liver tumor-derived regulatory Tcells Cord blood-derived dendritic cell vaccination after hematopoietic cell transplantation in children with AML; a pre-clinical study

December 2014

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A FUTURE HERITAGE Pavert, S.A. van de Schetters, S.T.T.

Gene-therapy for lymphedema Development of new glycan-based nanomedicines to induce DC-mediated T cell responses against glioblastoma tumors

Friday, December 18 time 12.45

Topic Moderator Molen, R.G. van der Lamers , C.H.J Theunissen , P. Berge, J.C.E.M. ten Boor, P.P.C Meijers, R.W.J. Taams, N.E. Kannegieter, N.M. Hiemstra, I.H.

Medical Immunology Hans Jacobs Anti-SSA antibodies are present in immunoglobulin preparations Graft-versus-graft reactivity early after double umbilical cord blood transplantation is associated with anti HLA class II reactivity by CD4 T-cells Normal b-cell recovery in children treated for b-cell precursor acute lymphoblastic leukemia Anti-retinal antibodies in ocular diseases The Jak1/3 inhibitor tofacitinib drives plasmacytoid dendritic cells into apoptosis and inhibits their function Thymic output prior to kidney transplantation is associated with the risk for acute rejection Diagnostic and prognostic value of serum anti-GD1b antibodies in immune-mediated neuropathies The effects of tacrolimus, a calcineurin inhibitor, on the p38 MAPK signaling in monocytes and T-lymphocytes of transplant patients Dexamethasone promotes granulocyte mobilization by prolonging G-CSF half-life in healthy donors for granulocyte transfusions

Topic Moderator Cornelissen, F. Girard-Madoux, M.J.H. Karrich, J.J. Brugman, S. Bar-Ephraim, J.E. Bastiaans, J. Bergen, Jeroen van Meddens, C.A. Liu, K.

Topic Moderator Tijhaar, E.J. Teodorowicz, M. Wagenaar, L. Rijt, L.S. van Tindemans, I. Vroman, H. Vlugt, L.E.P.M. van der Westerlaken, M. Heeringa, J.J. Gent, R. van

Topic Moderator Waterborg, C.E.J. Lebre, M.C. Freitas Alves, C.H. Koenders, M.I. Virakul, S. Di Ceglie, I. Virakul, S. Huitema, L.F.A. Affandi, A.J. Heij, Femke de Muris, A.

Topic Moderator Sprokholt, J.K. Ruben, J.M. Garcia Vallejo, J.J. Tok, M.N. van Jacobino, S.R.

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Mucosal Immunology Sharon Veenbergen Dendritic cells, T cells and ILC3 cooperatively regulate S1P biosynthesis by lymphatic endothelial cells IL-10 control of CD11c myeloid cells is essential to maintain immune homeostasis in the small intestine and colon Plet1 controls steady state migration of dendritic cells in the intestine T lymphocytes control microbial composition by regulating the abundance of Vibrio in the zebrafish gut Homing of human peripheral blood innate lymphoid cells in homeostasis Thrombin-induced retinal pigment epithelium (RPE)-monocyte interaction results in increased macrophage activity ILC-like lymphomas in refractory celiac disease type II respond to multiple common γ-chain cytokines and are sensitive to JAK-inhibitors Searching for novel IBD genes using 3D nuclear interactions The phenotypic and functional analysis of human fetal gut dendritic cells

Friday, December 18 time 12.45

Allergy Huub Savelkoul Identification and production of recombinant Culicoides obsoletus allergens for diagnosis and immunotherapy of Insect Bite Hypersensitive horses Soy processing induce formation of Maillard-type neoallergens with high allergenic potential Humoral and cellular characterization of immunotherapy in a peanut allergy mouse model Birch pollen immunotherapy in mice: inhibition of Th2 inflammation is not sufficient to decrease airway hyperreactivity Notch Signaling in CD4 T Cells is Required for the Induction of Allergic Asthma in Mice Activated CD103 conventional DCs have a tolerogenic role in allergic asthma Reduced B-cell IL-10 in response to LPS in Allergic Asthma patients: an impaired Breg function? A functional SNP in SIRL-1 associates with Atopic Dermatitis Differentiation pathways of blood and mucosal IgE plasma cells Macrophages initiate the anti-inflammatory IL-33-Th2 pathway induced by intravenous immunoglobulin therapy in humans

Friday, December 18 time 12.45

Autoimmunity Kris Reedquist Unexpected protective role of TLR4 on the splenic myeloid population in experimental arthritis CD141 DCs are present at the site of inflammation in rheumatoid arthritis and psoriatic arthritis, and promote inflammation via IFN-γ1/interleukin-29 Role of ß-catenin signaling to control dendritic cell function in collagen-induced arthritis Synergism between GM-CSF and IL-17 Causes Enhanced Joint Pathology via the Production of IL-6 and IL-23 Platelet-derived growth factor enhances adipogenesis by orbital fibroblasts Fc gamma Receptors enhance development of bone erosion in experimental arthritis by increasing synovial inflammation and activation of osteoclasts Targeting fibrosis with somatostatin analogues Extrathymic Autoimmune Regulator (AIRE) expression in rheumatoid arthritis synovial tissue CXCL4 Promotes Fibrosis by Increasing Expression of Extracellular Matrix–Modifying Factors and by Facilitating Epithelial/ Endothelial-Mesenchymal Transition HLA-DRB1*11 transgenic mice provide a model system for acquired thrombotic thrombocytopenic purpura Vitamin D status does not influence disability progression of multiple sclerosis patients over three years follow-up

Friday, December 18 time 12.45

Innate Immunology Erik Lubberts RIG-I like receptors sense dengue virus replication in dendritic cells and limit infection via type I interferon responses Interaction between plasmacytoid DC and renal epithelial cells; at the crossroad of allo- and anti-viral-immunity Traveling the endosomal pathway in dendritic cells with the help of DC-SIGN and TLRs Innate immune stimulation triggers altered IL-1a/b gene expression and experimental spondyloarthritis in HLA-B27/huß2m transgenic rats Human Amniotic Fluid Contains Maternal IgG Antibodies That Bind And Neutralize RSV

December 2014

Broeke, A.G. ten

Aa, E. van der Rachmawati , D. Wang, Q.

Regulation of the Fcalpha-receptor by Glycogen Synthase Kinase-3 and Protein Kinase C7, during cytokine-mediated inside-out signalling Neutrophils characterized by excellent intraphagosomal bacterial containment and defective killing: a detrimental combination in chronic granulomatous disease (CGD) Interaction of BDCA3 dendritic cells with HBsAg specifically inhibits IFN-lambda production Capacity of metal-ions activate human brain-microglia Age-dependent alterations of monocyte subsets and their response to pattern recognition receptor activation

Friday, December 18 time 12.45

Leliefeld, P.H.C.

Topic Moderator Griffioen, M. Scheenstra, M.R. Platteel, A.C.M.

Hartholt, R.B. Els, C.A.C.M. van

Adaptive Immunology Sonja Bushow Natural HLA class II ligands can be transferred between viable cells by extracellular vesicles Gata1 has an intrinsic role counteracting and fine tuning DC activation and migration Epitope determination by DNA tattoo immunization and immunogenicity enhancement by modulating antigen processing of three Mycobacterium tuberculosis proteins Comparative evaluation of the Cation Adjuvant Formulation CAF01 versus CAF09 in non-human primates Immunogenic and tolerogenic dendritic cells release extracellular vesicles with distinct immune-relevant protein profiles Investigation of a live attenuated and an adjuvanted-split vaccine against potentially pandemic H7N9 influenza in an intra-tracheal ferret challenge model Enhanced FcγR-dependent uptake of blood coagulation factor VIII containing immune complexes by antigen presenting cells Text mining of literature databases for knowledge-based rational vaccine design using correlates of protection (COPs)

Friday, December 18 time 12.45

Verreck , F.A.W. Grein, S.G. van der Spijkers, S.N.M.

Topic Moderator Gieselbach, R.J. Sarrami Forooshani, R. Vissers, M.E.P. Wicht, O. Sabogal Piñeros, Y.S. Hertoghs, Nina Jans, J. Mouser, E.E.I.M. Guichelaar, T. Heiden , M. van der

Infection & Inﬂammation Ingrid Schellens Determinants for attenuation of recombinant RSV-X Human immature Langerhans cells restrict transmission of CXCR4-using HIV-1 Antibody-dependent secretion of innate CXCL10 during RSV infection of infant immune cells Maternally derived antibodies do not correlate with protection against severe RSV disease in young infants Eosinophils display direct antiviral activity to respiratory viruses HIV-1 actively suppresses Dendritic Cell Maturation SIGLEC-1 mediates inhibition of T cell proliferation after RSV infection Soluble egg antigen (SEA) of Schistosoma mansoni modulates dendritic cell-T-cell interactions which interferes with Human Immunodeficiency Virus 1 (HIV-1) infection Altered regulatory T-cell population and frailty at old age in the cotton rat model of respiratory syncytial virus infection CMV-specific antibody levels increase with age but do not correlate with VZV- specific antibodies

Friday, December 18 time 12.45

Topic Moderator Tak , T. Lintermans, L.L. Frodermann, Vanessa Marsman, G. Kuipers, M.E. Back, D.Z. de Reijmers, R.M. Schie, K.A.J. van Rondaan, C.

Herpers, R.L.J.M. Wiegertjes, G. Pico-Knijnenburg, I. Barendregt, B. Maracle, C.X. Schijf, M.S. Bruggeman, C.W. Guislain, A. Chouri, E. Unger, W.W.J. Kostadinova, A.I. Dinther, D. van De Rond , L. Hombrink, P. Balraadjsing, P.

Infection & Inﬂammation Nienke Vrisekoop Immune suppressive neutrophils have an interferon response profile and a reduced capacity for protein synthesis Kv1.3 blockage modulates CD4 effector memory T-cell activity of patients with Granulomatosis with polyangiitis in vitro Proteasomal Inhibition Reduces Atherosclerotic Lesion Development Removal of nucleosomes from late apoptotic cells by the plasma protease FSAP enhances efferocytosis by macrophages Various Life Stages of Schistosoma mansoni Release Extracellular Vesicles Immune Adherence Clearance is dependent on RBC adhesion molecules Regulation of dermatan sulfate glycosaminoglycans in the control of the lymph node conduit system function Concentration, ratio and IgG subclass influence size of immune complexes formed between drug and anti-drug antibodies Subclinical reactivations of the varicella-zoster virus in systemic lupus erythematosus patients Poster without presentation Automated indirect immunofluorescence analysis of antinuclear antibody (ANA) screening Fish Il10 has anti-inflammatory activities on phagocytes, promotes proliferation of memory T cells and regulates B cell differentiation Insertion of an Alu transposable element in RAG1 as diease-causing mutation in SCID The presence of T-cells does not exclude the diagnosis of SCID Non-Canonical NF-kB signaling enhances angiogenesis in a novel 3D model of Rheumatoid Arthritis synovial inflammation Salivary Antibody Responses to a Meningococcal Serogroup C Conjugate Booster Vaccination in Adolescents FcγR expression on human splenic macrophages The functionality of tumor-infiltrating lymphocytes can be potentiated by relieving post-transcriptional regulation Targeting microRNAs in plasmacytoid DCs to predict and cease Systemic sclerosis development Regulated expression of sialic acids on antigen or tumor cells alters dendritic cells to impose tolerance on T cells Hydrolysis and peptide profiling crucial for choosing hypoallergenic milk protein formula suitable for tolerance induction and prevention of allergic sensitization Development of a CD169 macrophage-based vaccination strategy for melanoma Elevated IgG4 reponses in children reporting local side effects after the 5th DTP vaccination at 4 years of age Epigenetic histone modification of interferon-gamma locus is dynamic during T-cell differentiation Dendritic cell induced T-cell responses to biomaterials in presence of staphylococcal infection

December 2014

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Janssen in Immunology

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