IMMUUN Volume 3 - Issue 1 - March 2014 -
for every professional in the immunology chain
Ronald van Ree:
“A safer life for food allergy patients”
Meet the speakers at the NVVI Lunteren meeting
THEME allergy
Science across borders “Chemical Immunology
Lustrum packed with activities
is a missink link”
Your Power for Health
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COLOPHON 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 Foto front page Jeroen Oerlemans 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.
IMMUUN March 2014
contents
8 4 11 24 27 29
Science across borders
Column News
Chemical Immunology
Awards & Grants
Agenda
Lustrum
Heritage linked to future
Arnoud Gerritsen, Genmab:
Preview Lunteren
Mucosal Immunology
Antibodies show their versatility
12 15 20 18 22 Theme Allergy
Edward Knol Better diagnosis and treatment
Resarch Luud Gilissen Focus on quality of life
The clinic / Research Hans de Groot
Ronald van Ree
Allergy melts under the tongue
Safer life for food allergy patients
Mart Rijnen ThermoFisher:
Supporting clinical demand
dutch society for immunology
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Column
Inspire each other Allergies have a severe impact on a person’s life and on society as a whole. Many people suffer full time from allergies. Others suffer from allergies ‘only’ part of the year, for instance when hay fever attacks them. This spring edition of Immuun is themed ‘allergies’ – which is of course not
NWO Vici grants: Success for immunology applications NWO has awarded the annual Vici Grants to 31 leading scientists. Each researcher will receive 1.5 million euros for his or her research (team). All in all, 202 researchers applied for a Vici, so 15% of them actually received a grant. Criteria were the quality of the researcher and the innovative character plus the scientific impact of the research proposition. Many of the grants relate to current societal issues, such as the risk of flooding, cyber crime and health issues. A remarkable number of the grants was awarded to immunologists or scientists bordering on immunology.
coincidental.
Cancer research
Maybe you are not researching nor suffering from
Professor Huib Ovaa, researcher at Antoni van Leeuwenhoek (AvL), Amsterdam, is one of the scientists to receive a Vici grant. Huib Ovaa focuses on proteins which regulate cell processes (ubiquitine). If regulation fails, this may cause diseases such as cancer. Ovaa will assemble a molecular toolkit that enables scientists to study the processes that involve ubiquitine in detail. Ultimately this will help to develop new therapies. His colleague Jos Jonkers, by the way, also received a Vici for non-immunologic research into hereditary breast cancer. The Vici awarded to the cancer research by Professor Jolanda de Vries, Radboud UMC does involve immunology. Her aim is to develop an effective vaccine against cancer. Dendritic cell therapy is based on the knowledge that dendritic cells play a central role in immune reactions. This therapy can be successful, but in many cases it is not (yet). This research tries to unravel what happens in the patient with cancer when dendritic cells are injected. De Vries and her team in this way hope to get specific knowledge on the processes involved and on the required composition of a cellular vaccine.
allergies. Maybe this might induce you to lay aside this edition of Immuun. That would, however, be a mistake. It is always worth your while to inform yourself on fields related to your own research. Allergies are certainly no exception to this principle. Basic processes that apply to allergies, could be very relevant to other diseases as well. With allergies, the immune system is working too hard. This might give us insights in how we could manipulate the immune system when a better working system is needed, for instance when we think about immunotherapy for cancer. The NVVI (Dutch Society for Immunology) strongly supports the ambition of immunologists to break down the walls and to inspire each other. We hope that Immuun contributes to this.
Prof. Dr. Reina Mebius, president of NVVI
Chronic inflammation D.L.P. Baeten PhD, at the UvA Amsterdam receives a Vici for his research on tissue inflammation. Chronic inflammation leads to a loss of structure and function of tissues and organs in many diseases. Tissue damage is considered to be one of the most important consequences of inflammation. Based on findings in certain types of rheumatoid arthritis, the project researches the reverse mechanism: why and how does the tissue drive the inflammation? Professor Gijs van den Brink, AMC, also receives a Vici. Our intestines normally tolerate the presence of billions of peaceful bacteria. This, however, requires adaptations that may provoke chronic inflammatory bowel disease (IBD) and colon cancer. In their Vici project, Van den Brink and his team will study the bowel cells that seem to play a central role in the process. The third Vici for immunology-related inflammation research also goes to Amsterdam. Marjolein van Egmond PhD investigates intestinal bacteria at the VUmc. Our intestines are home to many bacteria. A healthy immune systems prevents us from falling ill thanks to these bacteria, whereas deviating immune reactions may lead to chronic inflammation of the intestinal track. Van Egmond’s research focuses on the role of the antibody IgA in this delicate balance. (Sources: AVL, NWO)
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NEWS: AWARDS & GRANTS editorial
Rheumatologist Josef Smolen honorary doctor On February 7th 2014, the Austrian rheumatologist Josef Smolen received the honorary doctorate of the Leiden University for his impressive contribution to the field of rheumatoid arthritis. Professor Tom Huizinga acted as his honorary promoter. The acclaimed rheumatologist Josef Smolen is known as a multi-faceted, extremely productive, inspiring and innovative scientist. He investigated the role of TNF in relation to damage to the joints and inflammations. From the start, Smolen was involved in developing TNF-blocking therapies. This has led to breakthroughs in the treatment and prognosis of rheumatoid arthritis and other inflammatory diseases, such as uveitis, Crohn and Bechterew. Pain reduction is a priority. His major research activities relate to the analysis of auto-antibodies, studies on cytokines in body fluids and in tissue, studies on T cell activation by conventional and self-antigens; studies of cell-cell interactions (mainly investigations of interactions of dendritic cells with T cells), cloning of auto-reactive T cells and studies on apoptosis in autoimmunity and health. Smolen revived the European League Against Rheumatism (EULAR), leading to a better classification of rheumatic diseases, to treatment guidelines and to European research projects. Researchers of the LUMC participate in these European research programmes. Smolen is president of the Department of Rheumatology and of the Department of Medicine 3 at the Medical University of Vienna, and is vice-president of the Center for Rheumatic Diseases of Hietzing Hospital in Vienna.
This edition of Immuun is the first edition to be published in English. We are highly interested in your comments on this change. Please take a minute to fill out the questionnaire on page 31, scan it and send it to info@lorient.nl.
(Photo Wikipedia)
Ton Schumacher (AVL) receives two million euros for immunotherapy Professor Ton Schumacher of Antoni van Leeuwenhoek (AVL), Amsterdam, will receive the Koningin Wilhelmina Onderzoeksprijs for his leading research in immunotherapy. The prize, awarded by KWF Kankerbestrijding, amounts to two million euros. Immunotherapy is a promising development for the treatment of cancer. Science magazine claimed it to be the breakthrough of the year 2013. Cancer immunotherapy aims to induce the patient’s immune system to clean up the cancer cells. The approach is still in its infancy. Today, there is immunotherapy available for metastasized melanoma, a severe type of skin cancer. In the upcoming years, research will probably develop immunotherapy for patients with kidney cell cancer or lung cancer also.
Controlled manner Unfortunately, not all patients respond well to immunotherapy. Also, the therapy holds the risk that the immune system runs amuck: it not only attacks cancer cells, but also healthy tissue, causing side effects that are uncalled for. Prof. Ton Schumacher: “How does the body distinguish between healthy cells and tumor cells? What cell properties of a cell enable the immune system to distinguish between good and bad? That is the object of our research. We hope to develop a way to activate the immune system in a more controlled manner, for both patients who do, and patients who do not spontaneously develop an immune response to cancer cells.” (Source: AVL)
(photo Bureau Lorient Communicatie)
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UMC Utrecht joins FOCIS global network for immunology The UMC Utrecht is acknowledged as a Center of Excellence by the Federation of Clinical Immunology Societies (FOCIS). FOCIS represents over 65,000 clinical and preclinical researchers worldwide, working on diseases which involve the immune system, such as allergies, asthma, rheumatic diseases, cancer, infections and organ transplants. FOCIS facilitates education as well as a platform that reinforces treatment and diagnosis of these affections in a multidisciplinary way and through international collaborations. The UMC Utrecht is the 70th Center of Excellence within FOCIS, the 20th in Europe and the 2nd in The Netherlands. Professor Timothy Radstake, Edward Knol PhD and Professor Erik Hack constitute the board of the Utrecht FOCIS Center of Excellence. Timothy Radstake says the denomination can be seen as a recognition of the quality and ambitions of the UMC Utrecht in the field of infections and immunology. “It helps us to profile the UMC Utrecht at the global level and positions us perfectly for collaboration, exchange of top researchers and knowledge, and participation in multi-centre studies to improve diagnosis, monitoring and treatment of patients who suffer from diseases of the immune system.”
Edward Knol PhD and Professor Timothy Radstake
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Former Crucell man joins to-BBB Leiden based biotechnology firm to-BBB appoints former Crucell manager Leon Kruimer as its new financial manager. To-BBB with about twenty employees, expects to launch its first medicine on the market in 2017. In 2014 the company plans to start preparations for a stock market entry. To-BBB specialises in methods to get drugs across the blood brain barrier. Normally, drugs cannot pass this barrier which keeps the delicate brain free from harmful substances and organisms. To-BBB ‘packages’ drugs inside nano-size lipid particles coated in antioxidants.
Micro-needle vaccination to break with limitations of injected vaccines Intravacc, the Institute for Translational Vaccinology in Bilthoven and MyLifeTechnologies, a Dutch drug delivery technology company in Enschede, announced the start of a cooperation to develop intra-dermal vaccination technology. In this cooperation, MyLife Technologies and Intravacc combine their respective know-how of micro-needle technology and vaccine technology. The partners aim to develop a safe micro-needle-patch combination loaded with vaccine. This combination specifically targets the dentritic cells in the skin. Dendritic cells can induce protection against disease. Intra-dermal delivery of vaccines has several advantages over conventional intramuscular administration of vaccines: it is painless, has increased efficacy and induces dose-sparing. Furthermore, it is easy to use and may thus allow vaccine self-administration. Finally, it has increased stability, obviating the need for cold storage of vaccines, which is specifically important for vaccination in developing countries. Intradermal vaccination technology therefore might mean an important step forward in the development of safe and effective vaccines.
news editorial
MIMETAS and Galapagos to develop human disease models on-a-chip MIMETAS and Galapagos will collaborate to develop miniaturized 3D cell culture models that mimic specific aspects of human diseases. These models will be applied to the identification and improvement of novel compounds. Richard Janssen PhD, Senior Director of Target Discovery at Galapagos, states: “The MIMETAS platform is the first to combine organ-on-a-chip technology with our high throughput screening of primary human cells. As we see it, OrganoPlates™ make 3D culture as straightforward as traditional cell culture.” According to Jos Joore PhD of MIMETAS, the agreement is a crucial step forward for MIMETAS and for the organ-on-a-chip field in general. “Galapagos sets an example as one of the first drug discovery companies worldwide to implement innovative organon-a-chip technologies. This collaboration helps us to further validate our technology, by enabling development of unique novel compounds with unique human disease models.”
Galapagos builds platform for fibrosis research The Flanders ‘Agentschap voor Innovatie door Wetenschap en Technologie’ (IWT) awards a 2.3 million euros subsidy to Galapagos NV for fibrosis research. Galapagos already has a portfolio of fibrosis targets and molecules. The main goal of the IWT subsidy is to enable building a platform, based on the combined expertise of Galapagos and a number of university laboratories. In a two year project, Galapagos will build a research platform with integrated knowledge of fibrosis diseases, such as lung, kidney, liver and skin fibrosis. The new platform will contribute to drug development. Academic partners are Professor Wuyts of Pneumology at KU Leuven, Professor Naesens and Professor Kuypers of Nefrology at KU Leuven, Professor Van Vlierberghe of Hepatology Gent University, Professor F. De Keyser and Dr Smith, Scleroderma, U Gent, and Professor Van Grunsven of Hepatology at VU Brussel.
BiocerOX and Janssen develop monoclonal antibody BiocerOX Products B.V., a subsidiary of biotech company Bioceros, has granted Janssen Pharmaceuticals, Inc. exclusive worldwide rights to develop a monoclonal antibody directed at an immune checkpoint modulator. Bram Bout, CEO of Bioceros, said: “The impressive expertise of Janssen’s R&D provides for professional development of the asset.” Bout is proud that Bioceros has been able to generate IP to protect high value therapeutic monoclonal antobodies.
AngioVacs and VUmc Cancer Center Amsterdam determined to starve tumour blood vessels The Amsterdam VU medical center will test a vaccine by the new company AngioVacs that restrains the growth of blood vessels in tumours. Since a tumour needs new blood vessels to be able to grow, this promises to effectively stop tumour growth. Surgery, radio therapy and chemo therapy can all be applied to treat cancer. Prof. Arjan Griffioen (VUmc Cancer Center Amsterdam) is convinced that now the concept of chemo therapy is nearly at its point of culmination, new roads have to be explored to enable further progress against cancer. “Small steps remain possible, but if we want a big leap forward, we must change our tactics”, he says. A new approach is to starve the tumour. This can be done by restraining the growth of blood vessels in the tumour. If no new blood vessels can develop, the tumour cannot grow any further. “Medication that restrains the growth of blood vessels in the tumour already exists, but this medication induces a resistance. The tumour adapts itself and the medication is no longer effective”, says Prof. Griffioen, also founder of AngioVacs BV. Griffioen and his colleagues apply a new approach. They remove endothelial cells – which cover the inside of vessel walls - from a tumour and compare the genetic profile to the endothelial cells of healthy blood tissue. Comparison of the respective genetic profiles brings genetic differences to light, which may be useful for developing medication. “Thanks to the latest gene sequencing technology, we have found a number of possible targets that we will now investigate.” To this end, AngioVacs received a 100.000 euros grant of the Ministry of Economic Affairs and VUmc.
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‘Gravity Grant’ for Chemical Chemistry enters the immu The field of Chemical Immunology doesn’t really exist yet. The more impressive is the fact that the new Institute for Chemical Immunology (ICI) received a ‘Gravity Grant’ of 27.6 million euros for ten years. This is a structural investment in immunology in The Netherlands. Immunologist professor Jacques Neefjes Ph.D. of the NKI and Hermen Overkleeft Ph.D, professor of bio-organic synthesis at Leiden University, explain why this field creates many new opportunities for immunology. Neefjes: “It is a new and necessary step. Immunology without chemistry will hamper the development of many new treatment options in the clinic. You need chemistry to make medication. And chemistry will get a lot of inspiration from the immunology domain.”
Neefjes: “ICI could lead to a number of phase I clinical candidates, and beyond.” (Photo Bureau Lorient Communicatie)
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“Chemical immunology is the identification of an immunological problem, for which the solution can be found with the help of fundamental chemistry”, Neefjes explains. “For a complete chain of activities, from fundamental immunological knowledge towards its application in the patient, chemistry is usually indispensable.” Whereas biology in general follows an increasingly more molecular approach, for many immunologists it remains unusual to consider the atomic aspects of their cell biological processes. Neefjes: “Until now, the application of chemical knowledge into the field of immunology has at best been on a one-to-one basis and haphazard, neither structural nor very methodical. Steps of immunologists into chemistry have been attempted, but without the proper chemical knowledge it is hard to methodically work towards molecules that can make the difference in manipulating the immune system. The number of drug-candidates going from fundamental immunological studies into translation into clinical trials is far too low at the moment. It doesn’t live up to its full potential. The ICI intends to change this. In addition, chemistry can provide immunologists with tools that will give them a unique position in the scientific competition, simply because others do not have these.” The creation of the field of chemical immunology is vital to Neefjes and Overkleeft. “We are highly ambitious, as we know that immunologists and chemists mutually have a lot to offer. It is a bonus that all ingredients are already there. Now we have to assemble them in a new field in which these activities are integrated. In this new field there is at present quite a lot of low-hanging-fruit for picking. The new combination of fields might lead to novel and original solutions for treating autoimmune diseases, infectious diseases and cancer by either activating or inhibiting immune responses. Solutions might be provided by small molecules and proteins, oligosaccharides and other polymers, but also through the development of new tool
SCIENCE ACROSS BORDERS
Immunology: unology domain compounds allowing visualization of immunological processes. Chemistry has a lot to offer to immunology, as immunology has a lot to offer to chemistry. A great win-win situation, in our opinion.”
other to have a long and happy life.” An educational program to drive mutual understanding of both fields for the participants is part of the Institute’s curriculum and will support a prosperous relationship.
Targeted molecule design
Now’s the time
Hermen Overkleeft: “Chemists should be aware of the main questions in the field of immunology, in order to design molecules that could be instrumental in solving immunological problems. These answers might come from a wide variety of chemical approaches including analytical chemistry, biochemistry, proteomics and metabolomics and tailormade chemical compounds and tools. All relevant chemistry disciplines allowing bench to bedsite activities are represented in the ICI consortium.” In order to actually pick the low-hanging fruits, it is necessary that both specializations get to know each other’s knowledge and learn to understand each other’s language, both Neefjes and Overkleeft emphasize. Neefjes: “This requires an effort, as immunology is often descriptive and uses terminology and a language that is systematically different from that of chemists and vice versa.” In that perspective, Overkleeft underlines the importance of posing the right questions: “Collaboration is not about asking the other discipline to do your work or to perform a Nobel-prize worthy task. A question like: ‘Can you make a molecule that enables specific selection and imaging of one gene at the DNA level’ doesn’t reflect the proper level of understanding the opportunities, because it represents unreasonable expectations. We can make a lot of different molecules and there are about 25,000 different proteins in the human proteome. The vital questions are: which molecule should we make and why this particular one? These questions enable targeted molecule design and can only result from a properly understood immunological question, hence from a viable collaboration. This asks for bridges from both sides, over the gap of each other’s far-reaching specialization. Mutual understanding will open up a huge potential.” The immunologists usually have clinically relevant questions, excellent in vitro and in vivo model systems and patient data, says Overkleeft. “The big challenge is to combine these with the design of new compounds or tools for visualization. Essential is to use the different knowledge in the fields to define the best design with the best need for such new materials. The opportunities are subsequently great!” Neefjes compares it to a marriage: “You have to learn to understand and respect each
Getting the NWO Gravity Award is a milestone for Dutch Immunology, but also for the Dutch chemists sharing an interest in solving biological problems. “It was by no means easy to get it”, Neefjes remembers. “In order to stand a chance, you
Overkleeft: “A targeted molecule design can only result from a deep understanding of an immunological process and be exploited by a proper collaboration.” (Photo Bureau Lorient Communicatie)
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understand at what point to intervene, and with what kind of molecules to modulate the immune system. These new opportunities are recognized worldwide, following people like Hidde Ploegh – the Dutch professor of Biology at the MIT Whitehead Institute in Boston, USA, who laid the foundations for chemical immunology there ten years ago. Worldwide, collaboration between chemistry and immunology is regarded as a unique integration of fields, with the opportunity to attain huge added value. Here in The Netherlands we now get the unique opportunity to make it a reality. It speaks volumes that some of the reviewers of our proposal wished to join in - and were even willing to get the Dutch nationality for this - as they expressed in the anonymous review comments of our proposal.”
“Mutual understanding will open up a huge potential” The Gravity Award involves an impressive budget, but the task ahead at least equals it. Neefjes points out: “Our ambition is, to have chemical immunology as a field established within the coming ten years. This means: a better understanding of the immune system plus the chemical requirements for translational medicine, a pipeline and an entire supply chain. Apart from the educational program, this for instance also asks for tools to follow immunological processes in time and place.”
Responsibility Jacques Neefjes (L) and Hermen Overkleeft (R): “Chemical immunology is a missing link, a necessary step that has not yet been explored. In this way, it offers great opportunities to the Dutch immunology community but also to the chemistry community.” (Photo Bureau Lorient Communicatie)
need to have the right people with the right CV’s on board of your consortium. It requires a shared vision and the support of heavyweights from several universities.” The founders of the ICI are prof.dr. Carl Figdor (UMC st. Radboud), prof.dr. Piet Gros (biomacromolecular cristallography, UU), prof.dr. Albert Heck (biomolecular mass spectrometry, UU), prof.dr. Ton Schumacher (immuno-technology, NKI/AVL) and Overkleeft as co-applicants alongside with Neefjes. Last year the proposal failed by a margin, this year it was successful. Overkleeft: “This is not a matter of just applying again. You need to win the full support and commitment of a university – in our case Leiden University – for the second year in a row. This is then at the cost of other proposals. We are grateful for this support, since we fully believe that now is the time for this initiative. More and more immunological processes are being unraveled, resulting in significant understanding of their molecular details and networks. We are beginning to
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Neefjes and Overkleeft are aware of the responsibilities and high expectations associated to this grant. Neefjes: “During the past years of collaboration, we have already seen glimpses of the huge possibilities when combining the model systems and patient material that are the domain of immunologists with the methodical approach of chemists. We now have to deliver upon the opportunities we get. We have to extend and scale up the chemical immunological activities into a sort of ‘top institute’.” Neefjes brings forward that the Institute for Chemical Immunology includes all processes found in a medium sized pharmaceutical company. Drug development will not be easy but is feasible in this consortium and -in fact- is already being initiated. As Pharma is stepping away from fundamental science activities and even from Phase I studies, the ICI can provide academia with a platform for developments which were previously available to Pharma. It is vital to our initiative to include translational research. We have received this funding to create a new field and regard it as a lever towards even larger funding, once patient organizations and other investors see opportunities for translational research emerging. Chemical immunology is a missing link, a necessary step that has not yet been taken. In this way, it offers enormous opportunities to the Dutch immunology community.” It is easy to allocate funding to research that does not really contribute to this new field. Neefjes and Overkleeft are well aware of this. Neefjes: “This kind of funding always attracts attention and many want to join such consortia for financial reasons. This is not unexpected but also not according to our
SCIENCE ACROSS BORDERS
ambitions. We aim to invest in activities that fuel the field of chemical immunology rather than the separate fields only.” Overkleeft: “Candidates should, therefore, share our vision that only maximum effort will lead to attaining our goal. It will not do for an immunologist to just go looking for a chemist for opportunistic reasons. We are keen on commitment and real multidisciplinary collaboration.”
Opportunities The ICI will also establish four tenure track positions in the field of chemical immunology. Neefjes: “This is very important. Young scientists now are the first generation able to regard this combined field as their natural scientific habitat. They are the future of this field. Apart from intangible scientific culture, the institute with its wide, deep, fundamental and exploratory nature, should also lead to a number of phase I clinical candidates. It is necessary to include translation.” The ICI starts out by concentrating on two target diseases, in oncology and in rheumatoid arthritis, as representative of
AGENDA April 30 – May 03 2014 ESCI and the Phagocyte Workshop Utrecht www.esci.eu.com
May 8 2014 (start) Medische Immunologie 10 weekly meetings from 18.00 to 21.00 hrs. Fee: € 850,- excl. optional practicum (€ 300,-) Hogeschool Utrecht, Centrum voor Natuur & Techniek Information: www.cvnt.nl, counselor Life Sciences 088-481 8888 or info@cvnt.nl May 14 – May 16 2014 Innate Host Defence Mechanisms in Infections Hotel Mitland, Utrecht Immuno Valley, Altant Conference http://events.immunovalley.nl/altant-conference-2014 May 21 2014 - May 23 2014 ISHEID Congress: HIV and Emerging Infectious Diseases Marseille, France www.isheid.com May 22 and 23 2014 Workshop analyse van next generation sequencing (NGS) data (PH-3111) NIEUW Fee: € 795,Information: Hogeschool Leiden, CBD, website: cbd@hsleiden.nl
“Some reviewers of our proposal were even willing to get the Dutch nationality to join in” situations where the immune system should be stimulated or quenched, respectively. Neefjes: “It won’t limit itself to those two diseases. We have the proper expertise on board to make us attractive to pharmaceutical partners. If disease-organizations realize that our platform allows genuine translation of findings in the lab to materials for in-vivo manipulation, they may be interested in joining our activities. This would expand the activities of ICI beyond the two diseases where the partners initially focus on.” Thanks to this Award, an entire field may get opportunities towards a new direction. Overkleeft: “The very existence of the platform for chemical immunology offers enormous opportunities for those willing to seize them.” Leendert van der Ent
June 12 - June 13 2014 Radboudumc Summer Frontiers Symposium ‘Age & Immunity’ Nijmegen June 17 - June 18 2014 Workshop primer en probe design (PH-3105) Fee: € 695,- (register before April 8 € 630,-) Hogeschool Leiden, CBD, website: cbd@hsleiden.nl September 1 2014 (start) Moleculaire Biologie (theorie) Twelve weekly meetings, 14.30 - 17.30 hrs. Fee: € 1.250,UEC points: 38 Hogeschool Utrecht, Centrum voor Natuur & Techniek Information: www.cvnt.nl, counselor Life Sciences 088-481 8888 or info@cvnt.nl September 5,12 and 19 2014 Kwaliteitsaspecten en troubleshooting bij PCR-technology (PH3104) Fee € 1.075,- (register before July 11 € 975,-) Hogeschool Leiden, CBD, website: cbd@hsleiden.nl September 16, 23, 30, October 7 2014 ELISA theorie; achtergronden en kwaliteitsaspecten (PH-3152) Fee: € 1.280,- (register before July 14 € 1.165,-) Hogeschool Leiden, CBD, website: cbd@hsleiden.nl
June 07 2014 – June 11 2014 EAACI 2014 Copenhagen, Denmark Congress of European Academy of Allergy and Clinical Immunology www.eaaci2014.com
September 17 2014 (start) Klinische chemie Twelve meetings, 18.00 to 21.40 hrs. Fee: € 1.525,-, practicum included UEC points: 51 Hogeschool Utrecht, Centrum voor Natuur & Techniek Information: www.cvnt.nl, counselor Life Sciences 088-481 8888 or info@cvnt.nl
June 10 2014 Introductie tot Real Time PCR Three meetings from Monday to Wednesday, 9.30 - 17.30 hrs Fee: € 1.500,-, practicum included UEC points: 32 Hogeschool Utrecht, Centrum voor Natuur & Techniek Information: www.cvnt.nl, counselor Life Sciences 088-481 8888 or info@cvnt.nl
October 16 2014 (start) Antibiotica en resistentie Three meetings, 9.30 to 17.00 hrs. Fee € 1.150,-, practicum included UEC points: 27 Hogeschool Utrecht, Centrum voor Natuur & Techniek Information: www.cvnt.nl, counselor Life Sciences 088-481 8888 or info@cvnt.nl
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Edward Knol
Better diagnosis, more effective About a decade ago, it was seriously thought that allergy could be banned altogether. Despite, or maybe rather thanks to, our increased insight this thought is now far away. But the increased insight, for instance on the individual protein level, has indeed led to better diagnosis and more effective treatment, with the promise of further improvement in the near future. Edward Knol PhD leads us through some recent developments in allergy research and explains how IgE as one of the key players in allergy is still a mystery. For a long time already it has been known that allergens bind to the antibody immunoglobulin-E (IgE) on mast cells and basophilic granulocytes, which stimulates the innate immune system vehemently, causing allergic reactions. The actual allergens were only known as belonging to a group of proteins which caused the problems. “During the last decade, however, science has been able to distinguish more and more individual proteins. These are, within an allergenic source, actually recognized by IgE”, Edward Knol PhD, immunologist at the University Medical Centre Utrecht comments. “Some of these allergens in some way or another destroy the barriers of skin and mucosal tissues. For example, many of the 23 proteins Der-P1 to Der-p23, the allergenic proteins at work in dust mite allergy, work directly on the epithelial cells in the lungs, all in slightly different ways.” Another example are the proteins Ara h1 to 11, together responsible for peanut allergy. Knol: “Especially in food allergies, our knowledge of the responsible allergens in food has increased a lot. Ara h1 stimulates the receptor DC-sign, as described by professor Yvette van Kooyk of the VUmc. DC-sign in turn stimulates dendritic cell activity, leading to Th2-skewing. This is the allergen-specific t-cell reponse that drives allergy via production of interleukin (IL)-4, IL-5 and IL-13. In the Dutch population, Ara h 2 and Ara h 6 are the most potent peanut allergens. Another way to put this: it activates mast cells most successfully in this specific population. In other populations things can be different: people in various parts of the world react in a different way to the same allergens. An example is apple allergy. In north-west Europe patients react to the allergen Mal d 1. It causes
tingling in the mouth and cross-reacts with Bet v 1 from birch. In southern Europe patients mainly react to to Mal d 3, which causes severe allergic reactions.”
False positives Ara h 8, on the other end of the Dutch peanut allergy spectrum, is only a mild allergen. But it has a characteristic that makes it stand out: just like Mal d 1, it cross reacts with the birch pollen allergen Bet v 1. Knol: “This is a nice example of what the new knowledge and insights have brought the patients. Formerly, skin prick allergy tests only looked for IgE activity of a peanut extract containing all allergens. IgE is not able to distinguish between Ara h8 and the fairly common birch pollen allergen Bet v 1; it binds to both. Clinically relevant binding for peanut allergy (Ara h8) on the one hand and clinically irrelevant binding on the other hand (birch pollen Bet v 1) led both to the same conclusion: that it would be better for the patient to abstain from peanut and foodstuffs with peanut traces altogether. Potentially, birch pollen allergic patients were tested false positive to peanut causing a lot of people to follow a very strict diet, with deep impact in everyday social life, when it was not even necessary. At present,
Edward Knol: “IgE is present in all humans, so there must be some sort of drive to prolong its existence. But its evolutionary role is still unclear” (Photo Bureau Lorient Communicatie)
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THEME: Allergy
treatment now the individual allergens are taken into account, there is no difficulty anymore in distinguishing between both proteins. These false positives have become a thing of the past. On the other hand detecting of IgE binding the peanut allergen Ara h 2 indicates real peanut allergy.”
Chip testing More detailed information about individual allergen proteins has led to a different way of testing. Formerly, the skin prick test was popular for establishing allergy, or alternatively, the in vitro binding of IgE to allergen extracts on a solid phase ship pulse test. Now, the more refined approach could necessitate more than twenty skin prick tests to define which individual protein is responsible for a certain allergy. Therefore serology tests have been added to complete or replace them. By array chip analysis now one drop of blood enables testing for more than one hundred allergens per grid at the same time. Via fluorescence signals all the spots on the arrays tells the tale of the allergenicity of each particular protein for each patient. Knol is enthusiastic about this evelopment, available for some years now, because now it also become possible to generate IgE binding patterns per patients that enables a rather complete overview of the allergens to which the patient is allergic.
Allergy diagnostics with effector cells To be even more close to the real life interaction of allergen and IgE, now also activation of basophilic granulocytes is implemented in allergy diagnostics. In this was also multivalency of allergen-IgE interactions, the affinity of IgEallergen and the role of other blocking antibodies is taken into account in the allergy diagnostics. Knol is thrilled about this newest development more so because this is based upon findings he presented for the first time during the special 35 years anniversary of the Dutch Society for Immunology in 1989. “I found in my research that activation of basophilic granulocytes can be measured with CD63 antibodies and flow cytometry, which parallels the release of the potent mediator histamine. Effector cell / Basophil stimulation is used in several commercially available tests. The large European consortium EuroBAT is now busy standardizing the diagnostics for several kinds of allergies, next to food allergy also drug allergies and insect venom allergies. In addition the Basophil Activation Tests (BAT) can be used to follow the patient’s immune reactions during immuno therapy, or spontaneous development of tolerance. The BAT is very sensitive and easily detects 1/1,000,000,000 of a peanut.”
Treatment Apart from this leap in allergy diagnosis, also large steps have been made, in food allergy treatment. “Ten years ago, antihistamines, allergen avoidance and in severe reactions adrenaline auto-injectors were the only available option. We are now heading towards immuno therapy with individual proteins or protein mixes to finally cure food allergies”, Knol describes the trend. This is quite a solid promise, although some caution is justified. The immunotherapy with foods is now via oral of skin administration of the allergens. Especially, for the oral administration it is now described that the clinical success is hampered by severe side-effects during treatment and also the long-term protection seems to be less than the established immunotherapy for insect venoms.
“Apart from IgE, there have to be other factors related to allergy” On the other hand we have come back from the euphoric reactions following the market introduction of the biological recombinant humanized anti-IgE (Omalizumab) about fifteen years ago. Knol: “It forms complexes with free IgE, blocking its interaction with mast cells and basophils. Thus, it was thought to be able to ban allergy altogether. Alas, this proved not to be the case. It was found that anti-IgE has only a very limited effect, after months of administration with allergic inflammatory reactions such as asthma, hay fever and eczema. This inspired an important conclusion: apart from IgE, there have to be other factors related to allergy. It goes to show how an immunologic therapy provides insight into a disease, even when it is not yet able to cure it. An even more positive conclusion was, surprisingly, that anti-IgE worked like a charm and very rapidly against chronic urticaria, a formerly hard-to-treat disease that was thought to have nothing to do with IgE. This phenomenon has as yet not been explained, although scientists the world over are looking for an explanation. IgE is still a mystery in some ways, as it has no real clear biological function whatsoever. IgE is present in all humans, so there must be some sort of drive to prolong its existence. But its evolutionary role is still unclear.”
The toggle of the tissue Back to IgE and inflammatory allergic reactions, more specifically dust mite allergy. “Half of the individuals that have IgE to house dust mite show no clinical problems, the other half struggle with skin, lung and / or nose problems”, Knol
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explains. “IgE has no role in the manifestation of problems in one, two, three or none of these organs. The organ itself must play an important part in the problems: it ‘allows’ IgE to develop into a clinical disease. RNA analysis of peripheral blood T-cells in our lab here in Utrecht has brought to light that another inflammatory allergic reaction, eczema, has little to do with Th2-skewing, the allergic immune response to IgE, but rather with the movement of T-cells to the skin, as well as the decreased activation threshold of these T cells. This shows that inflammatory allergic reactions go together with genetic predisposition in the organs.” Knol thinks, that an eventual cure of inflammatory allergic diseases requires deeper knowledge of organ involvement. “Here again, the innate immune system plays a certain role. But other than with peanut allergy, where it can be sufficient to catch IgE to prevent the problems to manifest themselves, several problems have to be solved simultaneously to treat inflammatory allergic diseases. Moreover, this area requires first-in-man research, as inflammatory allergic diseases cannot be modeled in mice.” It is quite clear that banning allergy is still far away today. But the recently improved insight, for instance in the role of IgE and mast cells, allows a better grip on the allergy problem and holds the promise of better combination therapies to improve the quality of life of numerous allergy patients. Leendert van der Ent
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Who is Edward Knol? Edward Knol Ph.d. works as associate professor at the Utrecht University Medical Centre (UMC). At the departments of Immunology and Dermatology he does allergy research, especially into food allergies and eczema. Apart from that, he is intrigued by the question why people in different countries react differently to the same allergens. Allergy diagnostics also have his warm attention. From 2011 till 2014 he was chairman of the board of the section Immunology of the European Academy of Allergy and Clinical Immunology (EAACI) and he currently is the scientific coordinator of the EAACI’s annual meeting. The EAACI aims at promoting a better understanding of allergies throughout the European Community, in research, treatment as well as education.
THEME: Allergy Luud Gilissen
Towards an improved quality of life for food allergy patients Dr. Luud Gilissen focuses his research at Wageningen University & Research Centre (WUR) especially on apple allergy and celiac disease. Gilissen was co-initiator of the EU-SAFE project on apple allergy and, together with Frits Koning (Leiden University Medical Centre, LUMC) and Cisca Wijmenga (University Medical Centre Groningen, UMCG), laid the foundation of the Celiac Disease Consortium. He also was co-initiator of the Allergy Consortium Wageningen, together with Huub Savelkoul and Harry Wichers (both WUR). Gilissen states that allergies have a great impact on a person’s life and on society: “They can cause debilitating illness, raise the cost of direct and indirect health care, and result in lost working days. They also hinder to leading a normal social life.” Silencing allergen genes in food crops is one of the options to improve patients’ quality of life. Why does one person respond violently to a compound that is completely innocent to another? Gilissen: “Things go wrong in the interaction between genetic, physiological and environmental factors. This causes, often in combination with the composition and the activity of the intestinal micro-flora and the allergen itself, a misbalance in the immune system.” The big question is, whether an allergy can be prevented. Gilissen: “There are several ways to try and achieve this. Firstly, regarding environmental factors, it may be wise to prevent exposure to risk factors such as smoking, especially during pregnancy or in the presence of a baby. But also our increased hygiene, the almost unlimited application of antibiotics, and our western lifestyle including much stress and changed food habits have their negative impact on the proper functioning of our immune system and the quality of our intestinal microflora. Further, if young parents are allergic to certain substances because of their genetic predisposition, they should try to keep their baby away from or postpone the contact moment with allergens as long as possible. This advice is, however, currently under discussion: it might be that early exposure has a protective effect through the induction of tolerance to the allergen.”
Luud Gilissen: “Currently, proteomics technology is under development to enable the identification and quantification of celiac-toxic gluten fragments in foodstuffs and in human body fluids. (photo Bureau Lorient Communicatie)
Allergy An allergy is an abnormal and violent reaction of the immune system to a compound – generally a protein – which normally is harmless and tolerated by the immune system. The body produces the antibody immunoglobulin E (IgE) that specifically recognizes allergens. This may lead to an acute inflammation or even anaphylactic shock. Symptoms present themselves in organs which are in contact with the outside world: lungs, skin and intestinal track, but can also be systemic, causing shock.
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If somebody has become sensitive to a certain allergen, a reaction does not occur as long as contact with the specific allergen is avoided. “Check for instance the pollen calendar and read the lists of ingredients and declarations of allergens on foodstuffs”, says Gilissen. When, nevertheless, the allergy is a fact and exposure cannot be avoided, intervention becomes the next option. Interventions may include medication, or the consumption of foodstuffs with immuno-modulatory properties to restore the immune balance.
Developing hypo-allergenic foods It is hard when you cannot eat an apple without being punished with painful swellings or blisters in mouth and throat, Gilissen says. “Therefore we try to design hypo-allergenic foods, such as hypo-allergenic apples.” It was one of the reasons for the European Union to finance the EU-SAFE project. Gilissen was co-initiator of EU-SAFE. “Together with the University Medical Center Utrecht, Sanquin (Amsterdam) and a number of European partners we examined the effects of twenty commercial apple varieties on volunteers with apple allergy using the skin-pricktest.” The protein Mal d1 (a member of the plant PR10-protein family) causes serious problems in 5-10% of the North-West European (including the Dutch) population. “From our research it appeared that the composition of the amino acids and the degree of expression of Mal d1 differed from one apple variety to another. The test proved the variety Santana to be low-allergenic.”
Allergic reaction: how does it work? Proteins from food or environmental sources are picked up by antigen presenting cells (APCs) and are fragmented. Protein fragments are presented at the exterior of the APC and controlled by Th2 cells. After recognition as harmful, the Th2 cell becomes activated making an isotype switch to initiate B-cells producing allergen-specific IgE instead of IgG antibodies. The IgE produced by B cells circulate in the blood and bind to special high affinity IgE receptors on mast cells, the last step in the sensitization process. Once the mast cells are loaded, a person re-exposed to the allergen the allergen may bind to and crosslink two IgE-molecules, resulting in mast cell activation to release inflammation causing mediators, amongst others histamine, leading to the organ specific allergic symptoms.
“If we could simply delete gliadin from gluten protein, we could strike gold” Braeburn, Elise and Topaz also demonstrated to be relatively low allergenic. “It may be possible to reduce the allergenicity even further through cross-breeding”, Gilissen says. At the same time, the researchers also examined the possibility of genetic modification (GM). “Based on cloned genetic Mal d 1 material, we have built a ‘gene-silencing’ DNA construct and brought it to expression in the high-allergenic apple variety Elstar. In this way, we succeeded in significantly reducing the expression of Mal d 1 in the transformed Elstar apple plants and fruits. Unfortunately, GM is not yet embraced by the European society, although this type of GM with personal benefit to the consumer has a relatively high acceptability.” By now, from world-wide research, all important allergens in our food and environment have been identified at the genetic and the protein levels, and the data are stored in international databases. It is also known how allergens from environmental and food sources can cross-react. From this research it appeared
Luud Gilissen: “We succeeded in reducing the expression of Mal d 1 in apple plants and fruits significantly through variety selection and through genetic modification. The selected and organically grown variety Santana is on the market and labelled as low-allergenic suitable for individuals with mild apple allergy. The GM ‘Mal d 1 gene-silenced’ variety is not on the market.” (photo Bureau Lorient Communicatie)
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THEME: Allergy
that proteins from only a limited number of protein families have allergenic potential. Gilissen: “A good example of allergenic crossreactivity is that of Bet v 1 in birch pollen with the apple Mal d 1 protein: Both representatives of the PR10 protein family look very similar to the immune system, with the result that a patient with a birch pollen allergy may also experience an oral allergic reaction while eating an apple. Knowing the most abundantly occurring allergens and their cross-reactivity profile, while introducing genetically modified as well as exotic ‘novel foods on the market, we can map and assess the expression and the allergenicity of the newly introduced transgenic proteins by using high-throughput genomics (transcriptomics) and proteomics. This can significantly shorten or even make redundant the clinical test phase.”
Quantification of gluten Another area of interest in Gilissen and his colleagues’ research are gluten, a large and complex group of water-insoluble proteins in wheat, spelt, rye and barley. “The food industry is especially fond of wheat gluten, since this is an excellent binder with unique visco-elastic properties”, says Gilissen. “This made wheat our most important food crop, with wheat ingredients the most popular in food industrial applications: over thirty percent of the processed and packaged food products in the supermarket contains wheat, gluten or other wheat ingredients such as wheat starch or derived compounds. This fact highly complicates the life of people with gluten intolerance.” The degradability of gluten proteins in the human intestine is low, resulting in large peptide fragments with immunological activity, for example the alpha-gliadin 33-mer with up to six overlapping epitopes (immunologically active amino acid sequences). In most persons, the immune system develops a tolerance for these gluten fragments. But in people who are genetically predisposed to express HLA DQ2 or DQ8 receptors, gluten may cause celiac disease. The consequences are severe: celiac disease may cause chronic inflammations in the small intestine, with possible further reactions everywhere in the body from brain to bones. In the small intestine, inflammation causes deteriorated take-up of nutrients leading to deficiencies. The Dutch government since 2004 supports the Celiac Disease Consortium (CDC). Gilissen and colleagues are involved in the CDC from a plant perspective. “At Wageningen UR we have sequenced thousands of gluten genes and checked them for toxic gluten fragments and their genetic expression. We also analyzed hundreds of wheat varieties and were able to select some low-celiac immunogenic varieties. We are now growing these for further research of their agronomic and food-technological qualities. We also investigated the possibility of silencing specific gluten genes and the deletion (by way of mutation) of specific gluten gene-containing wheat chromosome fragments. It might thus be possible to reduce the celiactoxicity of wheat, while maintaining the nutritional and baking qualities.” Another research line at Wageningen UR concerns alternative grains. Rice, corn and oats contain proteins which resemble gluten, but are not harmful to people who suffer from celiac disease. “We focus on oats, very healthy for their high dose of cholesterol-reducing and blood-glucos regulating soluble
fibres (bèta-glucans) and other interesting health-promoting components (e.g. the polyphenolic avenanthramides with interesting anti-oxidant activities), as an excellent addition to the lowin-fibre gluten free diet. An important requirement is, that the production method is guaranteed gluten free, from cultivation to the plate.”
Less toxic Recently, Wageningen UR obtained funding to develop a quick, non-invasive diagnostic test based on genomics and proteomics technology and on gluten induced antibodies. Currently, proteomics and cellular technology is also under development to enable the identification and quantification of celiac-toxic gluten fragments in foodstuffs and in human body fluids. Gilissen: “In this project, we join forces with the colleagues from sister institute RIKILT, Canisius-Wilhelmina Hospital in Nijmegen and several diagnostics companies. With the results, we will be able to better guarantee the proper labelling of products as ‘free from gluten’.” This project runs until the end of 2015. In the meantime, Gilissen and colleagues are working on other strategies to reduce the celiac-toxicity of foodstuffs. “The gluten protein in wheat consists of two types: gliadins and glutenins. Gliadin is the most important source of celiac-toxicity, glutenin is the most interesting ingredient as binder in all kinds of food products and as bread improver. If we would be able to simply delete the gliadin from the gluten protein, we could strike gold.” Alinda Wolthuis
Luud Gilissen Studied Biology at the Radboud University, Nijmegen Got his PhD on the physiology of flowers Works at Plant Research International, Business Unit Bioscience, of Wageningen UR Focuses on allergy, celiac disease and immunity, oats and health
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Hans de Groot
Allergy melts under the tongue Some major recent developments in the allergy clinic originate from immunology, Hans de Groot MD PhD states. De Groot is allergist at the Reinier de Graaf Group, location Diaconessenhuis Voorburg. At present immunotherapy injections are applied to induce tolerance and melting tablets too have become available to treat hay fever. The industry is working hard to extend the portfolio of melting tablets, possibly even towards food allergy applications. Furthermore, blood tests can perhaps replace provocation tests for more precise allergy diagnosis.
“The idea of allergy immunotherapy was originally developed in 1911”, says De Groot. “The concept is built on the idea that the immune system can get accustomed to allergenes. Over time, the regulatory system develops tolerance. Hay fever and dust mite allergies are treated like this since 1960.” Patients receive weekly injections for 2-4 months, followed by monthly injections for three to five years. After this period the tolerance has so much increased, that no longer an allergic reaction occurs when the patient encouters allergens.
“We want to define which specific protein in what quantity is how likely to provoke an allergic reaction” Due to the injections in the hospital, it is not a very pleasant treatment method, however, especially for children. “There have been experiments with drops under the tongue, but these were not potent enough”, says De Groot. “Therefore melting tablets against hay fever have been developed, which have recently become available. This sublingual application is as effective as an injection. Because treatment is more convenient, the field of application can be enlarged. Furthermore, the tablets can be taken at home - only the first dose is given at the Doctor’s office.” De Groot was principle investigator of the Magic-study into the applicability of these melting tablets. “The downside to home use is the lack of compliance. It is known that without measurements, compliance is likely to drop to ten percent, as a reaction to side effects or discomfort. It turns out that a follow up with regular phone calls from the hospital for example caused compliance to remain at seventy-five percent, which was very satisfactory.”
Peanut flour After the success with hay fever, the industry is now busy developing melting tablets against dust mite allergy. These are expected to be launched within three years. After this, melting tablets against other allergies such as tree pollen will follow. De Groot: “There is even hope for melting tablets against food allergies
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in the long run. Treatment with injections doesn’t work for these allergies due to the many possibly even dangerous side effects.” Just now, a publication in The Lancet described treatment of peanut allergy in children by using peanut flour to build up tolerance. “The first results are positive”, says De Groot. “But once the treatment stops, the effect is immediately gone. It is rather desensitization than tolerance induction. A more lasting effect could possibly be reached with higher dosages – in melting tablets.”
Improved diagnosis A second study De Groot is involved in is jointly carried out with the UMC Utrecht, the AMC in Amsterdam and the Diaconessenhuis Voorburg / Reinier de Graaf Group. It aims at defining possible recombinant (food) allergens from blood tests. “The conventional allergy test is a radioallergosorbent (RAST) test or a skin prick test. When a positive reaction occurs, the person is said to have a sensitization for this substance”, De Groot explains. “But sensitization does not always equal allergy manifestation. It is quite something to abstain from peanuts – as traces of peanuts can be found in many processed foodstuffs - when the basis for this advice is unsure. A more refined approach would be welcome. That is what we’re working at.” In a conventional RAST-test a mix of proteins is applied. If a person reacts, it doesn’t necessarily mean he is allergic to all of these proteins; there can even be a cross reaction. “Therefore we now distinguish possible recombinant allergens like Ara h 1, 2, 3, 6 or 9 in a blood test on the basis of antigen profiles. We want to define which specific protein in what quantity is how likely to provoke an allergic reaction, allowing more precise diagnosis. In the RdGG the blood test which defines which proteins cause sensitization, is followed by a doubleblind provocation test that the allergen (peanut) to establish whether a clinical reaction follows, to what amount of protein and how severe the reaction is. It would be marvellous if these new blood tests on the basis of recombinant major allergens could lead to a more precise prediction of an actual clinical peanut allergy. Then less –possibly dangerous- food provocations would be necessary in the future.” Leendert van der Ent
THEME: Allergy
Hans de Groot MD PhD: “Immunology has led to more precise allergy diagnosis” (Photo by kind permission of NIV)
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Ronald van Ree
FAST:
Creating a safer life for food Although a hot topic at present, subcutaneous immunotherapy is hardly a new phenomenon. For application against food allergies, however, overcoming side effects is still challenging. The FAST consortium takes up this challenge on behalf of fish allergy patients. Ronald van Ree PhD, professor in molecular and transational allergology at the Amsterdam Medical Center: “We think that purification in combination with lowered IgE binding could do the trick.”
For over a century now patients are being injected with allergens to counter allergic reactions. Today this classical allergen-specific immunotherapy (SIT) still is a popular therapy against inhalation allergies, such as grass and tree pollen, as well as dust mite allergy. For food allergies this subcutaneous treatment method is also attractive, but quite hard to realize. “In the nineties in the USA vaccination against peanut allergy was attempted. It came with numerous side effects and was eventually stopped”,Van Ree comments. “It is unclear why this is, but side effects appear to be more severe with food allergy. We have learned that adsorption to aluminium hydroxide protects the epitopes for IgE antibodies, which diminishes side effects. The American trial didn’t apply this adsorption process to the peanut extract. In the European research project Food Allergy Specific Immunotherapy (FAST) we do.”
Allergy patients could live more safely under the threat of unintentional exposure Ronald van Ree: “We aim at a safe and effective treatment for fish allergy”
Memory and compliance There are also trials with oral immunotherapy against food allergies. Van Ree: “These are based on a day by day very slightly increased dose of a foodstuff to steadily induce tolerance. It seems to work, but comes with a drawback: once the treatment is stopped, the effect seems to disappear quite rapidly. Injections, on the other hand, have a sustained effect for years on end. Apparently, the oral route and the sublingual route reach the immune system in such a way, that no ‘effective memory’ is formed.” The subcutaneous method also has compliance and safety edges to it, Van Ree says: “Allergens are injected once a month
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(photo Jeroen Oerlemans)
under supervision of hospital specialists. Firstly, we can be sure that it is indeed given – not the least important factor with a predominantly young adult target group. And should side effects arise, which is not unthinkable among patients with severe pathology, we can intervene immediately.”
Orphan drug Van Ree and his fellow FAST-researchers are therefore determined to overcome the present flaws of subcutaneous
THEME: Allergy
allergy patients injections against persistent and severe food allergy. They aim at developing safe and effective treatment, beginning with fish allergy. “We replace the food extract with only one purified active protein, the hypoallergenic recombinant variant of the major allergenic parvalbumin. We hope that as a result of the purification and modification step, side effects are diminished. The protein is still recognized by IgE antibodies, but the slight mutation causes a hundred to thousand fold lesser IgE binding than the original parvalbumin.” Van Ree now awaits the results of safety trials and dose tests held in Denmark. “This phase is well under way, we expect results in the summer. If these results are satisfactory, the next phase of establishing effectiveness will start at the beginning
of 2015. As the number of fish allergy patients is limited, the product will be filed to get the orphan drug status. This would speed up market launch.” Although primarily aimed at fish allergy, the results might find wider use. Van Ree: “Results will also be evaluated outside the scope of this project for use in allergies with higher prevalence, such as peanut allergy. We think that lowering the allergen threshold among patients with severe pathology is an attainable goal. It would give them the opportunity to live more safely under the threat of unintentional exposure. We don’t expect to completely cure food allergy altogether.” Leendert van der Ent
News Additional feeding prevents food allergies in children The VU University Medical Center, the Dutch Ministry of Health and ZonMw advice to start giving children of four months of age already small portions of additional feeding. Together with pediatricians, youth healthcare physicians and general practitioners, VUmc developed a guideline for food intolerance. Parents are to start with vegetables and fruits, then add products like eggs, fish and peanuts. This helps to prevent food allergies in young children. The new directive also addresses prevention of gluten intolerance (celiac disease). Small quantities of cereals, in addition to breast feeding, may prevent intolerance for cereals in children. Also new is, that from now on the infant centre can perform tests for cow milk allergy. This is cheaper and much more convenient for parents than the previous situation with testing at the hospital.
Hay fever alone causes more severe allergy reaction The more allergic, the more sick, one would expect. So people with hypersensitivity to grass pollen ánd dust mite ánd cat fur will react more a violently to each of these allergens than people who are hypersensitive to only one allergen? This is not the case, AMC ENT-doctor Susanne Reinartz discovered in a double blind study. A group of patients with grass pollen allergy and a group with multiple allergies were both given pollen allergen. The group with only hay fever reported more severe problems. Remarkably, the same doesn’t apply to for instance dust mite allergy: people with this single allergy react in the same way to the allergen as people with multiple allergies. Reinartz’ research was primarily aimed at unraveling the underlying immunological processes, but she also discovered another epidemiological fact: hay fever patients also stand out, because antihistamines are less effective with them than with people suffering from multiple allergies. This is in line with the recent evidence based treatment guideline for hay fever, giving preference to steroids over antihistamines as a first choice. Source: AMC Magazine
More information: www.ncj.nl. (photo Wikipedia)
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In support of clinical demand Progress in allergy research and diagnosis has become rapid lately. The ImmunoCAP ISAC for instance enables testing for hundred and twelve allergen components at once. Time for a large scale roll out? Hardly, says Allergy Franchise Manager NL Mart Rijnen at ThermoFisher Scientific, who is rather restrictive in distribution of the system. “Yes, the ISAC system is the future in allergy diagnosis”, he admits. “But the abundance of information it offers asks for scrutinous interpretation. Thanks to intensive information exchange between the academia and us, we gradually widen the scope of effective application.”
In the nineties it dawned, that there was more to allergy than an IgE-reaction to a large number of possible allergens. An anamnesis and positive test result for a certain allergen extract could indicate a certain allergy. But especially with food allergies, the patient’s reaction with the same diagnosis could range from mild to extremely severe. It indicated that sensitivity to for instance peanut had to be one step more complex than thought until then. This has inspired a quest for the various individual allergen components causing the differing development of Immunoglobulin E antibodies. Extracts were broken down on blots into various individual proteins. It became apparent that patients with mild reactions were sensitive to other individual proteins than patients with severe pathology. “Jonas Lidholm at our Uppsala laboratory closely followed the scientific publications in this field and tried to introduce the conclusion into our allergy measurement system”, Rijnen explains. “Halfway the nineties a test program with tree, grass and weed pollen as well as aspergillus fumigatus allergens started. Results were gradually introduced into the clinic. We have a very restrictive introduction policy and only admit results to our operational systems after thorough clinical validation.”
Differentiation Demand for this so called ‘component resolved diagnosis’ came especially from the complex field of food allergies. Here the impact of unnecessary avoidance of certain foodstuffs was high. On top of that, the consequences of exposure to certain
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proteins would for some be grave indeed. Rijnen: “During the last five years we’ve cooperated intensively with dermatologist André Knulst and immunologist-allergist Edward Knol at the Utrecht University Medical Center (UMC) to establish which proteins play a role in severe peanut allergy. Later we also cooperated with Laura Masthof regarding hazelnut allergy. Their observations in the clinic are vital to find scientific explanations for these phenomenons. Subsequently, on their request, we can develop and introduce new components in our measurement systems.” The first of these is the ImmunoCAP system. It consists of a small cup with a sponge in it, on which allergen proteins are applied for testing. The range consists of more than six hundred different caps with allergens. On top of that, there are now 95 individual allergen components for component resolved diagnosis. Rijnen: “Partly on the basis of such a cap-test, an allergist can establish what will happen after a possible future exposure and take measures accordingly. I’d like to stress that the test is only a supportive part of the diagnosis. First you need an anamnesis to painstakingly pin down the when, how and what of possible past exposures.”
Chip technology The second test system is on the market since 2008: ImmunoCAP ISAC. It is based on chip technology and
IgE and allergy diagnosis Thermo Fisher Scientific ImmunoDiagnostics specializes in allergy and systemic auto-immune diagnostics. A number of names are connected to the discovery of the antibody class Immunoglobulin E (IgE) and its role in allergies. Apart from Teruko and Kimishige Ishizaki, Benach and Leif White, Gunnar Johansson of the University of Uppsala is among these. After the discovery, Johansson started developing a measurement system for IgE in medical laboratories in his garage, resulting in 1970 in the Phadebas measurement system. In 1974 the Radio Allergo Sorbent Test (RAST) was developed to specifically detect IgE against dust mite, grass and tree pollen. The name RAST survives to this day, although the process became enzymatic since 1981 and replaced (1989) in a second test generation: ImmunoCAP. In 1986 the Phadiatop (and later Phadiatop Infant for children) tests were launched, enabling diagnostics and allergy tendency against certain clinical relevant (food) inhalant allergens.
THEME: Allergy
Mart Rijnen: “Added value of new tests is confirmed in a clinical setting” (Photo Bureau Lorient Communicatie)
consists of a glass strip with four grid chips to test four patients. Each chip or grid contains 336 tiny spots with 112 different allergen components – which have been selected in close collaboration with clinicians. The components are present in triplo in order to rule out variance as much a possible. Rijnen: “The ImmunoCAP ISAC does not replace the regular ImmunoCAP tests – unless it is unclear how many ImmunoCAP tests will be necessary to explain a certain case. The ISACsystem requires a totally different approach. That is why, after its launch in 2008, the practical application is still largely restricted to academical clinical settings as they are now at the AMC, in Maastricht, Rotterdam and Utrecht. On the basis of scientific research and clinical practice we have to carefully and elaborately establish the added value in the clinical setting. That process is ongoing; the outlooks are positive. It undeniably represents the future of allergy diagnosis, but it must go together with another way of judging results.”
Dialogue and interaction The ‘allergy diagnosis triangle’ still remains the leading principle. Anamnesis, test result and the patient’s physical reaction all contribute to careful diagnosis. “Because it provides so much information, it is tempting to think that an ISAC-test is a routine test which in itself explains everything in an allergy case. It cannot replace anamnesis. Far from it; without proper anamnesis, it only creates confusion. The anamnesis provides meaning to the information. The ISAC-information can in turn support and verify the anamnesis. Users have to learn to handle the meaning of the info.” Also, they have to know beforehand why they wish to have this information, Rijnen adds. “It can be an invaluable help to explain
an otherwise inexplicable anamnesis in a complex food allergy case, for instance in early diagnosis of multi-sensitized young children.”
The ‘allergy diagnosis triangle’ still remains the leading principle. It can also help to provide answers to ‘dr. House-like’ clinical questions. Rijnen gives an example: “Allergy professor Adnan Kustovic, Centre Lead for Respiratory Medicine and Allergy at the University of Manchester, used historic serum samples on the ImmunoCAP ISAC to find and prove patterns in the complex relation between asthma and allergy. This knowledge could in due time perhaps contribute to more specific treatment of children, to reduce clinical effects of asthma.” Rijnen suspects there are more possibilities like these, but underlines the importance of a step-by-step approach. “In a continuous dialogue and interaction with specialists we will explore the future possibilities.”
This article was enabled by ThermoFisher Scientific, main sponsor of the European Academy of Allergy and Clinical Immunology Conference, June 7-11, Copenhagen.
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Five decades of Dutch immunolo Spotlights on heritage and futur In 2014 the Dutch Society for Immunology (NVVI) can look back on a history of half a decade. The NVVI is determined to not let this milestone pass unnoticed. A large number of activities will be deployed to guarantee this. A daily calendar, a canon of Dutch immunology, a tour of all eight Dutch university medical centers and a debate in the Amsterdam hot spot ‘Rode Hoed’ will all contribute to attention for the history of Dutch immunology and immunology in general.
The NVVI was officially founded on November 20th, 1964. Founding fathers were Prof.Dr. Joghem van Loghem, Prof.Dr. Jon van Rood, Prof.Dr. W. Hijmans, Prof.Dr. F.J. Keuning and Prof.Dr. Dick van Bekkum. Their main objective was to join immunological forces in The Netherlands, from both clinical and fundamental research angles. In this period the profession was only practiced by a handful of pioneers. They were organised in a few small groups which were mostly still embedded in classical (pre)clinical departments. Fortunately, immunology research was growing rapidly. A society was needed to boost and maintain progress in immunological research and to provide a platform for clinicians and researchers to meet and interact. Nowadays, all University Medical Centers and many other institutes and hospitals include one or more groups engaged in basic, clinical or medical immunology. The NVVI has grown into a mature and large society, attracting more than six hundred immunologists from The Netherlands and abroad at their annual meetings. During the NVVI’s lifetime, Dutch researchers, teachers and medical professionals have contributed substantially to the unfolding of immunology, both nationally and world-wide.
Daily Calendar Now, five decades later, it is time to celebrate a milestone: in November 2014 the NVVI exists for fifty years! The NVVI Board and the Lustrum committee (see box) wish to pay tribute to this success. Several committees have been created that are now working on various events to be held throughout the year. The Daily calendar (‘scheurkalender’) app-committee is working on the design of a daily calendar (‘scheurkalender’) in digital format. This calendar will provide each Dutch immunologist with a daily update, be it an anecdote, a beautiful histology or confocal picture, a biography of a famous immunologist, information on various subjects related to immunological science, a quiz or a puzzle. In this way, we can start everyone’s day with a smile or a thought. The team is currently working on the exact format. They can use the help of their colleagues to collect the input they need. So, here is a request to everyone: think carefully and send in your ideas! What can be put on the calendar? Do you have a nice picture, a funny anecdote, or a silly cartoon? Is there an immunologist/discovery you admire and would you like to write a small piece on…..whatever, please help them out! Send all your input (text approximately two hundred words) to: nvvi50app@gmail.com. In this way, we can all enjoy a beautiful app in 2015!
Canon of Dutch Immunology A Canon of Dutch Immunology will be presented in December. The Canon will follow the approach of a timepath with a matrix, on which the major developments and achievements in different fields of immunology are plotted. It will of course also feature the history of important immunological discoveries made in The Netherlands. Special attention is given to the contribution of immunology to health care in general.
A variety of mini symposia will be held in all eight University Medical Centres in The Netherlands. The Groningen UMCG in this picture focuses on healthy aging with a systemic autoimmune disease. (Photo Bureau Lorient Communicatie)
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Lustrum
gy: e heritage Sponsoring To make all these things happen funds are needed. A sponsor committee was set-up by Leendert Trouw. Together with Congress Company the committee members are busy trying to obtain the necessary funding for all the activities planned. Apart from the Annual meeting in December, also the other events such as for instance the 8-UMC tour or the Calender App provide unique possibilities for sponsors. For more info on the sponsoring possibilities please contact Congress Company via: sponsoring@congresscompany.com.
deficiencies are at the centre of attention and in Utrecht UMCU (food) allergy. Each centre will provide an introduction into immunology. This is followed by several short speeches by doctors who present patients and researchers the local state-of-the art in research. There will be poster presentations by young researchers. The audience will be given ample time to discuss the presented topics while drinking coffee and eating a small snack. All visitors receive the book ‘Je wonderbaarlijke immuunsysteem’, in English ‘Your miraculous immune system’, which was arranged to be translated from Japanese into Dutch by Ger Rijkers and Frans Kroese as a commemorative gift to remember an interesting day.
Rode Hoed debate The roles of prominent Dutch immunologists will be highlighted, partially including interviews. The Canon is aimed at a broad target group: immunologists and students, colleagues from other disciplines, interested basically knowledgeable citizens, administrators and policy makers. The Canon will take the form of a series of, possibly digitally supported, time-window posters and will also be accessible through the NVVI website. A first impression of this set-up is presented in early April during the annual Lunteren symposium.
The ‘Rode Hoed’ in Amsterdam will be the scene of a debate evening with the theme ‘Immunology is Everywhere’. This debate is meant to inform various stakeholders on the impact of recent advances in immunological research. Also, it is aimed at celebrating previous immunological successes that have led to
8-UMC tour On October 11 the 8-UMC tour will take place. A variety of mini symposia will be held in all eight University Medical Centres in The Netherlands. These symposia are aimed at the general public. The spotlight lies on fifty years of immunology. In each UMC, a specialized topic will be presented, highlighting the local research and clinical applications. The themes for the mini-symposia are as diverse as our field of research is: The Amsterdam AMC highlights HIV and AIDS, the Amsterdam VUmc comments on haematological tumours and stem cell transplantation. The Groningen UMCG focuses on healthy aging with a systemic autoimmune disease, whereas the Leiden University Medical Center (LUMC) has chosen arthritis.
Knowledge of the immune system has provided real solutions for patients The ‘Rode Hoed’ in Amsterdam will be the scene of a lively debate, meant
The Maastricht MUMC has picked organ-specific autoimmune diseases as its focal point and the Radboud Medical Centre Lyme’s disease. In the Rotterdam Erasmus MC humoral immune
to inform various stakeholders on the impact of recent advances in immunological research. (Photo Wikipedia)
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treatment of a large variety of disorders. A sensational example is the huge advance in the treatment of the autoimmune disease rheumatoid arthritis. In the field of immuno therapy against cancer, recently quite spectacular progress was made to redirect the immune system to eliminate cancer cells. Further breakthroughs are expected in many other immune-mediated diseases like type 1 diabetes, coeliac disease and narcolepsy. Finally, it is becoming increasingly clear that deregulated immune responses also play a role in very common disorders like metabolic syndrome caused by obesity, affecting a rapidly increasing number of individuals world-wide. Indeed, during the debate the immunologists will stress the fact that knowledge of the immune system has provided real solutions for patients. In that light, the future of immunological research in The Netherlands will be addressed. Stakeholders not only include patients and patient societies, but also health care organizations, health care insurance companies, the pharmaceutical industry, funding agencies and policy makers. We are looking forward to an exciting debate and hope to welcome you on the NVVI birthday, the 20th of November in the “Rode Hoed”.
Lustrum Meeting: Future Heritage Finally, a ‘once in a lifetime’ 50 years anniversary Lustrum Meeting is organized. This will be a three day conference at ‘De Efteling’, Kaatsheuvel from December 17 to December 19. The NVVI is aiming to set up an exceptional and unique program, with excellent expert speakers from many different fields of Immunology. In addition, scientific interactions and networking will blossom in the warm and special ambiance of the exceptional location of ‘De Efteling’. Here, the researchers will be welcomed in a special NVVI-village. They are invited to show their second talent - next to Science - to the NVVI community in a ‘NVVI got talent’ show and much more. Last but not least, the theme for this anniversary meeting is ‘Future Heritage’ and will form the foundation for the next fifty years! Don’t miss out, be there!
The lustrum is people’s work The Lustrum committee is formed by Esther de Jong (chair), Mieke Boots, Wilfred Germeraad and Leendert Trouw. The Daily calendar (‘scheurkalender’) app-committee is formed by four enthusiastic Dutch immunologists: Angelic van der Aar, Carla Ribeiro, Joris Sprokholt and Ger Rijkers. The Canon of Dutch Immunology committee has as its members Frits Gmelig Meyling (chair), Moh Daha, Bouke Hepkema, Georg Kraal, Jon Laman, Martijn Nolte, Dirk Roos and Marca Wauben. Members of the 8-UMC tour committee are Wilfred Germeraad as chair, Sonja Buschow, Victor Dalm, Andreea Ioan, Edward Knol, Jasper Koning, Frans Kroese, Ester van Leeuwen, Anne-Hilde Muris and Menno van Zelm. Rode Hoed debate committee: Mieke Boots (chair), Bert ‘t Hart, Irma Joosten, Frits Koning, Anje te Velde, Michiel van der Vlist and Lisa Vogelpoel. The Sponsor committee was set-up by Leendert Trouw (chair) and further consists of Bing Thio, Wouter de Jonge, Ellen van der Voort, Jos van Strijp en Stefan Nierkens. The Lustrum Meeting Committee: Esther de Jong (chair), Gaith Bakdash, Leonie van Duivenvoorde, Diahann Jansen, Rogier Reijmers, Hermelijn Smits, Sandra van Vliet.
On behalf of Mieke Boots, Frits Gmelig Meyling, Marieke Herbert, Rogier Reijmers and Leendert Trouw, Wilfred Germeraad
De Efteling is during the second half of December the scene of science. Here the ‘Fata Morgana’ by night. (Photo Wikipedia)
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immunotherapy
The field of antibody therapeutics in cancer immunotherapy is changing rapidly, says Arnout Gerritsen. He is associate director assay and bioanalytical science at Genmab in Utrecht. Antibody-drug conjugates and bispecific antibodies are being tested in the clinic, aiming to boost therapeutic efficacy.
The changing world of antibody therapeutics: Antibodies show their versatility Until recently, conventional IgG antibodies were used to target tumours. These can give anti-tumour activity by engaging antibody effector mechanisms via Immunoglobulin-G (IgG). One side of the antibody, the antigen specific binding site, finds the single target protein on the tumour and binds to it, the Fc tail on the other end of the antibody starts a number of effector mechanisms, such as complement activation. They can, alternatively, also block tumour growth by interfering with molecules involved in cell survival or growth. “Although this can work well, we and other parties now look at alternative routes to boost effectiveness”, Gerritsen remarks.
strengthens their specific killing ability, without altering their regular features.”
Bispecific Another novel approach in cancer immunotherapy is the use of bispecific antibodies. A classic antibody is monospecific: the two binding arms of the antibody both recognize the same target. A bispecific antibody contains two different binding arms, enabling it to recognize and bind to two different antigens. Gerritsen explains the implication: “This for instance enables developing antibodies that block multiple pathogenic
Antibody-drug conjugates One development in an attempt to improve efficacy is to create antibody-drug conjugates (ADC) which potentially can launch a more potent attack against a tumour cell than an antibody on its own: “To form an ADC, an antibody is connected to a toxin, a small molecule. This enables tumour specific chemotherapy. Thanks to the antibody’s specificity, the toxin is guided to the tumour in order to efficiently destroy it, while potentially causing fewer side effects than observed with conventional chemotherapy.” Gerritsen: “This calls for different antibodies with different characteristics: their most important ability should be to enter the tumour cell, to internalize, so that the toxin that comes with it can carry out its destructive task inside the cell.” There are already two drugs on the market that work like this, brentuximab vedotin, targeting the cellular marker CD30 for use in hodgkin lymphoma, and trastuzumab emtansine, for the treatment of patients with HER2-positive metastatic breast cancer. Genmab also started development of an ADC product, which is currently being tested in a phase I clinical trial. Gerritsen: “Apart from that, we have developed new IgG platforms, such as our HexabodyTM technology. As the name already suggests, it enables antibodies to more readily form hexameric structures after binding to tumour cells. This
Arnout Gerritsen: “We are also highly interested in collaborating with smaller pharma or biotech companies and academic groups” (foto Genmab)
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The future promises bispecific antibodies with a drug conjugate pathways and have the potential to be more effective. Another option is to enhance specificity for tumour tissue with less binding to healthy tissue, thereby further limiting side effects.” A further option is for one binding arm to aim specifically at the tumour and the other at T-cells. “In this way the antibody connects T-cells to the tumour and incites them to attack it”, says Gerritsen. For the future, Gerritsen foresees the combination of the ADC and bispecific approaches, resulting in bispecific ADCs.
Collaboration Bispecificity is hot, according to Gerritsen. “Our bispecific Duobody® platform stands out by its ability to work with the same bispecific antibodies from early discovery through large
Bio-One Genmab’s research involves a lot of high throughput screening. The company is one of the few parties in the Netherlands to use 1536 wells plates. Genmab has chosen Greiner Bio-One plates. In later research phases, 384 wells plates are used for cell based arrays. This article was enabled by Greiner
scale manufacturing. This combination approach is scalable in manufacturing from very small amounts in early discovery to large quantities in the clinical phases.” Big pharma is already persuaded by the qualities of the antibodies created with the Duobody platform, Gerritsen says. “We are also highly interested in collaborating with smaller pharma or biotech companies and academic groups to make full use of bispecific antibodies as differentiated therapies for the future.”
News Targeted inhibition of Inflammatory Bowel Diseases (IBD) The European Union donates 1.5 million euros to Saskia van Mil PhD of the Utrecht University Medical Center for research into inflammatory bowel disease (IBD). Van Mil hopes to develop new medication. “Crohn’s Disease and colitis ulcerosa, two types of IBD, are incurable. In The Netherlands alone 60,000 people suffer from these diseases”, says Van Mil. She is an expert in the field of the FXR receptor. “At present, the applied medication is very general and not effective in all patients. Also, the drugs sometimes provoke side effects. Through research into the bilious acid receptor FXR, I hope to develop new and smarter medication which aims at targeted inhibition of intestinal inflammations.”
From mouse to man She has already proven that switching on the FXR-receptor in mice helps to inhibit intestinal inflammations, but she will now look for a smarter way to switch on this receptor in humans. Based on her knowledge of the three dimensional structure of the receptor, she will test substances which only switch on the inflammation inhibitory effects and which do not influence the energy resulating system. For this part of her research Van Mil cooperates with the company TES Pharma.
Bacterial fingerprint Van Mil will also, together with Bas Oldenburg PhD of the department of Gastro-enterology and Hepatology at the Utrecht University Medical Center, study the composition of the bacteria involved in IBD. Van Mil and Oldenburg make several ‘fingerprints’ of the faeces. Changes in the composition may predict newly arising medical problems. If this approach is successful, it could lead to the development of a new drug. Also, the fingerprint analysis could replace the colonoscopy. In this particular study, Van Mil and Oldenburg will join forces with the company Enterome Bioscience.
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Janneke Samsom: “Participants will leave full of enthusiasm and full of new knowledge on mucosal immunology.” (Photo Erasmus MC Rotterdam)
This year the 42th NVVI Lunteren meeting will take place on the 3rd and 4th of April. The event is entitled “Mucosal Immunology: Crossing borders”. One of the speakers in this international symposium is Dr. Janneke Samsom, who is heading the Laboratory of Pediatric Gastroenterology at the Erasmus MC Rotterdam. In recent years (2005-2012) she was involved in the organization of this annual event; she was president of the Lunteren committee for three years. Excellent reasons to ask the expert about Crossing borders.
Lunteren 2014: Crossing borders, meeting speakers Why is an annual Lunteren Symposium a good idea and for whom exactly is it intended? “The Lunteren symposium is an important meeting for young researchers, such as PhD students, post-docs or technicians. However, the meeting is becoming more and more popular among senior investigators as well, because of the high quality overview talks in the program. In my view the success of Lunteren lies in combining a small scale event with a balanced selection of speakers who have the capacity to pass on their personal enthusiasm for science. This atmosphere stimulates young scientists to contact the speakers. Obviously, the meetthe-speaker breakfasts play a central role in this.” After forty years, the Lunteren Course has now changed its name into Lunteren Symposium. How do you see this? “It is a good development that has come naturally. A meeting like this has to keep up with times. I think it is essential that young people and technicians are encouraged to attend. In general, these groups visit international conferences less frequently and therefore benefit greatly from a reasonably priced, high quality meeting in the Netherlands. What makes co-organizing Lunteren meetings so attractive? “Many things….It is fun to search for excellent keynote speakers. Moreover, it is fun to brainstorm about a central meeting theme that would be right on target for many immunologists. The talks should not only be educational and well-structured, but also ‘Mucosal Immunology: crossing borders’ NVVI Symposium Lunteren, 2014, April 3-4 Congrescentrum De Werelt, Lunteren, The Netherlands
technically interesting. In the end, it is rewarding to see that the program as a whole presents a flow or chain from molecules via cells and animal models to patients.” What do you expect of “Mucosal Immunology: crossing borders”? “A wonderful and diverse symposium; participants will leave full of enthusiasm and full of new knowledge on mucosal immunology. I feel that everybody should go with his or her own goals in mind. It is easy to prepare well for the meeting, for example by going through the abstracts online and by background reading. Whereas a PhD student may go to the meeting with a clear aim to ask particular questions to one of the speakers, a technician may be looking for a broader context of his or her research or for detailed information about a specific technique.” Are there any particular borders that have to be crossed in mucosal immunology or immunology in general? “I think that mucosal immunologists cross borders all the time. We are semi-gastroenterologists, semi-pulmonologists and every now and then almost microbiologists. This cross-talk is the exciting part. The biggest challenge is the translation from mouse into man, which is hampered by the heterogeneity of diseases that mucosal immunologists study. This field requires smart experiments for which an unlimited range of molecular, cellular and immunological techniques is needed. The great thing is that all of this is actually present within the Dutch immunological landscape. So, it only comes down to money and people.” Why should every immunologist or non-immunologist attend? “For obvious reasons: the amazing program, featuring many inspiring speakers who are easily approachable.” Rudi Hendriks, Erasmus MC Rotterdam
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news Vaccine reduces chance of getting pneumonia Pneumonia is an important cause of mortality among the elderly. Vaccination reduces the chance for elderly people to develop pneumonia. A University of Utrecht Medical Center study among 85,000 participants has proven the efficacy of a vaccine against several variants of the pneumococcus bacteria in Dutch senior citizens (+65 years). The Community Acquired Pneumonia Immunization Trial in Adults (CAPiTA) study aimed at verifying the efficacy of the Prevenar-13 vaccine against thirteen different types of the Streptococcus pneumoniae in elderly people. Professor Marc Bonten of the University of Utrecht Medical Center: “For the first time in history it has been conclusively proven that vaccination can indeed prevent an important part of the cases of pneumonia in elderly people.” Pneumonia occurs about 450 million times a year and is worldwide responsible for over four million deaths per year.
Immunologic memory The American pharmaceutical company Wyeth developed the new vaccine that is aimed at protecting against thirteen of the ninety known types of Streptococcus pneumoniae. An existing vaccine contains ingredients against 23 varieties, but this vaccine is not very effective. It is not part of the Dutch State vaccination programme (Rijksvaccinatieprogramma). Since April 2006 there is a sevenfold vaccine against Streptococcus pneumoniae in use, but only with children. This is a so-called conjugate vaccine: it not only contains sugar molecules from the outside of the bacteria, but also a substance added to incite the immune system. The new thirteen-fold vaccine uses the same approach. It incites an immunologic memory, which means that people will only have to be injected once to cause the protective effect. Bonten: “The new vaccine is almost identical to the sevenfold vaccine for children, only the effect on elderly people was never studied previously. The vaccination programme in The Netherlands has led to seventy to eighty percent reduction of pneumonia cases in children.”
Noticeable effect Before the present study, it was unknown whether there would be a protective effect in elderly people and if so, what the extent of protection would be. Because it is about large numbers, minor effects would be hardly measurable. The new vaccine therefore had to have a major impact in order to become noticeable in the trial results – which it did. Sources: UMC Utrecht, Hart Long Stichting Utrecht
(Photo Wikipedia)
STW awards validation grant to drug against flu In her valorisation programme Demonstrator, meant to get new technologies beyond the proof-of-principle into the stage of a working demonstration model, technology foundation STW has selected two projects for grants. One of these projects, in the field of computer games, has little to do with immunology, but the other project, of Utrecht University, aims at the development of a medicine against the flu on the basis of a cleverly adjusted protein. The awarded project is called ‘Modified human SP-D: a new multifunctional antiviral drug against the flu’. Professor Henk Haagsman of the Faculty of Animal Health of Utrecht University, department Infectious Diseases and Immunology, is the main applicant. Annual flu epidemics with high sickness and mortality rates among man and the consistent threat of a pandemic flu outbreak show that protection via existing vaccination strategies and conventional anti-viral products are insufficient. Haagsman develops a new, directly active antiviral drug sgainst flu based on a cleverly adjusted, natural human pulmonary protein called SP-D. Laboratory experiments show that the new drug very effectively blocks potentially dangerous flu viruses for humans. The Demonstrator project will further investigate the efficacy of the new drug in a flu infection animal model. Source: STW Henk Haagsman, UMC (Photo ImmunoValley)
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