CIR Annual report 2014

Centre for Immune Regulation

CIR ANNUAL REPORT 2014 RESEARCH GROUPS PUBLICATIONS DISSEMINATION ACTIVITIES ABOUT

VISION STATEMENT

This centre identifies and investigates novel mechanisms of immune dysregulation to advance the development of therapeutics.

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2014 T-B collaboration. Importantly, dendritic cells are not needed for such collaboration.

n We described and characterized

Id-driven T B collaboration as a drive for anti-dsDNA B cells in the systemic autoimmune disease Lupus, demonstrating clonal expansion in lupus-prone mice – both in terms of BCR sequences and by demonstrating anti-dsDNA B cells in functional assays and flow cytometry.

n Monoclonal antibodies were

cloned from single gluten-specific plasma cells isolated from coeliac lesions (Nat Comm 2014). Glutenspecific IgA were found to have restricted VH/VL usage and limited numbers of mutations.

n Published an Ig double knock-in

mouse with an anti-Id BCR. Used this mouse to show that Id-specific T and B cells can recognize Id+Ig via conventional mechanisms for

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n Increased our understanding

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of the interaction between the serum half-life regulating receptor, FcRn, and albumin. Designed

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and characterized novel albumin variants with increased binding to FcRn that will be used as carriers of biopharmaceuticals to increase their serum half-life. n Defined a role for CCL28-CCR3

in T-cell homing to the human upper airway mucosa. n Showed that a specific Rab,

important in dendritic cells, interacts with the cytoskeleton and regulates both actin organization and cellular migration.

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DIRECTOR’S COMMENTS

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Ludvig M. Sollid Centre Director

2014 has been an active year for CIR. Perhaps the most memorable event was when its members gathered at the end of August for a retreat at Soria Moria. The three Scientific Advisory Board members Sirpa Jalkanen, Søren Buus and Rikard Holmdahl took part in the meeting. They discussed science with CIR scientists and they met with group leaders to advice on scientific matters and priorities to be made within the Centre. Rudolf Valenta from Austria gave a keynote lecture, as did Rikard Holmdahl. The retreat was organised by an organising committee together with Anders Sandvik. They did an excellent job and I thank them for their effort.

There have been a number of scientists who have visited CIR during the year to give guest lectures. These include Jacques Neefjes, Kunchithapadam Swaminathan, Matthew Collin, Patrick Holt, Ralf Küppers, Yueh-Hsieu Chien, Ana-Maria Lennon-Dumenil, Gur Yaari and Gabriel Victora. Most of the speakers were invited to take part in a seminar series organised by a postdoctoral committee. I take the opportunity to thank this committee for conducting this task which is of immense importance to CIR. In my comments from last year I described the effort we have made to recruit new faculty to CIR. Due to space constraints at the premises of CIR, the Board of CIR decided that rather than advertising a full professorship position, an associate professorship for a junior faculty member should be advertised.

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This was done in the autumn of 2014, and 10 applicants had submitted their application by the deadline. On writing these comments, I have just learned that the selection board has submitted their recommendation for the rank order of the best-qualified applicants.

Interviews will be made shortly and a candidate will be offered the position before the summer. This person then will have the opportunity to work two and half year at CIR before our Centre is history.

In 2014, CIR scientist authored or co-authored 47 papers in international peer reviewed journals. Two PhD students defended their thesis in 2014; Synne Jenum and Astrid Tutturen.

I congratulate the candidates and their supervisors. I also thank the opponents for their effort in evaluating the work of our candidates.

Our Visiting Professor programme had visits from Mark Davis (Stanford) and Susan K. Pierce (NIAID, NIH) in 2014. In 2015 we expect revisits from Mark Davis (Stanford) and Bana Jabri (University of Chicago) as well as a visit

by Bernhard Malissen (Centre d'Immunologie de Marseille-Luminy, France) who will be a new Visiting Professor at CIR. Anders Sandvik left his position as administrative coordinator of CIR. He got an exciting job offer from industry. I wish Anders the best of luck in his new job, and thank him wholeheartedly for the excellent job he did for us. We have been very fortunate what regards Anders’ successor – Lise Kveberg. Lise was working as an experienced postdoc in a neighbouring group at the Department of Immunology. Knowing her qualifications we successfully managed to convince her that the position as administrative coordinator of CIR would be a perfect next job station.

The transition has been seamless.

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CONTENTS

The Research Council of Norway has announced that the forth call in the Centre of Excellence (SFF-IV) scheme. Applicants will qualify in a two step application procedure.

The deadline for the first step application will be in November 2015. My hope is that the members of CIR will not be too distracted by this fact and that the inner life of CIR can continue undisturbed. I know there are many interesting project running that deserve to receive our full attention. I hope 2015 will be an interesting and rewarding year for all the scientists at CIR.

Vision statement Key accomplishments 2014 Director’s comments Scientific currency Innovation and industrialisation Core competency

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RESEARCH GROUPS Bakke group Bogen group Jahnsen group Munthe group Sandlie group Sollid group

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ABOUT CIR Facts and figures 30 Funding and expenditures 31 Staff and students 32 Collaboration 34 Education and career development 36 ACTIVITIES Visiting Professor program 40 Minisymposium 40 Work package (WP) symposia 41 Guest lectures 42 Internal activities 43 PUBLICATIONS Papers in scientific journals 46 Other papers 48 Books and book chapters 48 Patents 49 DISSEMINATION Invited lectures Oral presentations Poster presentations Other presentations Presentations to a targeted audience and the public Media coverage

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52 53 54 55 55 56

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SCIENTIFIC CURRENCY Impact factor distribution – CIR publications 2014

9%

6%

28%

57%

8 <5 5–10 >10 No IF available

CIR publications with collaborating institutions 2014

PAPERS CIR scientist authored or co-authored 47 papers in international peer-reviewed journals in 2014. The total number of publications per year remains stable. Of the papers published in 2014, four publications reached journals with an impact factor above 10.0 and more than one third of the publications reached journals with an impact factor above 5.0. In general the quality and visibility of publications from the centre is high. CIR scientists have extensive collaborations with national and international research groups. Close to 6 of 10 papers published in 2014 with one or more CIR authors are the result of collaborations with international institutions.

Impact factor distribution and publications based on collaborations is illustrated in the figures below. CIR publications in 2014 are presented on page 4 of this report. National and international collaborators are listed on page 4.

19%

53%

19% 9%

International International and national

PATENTS Researchers at CIR have a strong interest in, and record of, innovation and securing of intellectual property rights from research.

The accumulated number of patents granted or patent applications filed by CIR scientists since CIR commenced operations is 28. Read more in the innovation and industrialisation section on page 4.

National

DISSEMINATION OF RESEARCH RESULTS CIR members gave 32 talks as invited speakers at international scientific meetings in 2014. In addition 12 oral presentations and 20 posters were presented by CIR scientists at international conferences. Furthermore, CIR staff gave 25 lectures and articles aimed at a targeted audience and the general public.

These include postgraduate lectures, research seminars, training courses at universities and hospitals, as well as presentations to patient organisations and professional organisations. Talks, posters and dissemination activities aimed at a targeted audience and the public, as well as media coverage, are listed in the back of this report.

PRIZES AND AWARDS CIR scientist Inger Sandlie received the Inven2 honorary award. In 2011, Inger Sandlie was the first to receive UiOs inno­ vation prize, and now she received an honorary award for the registration of a total of 100 innovational ideas to Inven2.

The prize was presented at the Cutting Edge/Oslo Innovation Week at Forskningparken in October.

The Oslo University Hospital’s Excellent Researcher Award 2014 was awarded to CIR Director Ludvig M. Sollid for his outstanding research on the pathogenesis of celiac disease. The prize was presented at a staff meeting in August at Oslo University Hospital, Rikshospitalet.

Professor emeritus Per Brandtzæg was awarded the Nordic Fernström prize 2014 for his major contribution throughout his career to the understanding of the role and function of the immune system in the intestinal mucosa.

CIR-only

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Cinzia Progida was awarded the Research prize from Lab Norge 2014 for her work on molecular mechanisms for intracellular transport. This prize is given to stimulate young scientists below 35 years.

CONTRIBUTION TO LOCAL RESEARCH ENVIRONMENT CIR supports the Norwegian Society for Immunology (NSI) and has the ambition to contribute to the whole immunological research environment in Oslo. CIR members are collectively members of the NSI and the centre co-host lectures with the society.

Importantly, guest lectures and mini­sym­ posia hosted by CIR are open to anyone interested and we actively invite the broader immunology community to attend these events. Furthermore, we also invite researchers from outside the centre as speakers at these open events.

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Centre staff is involved in the education and supervision of basic scientists and clinicians at all levels. CIR scientists have organised or lectured at graduate courses in molecular cell biology and immunology including Basic immunology and immunological techniques and Advanced immunology offered by the University of Oslo.

Centre for Immune Regulation (CIR) FOCIS-COE CIR is a Federation of Clinical Immunology Societies (FOCIS) Centre of Excellence (FCE) (www.focisnet.org). The FCEs represents an exclusive community of institutions of outstanding clinical and scientific quality.

There are 70 FCE’s worldwide, with approximately 45 centres in North-America and 20 in Europe. The FCE status represents an international recognition of the quality and impact of CIR and provides an opportunity for CIR to strengthen our translational immunology activities.

Above: Oslo 14.10.2014, Oslo Innovation Week.

Cutting Edge: Inger Sandlie, winner of Inven2 Ærespris 2014. Photo: Gorm K. Gaare.

Top: Edward Leithe, Institutt for kreftforskning (Early Career Award 2014) Ludvig M. Sollid, Avdeling for immunologi og transfusjonsmedisin (Excellent Researcher Award 2014) Kyrre Eeg Emblem, Intervensjonssenteret (Early Career Award 2014) Photo: Ram Gupta/OUS

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CIR staff manages and operates advanced technology and share their technical expertise with the surrounding research environment. CIR group leader Oddmund Bakke heads an advanced imaging platform specialising in subcellular studies of live and fixed cells. In 2013, the NorMIC-UiO imaging platform opened as a national facility. CIR group leader Frode Jahnsen is head of the Confocal microscopy Core facility at the Department of Pathology, offering services within confocal laser scanning microscopy. CIR scientist Gustavo De Souza heads the Proteomics Core facility at Department of Immunology. The facility offers advanced analysis of proteins and peptides by mass spectrometry.

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INNOVATION AND INDUSTRIALISATIO

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VACCIBODY AS Two of the CIR groups (Bogen and Sandlie) have developed novel vaccine molecules, known as Vaccibodies, which induce superior immune responses in a variety of animals. A spin-out company, Vaccibody AS, was founded in 2007 based on the patented technology. Vaccibodies target antigen presenting cells for efficient delivery of antigen and induction of immune responses. The vaccines are delivered as DNA plasmids administered intramuscularly or intra­ dermally. The muscle or skin cells produce and secrete Vaccibody proteins that target antigen presenting cells and load them with antigen for presentation to lymphocytes.

The patent portfolio is continuously strengthened with clinical use and novel targeting units for a variety of applications.

In 2014 the European Patent Office granted European patent No. 1599504 and the U.S. Patent Office issued patent No. US 8,932,603 B2, covering the Vaccibody format. The patent protects Vaccibody’s platform technology on which the company has based its lead human drug candidate VBV1016, as well as a license agreement with the Phibro Animal Health Corporation, covering vaccines for poultry. The company has made significant progress with VBV1016, a therapeutic vaccine against cervical pre-cancerous lesions, and plans to initiate its first clinical trial in 2015. Vaccines for other indications within cancer and infectious diseases for human and veterinary use are also developed with academic and industrial partners. In July 2014, Vaccibody issued new shares for 35 million NOK. An investment by the Norwegian Cancer Society was instrumental in the process.

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NEXTERA AS Phage display is the dominating technology for discovery and refinement of novel protein-based diagnostics and therapeutics.

A significantly improved version termed SSIp display has been developed by the Sandlie group at CIR, and commercialized by a spinout company, Nextera AS. Nextera was established by key inventor CIR scientist Geir Åge Løset and Biomedical Innovation AS, and Geir Åge Løset has been the Chief Scientific Officer since the company was established in 2009.

Additional jointly developed IPR was aquired from Affitech AS in 2012 and Nextera has furthermore inlicensed innovations related to MHC class II through Inven2. These were jointly developed by the Sandlie and Bogen groups at CIR. Through 2013, Nextera were granted patent rights to W02009/024591, WO2010/097411, WO2010/097589, WO2011/036555 and WO2011/101681. The technology platform is continually strengthened and national IPR was granted in several major countries in 2014.

The core activity of the company is presently focused on phage display of T cell receptors and MHC class II molecules, socalled Phagemers.

Nextera AS is performing joint research with the Sollid and Sandlie groups at CIR partially funded by a major NRC BIA grant using Phagemers with the aim of developing novel therapeutics for Crohns disease.

In 2013 Nextera raised 550 000€ in private equity which secures continuous funding of research activities, as well as strengthening the Board of Directors, management and R&D team.

CENTRE FOR IMMUNE REGULATION (CIR)

ON

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EXTENDING IN VIVO HALF-LIFE OF SMALL DRUGS The efficacy of chemical drugs, peptides, small proteins and engineered antibody fragments are hampered by short serum half-life, ranging from minutes to a few hours. Therefore, strategies to tailor their serum persistence and biodistribution are needed. Inger Sandlie and Jan Terje

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Andersen have developed a unique technology that may extend the in vivo half-life of potentially all chemical and protein drugs. This will ultimately result in drugs with stabilized serum levels, which means less side effects and less frequent dosing. Together with Inven2, they have signed agreements with Novozymes Biopharma, and together with Novozymes, established a very success足足ful

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research program. So far, six patent families have been filed by Novo­zymes based on the results of the collaborative research.

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As a result of this collaboration, Novozymes has launched new products initially named Albufuse Flex and Recombumin Flex, and recently the Veltis® technology. In short, the new products are based on a list of new albumin variants. All have one or more amino acids that differ from normal albumin. They bind the neonatal Fc receptor with a range of different affinities, and when tested in rats and rhesus monkeys show greatly altered half-life. The best binders have increased and the poorest binder decreased half-life. Now, either genetic fusion (peptide or protein) or chemical conjugation of small drugs to either of these albumin variants will greatly alter the serum half-life of the drug. In 2013 and 2014, new albumin variants have been designed with increased half-life beyond that of earlier versions.

Novozymes presents the technolgy as follows: • Veltis® – engineered albumins for optimized drug dosing • Veltis® enables you to control dose frequency, drug tolerability and dose quantity. So, now you can optimize your therapeutic window easily, and naturally.

Novozymes Veltis® is a half-life extension platform based on engineered albumins designed to provide once-weekly, once twoweekly or once-monthly peptide or protein dosing and stricter patient adherence (compliance) for improved therapeutic impact.

In addition to being developed by worldleading science the technology is also

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backed up by the deep technical and regulatory support available from Novozymes.

Furthermore, based on Novozymes' decades-long experience of recombinant albumin GMP manufacturing, the access to large-scale yeast expression and protein production ensures a secure route to commercial exploitation of the system.

The unique advantages provided by Veltis® include: • proven clinical performance with significant half-life extension improvement over native albumin and other technologies • flexible and scalable manufacturing by fusion or conjugation for commercial supply • long life IPRs • patient-friendly dosing and low risk of adverse effects • provided by a technology developer with a strong heritage and track record in commercial albumin supply Copenhagen, Denmark – 13 March 2014 – Novozymes Biopharma, part of Novozymes A/S, a world leader in bioinnovation, has today announced a collaboration with Janssen Research & Development, LLC (Janssen).

The agreement will enable Janssen to evaluate Novozymes Biopharma’s engineered albumin-based VELTIS™ technology for potential drug candidates.

Novozymes Biopharma has entered a new collaborative research agreement with one of the world’s top vaccine companies. The partnership will enable the company to evaluate Novozymes Biopharma's modified recombinant human albumin VELTIS technology to assess the dosing and performance of a novel subunit antigen vaccine candidate.

CENTRE FOR IMMUNE REGULATION (CIR)

Human FcRn

His 161

His 166

Copenhagen, Denmark – 31 March 2014 – Novozymes Biopharma DK A/S, a subsidiary of Novozymes A/S, a world leader in bioinnovation, has announced that its albumin-based VELTIS half-life extension technology is being used by GlaxoSmithKline in the recently authorized Eperzan® (albiglutide) for the treatment of type 2 diabetes in Europe.

Trp 51 Trp 59

Trp 61 Val 52 Trp 53

The US Food and Drug Administration (FDA) has granted marketing approval to GlaxoSmithKline's new type 2 diabetes drug, branded Tanzeum in the US and Eperzan in Europe, which uses Novozymes' Veltis technology to achieve an extended half-life that means patients are only required to inject their medication once a week. The FDA approval follows GlaxoSmithKline's announcement in March that albiglutide received marketing authorization in Europe.

Rat FcRn Glu 163

PATENTS Patents and filed patent applications by CIR scientists are listed on page 6.

His 168 Trp 51 Trp 59

Trp 61

FcRn regulates serum half-life of albumin and IgG. Comparison of human and rat FcRn crystal structures.

The residues shown are involved in albumin binding.

The tryptophan residues shown in red make hydrophobic contacts with albumin. Histidine 166 in human and histidine 168 in rat FcRn regulate the pH dependence of the inter­action. Illustration: Kine M.K. Sand.

Modified by Millimeterpress with permission.

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Ile 52 Trp 53

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CORE COMPETENCY AT CIR 14

• A wide variety of cellular and humoral immune assays.

• Advanced methods in molecular biology, proteomics and cellular imaging.

• Disease models in humans and animals.

The models are used to understand the molecular mechanisms of immune regulation and autoimmunity.

• Transgenic mouse models.

• Functional characterisation of immune cells in human tissue.

• Study of immune molecules and their intracellular functions in antigen presenting cells.

• Molecular engineering for the development of new therapeutic agents and research reagents.

JAHNSEN GROUP • Human model of airway allergy in vitro and in vivo • Mucosal antibody system • Dendritic cells • Immunohistochemistry • Flow cytometry

SOLLID GROUP • Human cellular immunology • In vitro study of CD4+ T cells • Recombinant soluble HLA molecules • Mass spectrometry and proteomics • Characterisation of lymphocyte antigen receptors

MUNTHE GROUP • Cellular assays • Mouse experiments including xenograft • Cell culture, functional biology • Flow cytometry

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BAKKE GROUP • Live cell Imaging • Confocal microscopy • Characterisation of intracellular trafficking pathways • Transfection of cells and the study of binding kinetics of cytosolic molecules

SANDLIE GROUP • Structure and ligand binding properties of antibodies and T-cell receptors • Phage display • Recombinant molecule expression and purification • Interaction studies

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CIR

BOGEN GROUP • Cellular immunology • Experimental studies in mice • Transgenic mice

The centre consists of research groups with complementary scientific expertise. Two groups, headed by Inger Sandlie and Oddmund Bakke, are affiliated with the Department of Biosciences at the Faculty of Mathematics and Natural Sciences. Three research groups, headed by Bjarne Bogen, Ludvig A. Munthe and Ludvig

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Sollid are affiliated with the Department of Immunology at the Faculty of Medicine. One group, headed by Frode L. Jahnsen, is a member of the Laboratory for Immunohistochemistry and Immunopathology, Department of Pathology, at the Faculty of Medicine.

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CENTRE FOR IMMUNE REGULATION (CIR)

BAKKE GROUP

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Our group has since the early nineties aimed to understand the endocytic pathway and how peptide loading of the MHC class II complexes (MHC II) is regulated.

A special focus for the group is to elucidate the contribution of the invariant chain (Ii) to the biogenesis of an antigen presenting cell (APC) specific endocytic pathway (Landsverk et al., 2009, 2011, 2012).

OVERVIEW OF RESEARCH IN THE GROUP Invariant chain (Ii) plays a vital role in MHC II assembly and intracellular transport, but has been attributed an increasing number of additional functions in both antigen presentation, cell signalling and as a vehicle for loading antigens in immunisation protocols.

An evolutionary conserved property of Ii is to induce the convergence, or fusion of early endocytic vesicles, and this property may serve vital functions in antigen presentation, cell signalling and beyond. Further­more we study the influence of other regulatory molecules essential for the antigen loading compartment such as the small GTP-ases (Berg-Larsen et al., 2013, Borg et al., 2014).

The group consist of 2 researchers, 2 postdocs, 2 PhD students, 4 master students and 2 technicians. The Bakke group also runs the NFR- INFRASTUCTURE supported Norwegian Molecular Imaging Consortium, NorMIC-Oslo. NorMIC-Oslo opened as a national imaging facility in 2013 and was in 2014 recommended to become an Eurobioimaging node in a pan European network of imaging nodes.

KEY PROJECT SUMMARIES • The group is focusing on the properties of the endosomal pathway in cells in general and the adaptations to this pathway in immune cells. The projects can be divided into five sub themes: • Sorting and trafficking of immune mole­ cules in model cell lines and in dendritic cells.

• Regulation of vesicular transport between the Golgi network and the endosomal and auophagosomal pathway searching for new players.

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• Study of endosomal maturation and how the antigen loading compartment, the immunoendosome, is formed.

• Regulation of receptor signalling by endocytic sorting and endosomal effector kinetics in the endosomal pathway.

• Investigation of the mechanisms by which activated macrophages kill cancer cells in mice and humans.

Our work is primarily focused on understanding the process of antigen uptake, processing and presentation. These events are instrumental to the initiation and propagation of adaptive immune responses. The endocytic pathway common to all cells is uniquely adapted by specific immune cells to achieve this purpose. In order to achieve our ultimate goals with regard to discovering the specifics of immune cell functions, we have invested a large body of research on how the endocytic pathway functions in general in model cell systems. We have contributed to the current understanding of cell biological processes in the endocytic pathway in general and our current goal is to use this foundation to elucidate the unique adaptations to this system in antigen-presenting cells. This will provide the basis to better understand vaccination regimes and protocols for immune therapy of cancers, autoimmune-, and infectious diseases.

CENTRE FOR IMMUNE REGULATION (CIR)

Oddmund Bakke

Our main strategy employs a wide array of advanced live cell imaging technologies, supplemented by biochemistry, immuno­ logical assays and DNA/RNA techniques.

The group collaborates in studies within CIR, where we provide the cell biological outlook and essential microscopy expertise.

These include: • Uptake and sorting of targeted antigen (Bogen).

• B lymphoma cells with complementary BCRs delete each other in vitro (Jacobsen/ Bogen) • Intracellular trafficking of the FcRn receptor (Andersen/ Sandlie)

CENTRAL PUBLICATIONS IN 2014 Borg M, Bakke O, Progida C (2014) A novel interaction between Rab7b and actomyosin reveals a dual role in intracellular transport and cell migration. J Cell Sci.;127:4927-39 Knudsen Sand KM, Landsverk OJ, BergLarsen A, Bakke O, Gregers TF. (2014) The human-specific invariant chain isoform Iip35 modulates Iip33 trafficking and function. Immunol Cell Biol. 2014 92:791-798.

Wälchli S, Kumari S, Fallang LE, Sand KM, Yang W, Landsverk OJ, Bakke O, Olweus J, Gregers TF (2014) Invariant chain as a vehicle to load antigenic peptides on human MHC class I for cytotoxic T-cell activation.

Eur J Immunol. 44, 774-84.

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ACHIEVEMENTS IN 2014 • Showed that a specific Rab, important in dendritic cells, interacts with the cytoskeleton and regulates both actin organization and cellular migration (J Cell Science, 2014).

• Described how the human specific form of invariant chain may influence the trafficking of other forms of the molecule and thereby trafficking of MHC II (Immunol and Cell Biol, 2014).

• Developed a patented and invariant chain based vector for immune therapy against cancer (Patent submitted).

AMBITIONS FOR 2015 • Dissect elements of the molecular mechanisms for sorting to the intracellular antigen loading compartment based on high throughput antigen loading screens.

• Using an autophagosomal interaction partner of Rab7B we will elucidate how autophagy is connected to transport from the trans Golgi network.

• Characterise endosomal maturation in dendritic cells and the Meljuso model antigen presenting cells. Define a pathway to the MHC II antigen loading compartment.

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BOGEN GROUP

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The Bogen group runs projects with three areas, 1) Idiotype-driven T-B collaboration and its role in health and disease, 2) The mechanism by which CD4+ T cells can reject cancer cells, 3) Novel vaccine molecules for cancer and infectious diseases (organized in K.G. Jebsen Centre for Research on Influenza Vaccines).

INTRO Immunoglobins (Ig, antibodies) are extremely diverse, the heterogeneity being localized to their variable (V) regions. Bogen and co-workers showed more than 25 years ago that Ig is partially broken down inside cells and that proteolytic fragments of the V-regions [Idiotypic (Id)-fragments] are presented on Major Histocompatibility Complex (MHC) class II molecules to Id-specific CD4+ T cells. This phenomenon forms the foundation for the CIR-related projects of the research group, outlined below.

KEY PROJECT SUMMARIES The basis for Id-driven T-B collaboration is that B cells spontaneously degrade their Ig-receptor for antigen (BCR), and display Id-peptides bound to MHC class II molecules on their cell surface. Such Id/MHCII complexes can be recognized by Id-specific CD4+ T cells. Now, if a B cell happens to recognize a self-antigen with its BCR, and at the same time receives help from an Id-specific CD4+ T cell, the B cell receiving these two distinct signals will be activated, proliferate and differentiate. This may result in immune dysregulation, autoimmunity and B lymphoma development. To study Id-driven T-B collaboration in even more detail, we have generated novel BCR knock-in mice. In one of these strains, a mutated Id-sequence (3 amino acids) have been successfully inserted in a germ-line V gene segment. The latter mouse should represent a close to physiological model for Id-driven T-B collaboration. A project on elucidation of the ternary Id-specific TCR/Id-peptide/MHC class II (I-Ed) molecule is in progress (with Inger Sandlie).

Id-driven T-B collaboration is now being

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extended to human autoimmune disease and lymphoma development in collaboration with Ludvig Munthe (see his report) The basis for the tumor immunological experiments of the group is that Ig secreted by multiple myeloma cells (malignant plasma cells) is processed and presented on MHC class II molecules of tumor-infiltrating macrophages. An interplay between Id-specific CD4+ T cells and macrophages results in activation of macrophages that in turn kill the tumor cells. In 2014 we have reported that the above described mechanism does not confer bystander killing of antigennegative tumor cells. Moreover, we have detected a mechanism by which tumor cells can escape killing by CD4+ T cells. Ongoing experiments focus on the molecular mechanisms by which activated macrophages kill tumor cells. A bone-marrow model for multiple myeloma (the MOPC315.BM model), published by our group in 2012, has now been distributed to a large number (>20) collaborators world-wide. Our group is doing work in this model, and we have demonstrated that CD4+ T cells can kill tumor cells residing in the bone marrow.

Internationally, it is now increasingly recognized that CD4+ T cells play an important role in rejection of tumors, also in humans.

CENTRAL PUBLICATIONS IN 2014 Jacobsen J, Haabeth OA, Tveita AA, Schjetne KW, Munthe LA, Bogen B.Naive idiotopespecific B and T cells collaborate efficiently in the absence of dendritic cells. J Immunol.

2014 ,192(9):4174-83. PMID: 24706724

CENTRE FOR IMMUNE REGULATION (CIR)

Bjarne Bogen

Tveita AT, Schjesvold FM, Sundnes O, Haabeth OAW, Haraldsen G, Bogen B. Indirect CD4+ T cell-mediated elimination of MHC IINEG tumor cells is spatially restricted and fails to prevent escape of antigennegative cells. Eur. J. Immunol, Sep; 44(9): 2625-37. PMID: 24846412 Ruffini PA, Os A, Dolcetti R, Tjonnfjord GE, Munthe LA, Bogen B. Targeted DNA vaccines eliciting crossreactive anti-idiotypic antibody responses against human B cell malignancies in mice. Journal of Translational Medicine. Jul 25;12:207, 2014, PMID: 25059102 Fossum E, Grødeland G, Terhorst D, Tveita AA, Vikse E, Mjaaland S, Henri S, Malissen B, Bogen B. Vaccine molecules targeting Xcr1 on cross-presenting DCs induce protective CD8+ T-cell responses against influenza virus. Eur J Immunol Nov 20 doi:10.1002/ eji.201445080 [Epub ahead of print] PMID: 25410055

ACHIEVEMENTS IN 2014 • Published an Ig double knock-in mouse with an anti-Id BCR. Used this mouse to show that Id-specific T and B cells can recognize Id+Ig via conventional mechanisms for T-B collaboration. Importantly, dendritic cells are not needed for such collaboration.

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• Established an Ig VH knock-in mouse that, when bred with 2315-transgenic mice, establishes a model for an Id+ BCR. • Established a knock in mouse where 3 mutated amino acids have replaced 3 germline-encoded residues in a V gene segment. This is the first time such a knock-in has been generated. The mouse should be an important tool for studies on Id-driven T-B collaboration.

• Published that the CD4+ T cell/macrophage mechanism for tumor cell killing does not confer elimination of antigen-negative tumor cells.

• Detected a molecular mechanism by which tumor cells can escape elimination

by CD4+ T cells/macrophages.

AMBITIONS FOR 2015 • To investigate the importance of BCRligation by self-antigen in Idiotypedriven T-B collaboration, using the new BCR knock-in mice described above.

• To study interaction of B cells with complementary BCRs by use of the knockin mice generated in 2014.

• To explore the molecular mechanism by which CD4+ T cells reject tumour cells.

• To study CD4+/macrophage-mediated elimination of tumor cells in the bone marrow.

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JAHNSEN GROUP We study the mucosal immune system in the human gut and airways both under homeostatic conditions and during inflammation.

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OVERVIEW OF RESEARCH IN THE GROUP The turn-over rate of immune cells in the human body is an important characteristic of their function. However, surprising little is known about the turn-over and long­ evity of human immune cells. In collaboration with surgeons at the hospital we have established several new methods to study the longevity of immune cells in various human tissues, both during homeostasis and inflammation.

KEY PROJECT SUMMARIES By isolating cells from surgical specimens (cancer surgery and transplanted patients) we have been able to perform detailed characterization of immune-cell subsets (B cells, macrophages and dendritic cells) in the human small intestine and determined their phenotypic characteristics, their differentiation, longevity and replacement kinetics. Such studies have never before been performed in humans. We show that proinflammatory monocytes are constantly recruited to the intestinal mucosa and that they over weeks differentiate into anti-inflammatory macrophages. All subpopulations of intestinal dendritic cells are constantly being replaced by their pre­ cursors in blood with a very rapid turnover rate. Together, our results demonstrate that mononuclear phagocytes in the human gut consist of many functionally distinct subsets. Importantly, we find that plasma cells in the gut are very long-lived (>> 1 year).

This finding is surprising and may have important implications for future vaccinations strategies.

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Lymphocyte recruitment to peripheral tissues is fundamental for immune surveillance and homeostasis, but the chemokines and chemokine receptors responsible for tissue-specific homing of T cells to the upper airway mucosa have not been determined.

We found that CCL28 is preferentially expressed on endothelial cells in the mucosa and its receptor CCR3 is expressed on the majority of mucosal T cells. Functional studies indicate that CCL28-CCR3 interactions are involved in the homeostatic trafficking of CD4(+) T cells to the upper airways.

In an experimentally-induced human model for allergic rhinitis we find that CD14+ monocytes are rapidly (within hours) recruited to the nasal mucosa in response to allergen challenge in allergic patients. By transcriptomic profiling we find that mono­ nuclear phagocytic cells in the challenged nasal mucosa produce several Th2-associated chemokines during the inflammatory reaction, suggesting that these cells, including monocytes, are central players as proinflammatory cells in upper airway allergy recruiting and activating Th2 cells and eosinophils.

CENTRAL PUBLICATIONS IN 2014 Jenum S, Grewal HM, Hokey DA, Kenneth J, Vaz M, Doherty TM, Jahnsen FL, TB Trials Study Group (2014). The frequencies of IFNγ+IL2+TNFα+ PPD-specific CD4+CD45RO+ T-cells correlate with the magnitude of the QuantiFERON® gold in-tube response in a prospective study of healthy indian adolescents. PLoS One 9 (7), e101224

CENTRE FOR IMMUNE REGULATION (CIR)

Frode Jahnsen

Melum GR, Farkas L, Scheel C, Van Dieren B, Gran E, Liu YJ, Johansen FE, Jahnsen FL, Baekkevold ES (2014). A thymic stromal lymphopoietin-responsive dendritic cell subset mediates allergic responses in the upper airway mucosa. J Allergy Clin Immunol 134 (3), 613-621.e7 A role for CCL28-CCR3 in T-cell homing to the human upper airway mucosa.

Danilova E, Skrindo I, Gran E, Hales BJ, Smith WA, Jahnsen J, Johansen FE, Jahnsen FL, Baekkevold ES. Mucosal Immunol. 2015 Jan;8(1):107-14. doi: 10.1038/mi.2014.46.

Epub 2014 Jun 11.

AMBITIONS FOR 2015 • Study the blood monocyte compartment in experimentally-induced celiac disease.

• Functional characterization of monocytes, macrophages and dendritic cells in the human small intestine.

• Explore the relationship of immune cells and stromal cells in experimentallyinduced allergic rhinitis.

• Explore the relationship of immune cells and stromal cells in active celiac disease.

• Determine the longevity of resident memory T cells in the human small intestine.

ACHIEVEMENTS IN 2014 • Identified monocytes as a central component of the inflammatory process in allergic rhinitis • Determined plasma-cell subsets and their longevity in the human small intestine.

• Determined the half-life of monocytes, macrophages and dendritic cells in the human small intestine • Defined a role for CCL28-CCR3 in T-cell homing to the human upper airway mucosa.

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CENTRE FOR IMMUNE REGULATION (CIR)

23

MUNTHE GROUP

24

We study B cell biology in health, autoimmunity and cancer. As most B cell cancers have autoreactive specificities, the autoimmunity and cancer studies are closely linked. We have progressed to study how Th cells in patients can maintain autoimmune B cells as well as lymphoma cells.

OVERVIEW OF RESEARCH IN THE GROUP We are interested in how Th cells can regulate B cell responses, both in health, in autoimmunity and after malignant transformation. Our goal is to define the specificity of Th cells, the mechanisms of collaboration, to pinpoint targets for pharmacological interventions and to study heterogeneity between patients. We have made important contributions to explain the pathogenesis of CLL and would very much like to extend these results to Multiple Myeloma.

KEY PROJECT SUMMARIES We have the following research questions: • How can Idiotype-specific Th cells drive autoimmune B cell responses?

• How can Th cells drive the proliferation of human lymphoma?

• What is wrong with BCR signalling in CLL? • What is the drive for myeloma proliferation in human patients?

• How can we identify which drugs can abrogate lymphoma and myeloma proliferation?

• What allows reversal of B cell anergy in CLL and reversal of anergy in anergic B cell subsets in normals?

CENTRAL PUBLICATIONS IN 2014 Aas-Hanssen, K., A. Funderud, K.M. Thompson, B. Bogen, and L.A. Munthe. 2014.

Idiotype-specific Th cells support oligoclonal expansion of anti-dsDNA B cells in mice with lupus. Journal of immunology 193:2691-2698.

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Jacobsen, J., O.A. Haabeth, A.A. Tveita, K.W. Schjetne, L.A. Munthe, and B. Bogen. 2014.

Naive idiotope-specific B and T cells collaborate efficiently in the absence of dendritic cells. Journal of immunology 192:4174-4183.

ACHIEVEMENTS IN 2014 • We described and characterized Id-driven T B collaboration as a drive for anti-dsDNA B cells in the systemic autoimmune disease Lupus, demonstrating clonal expansion in lupus-prone mice – both in terms of BCR sequences and by demonstrating anti-dsDNA B cells in functional assays and flow cytometry. Aas-Hanssen et al, The Journal of Immunology 2014.

• We demonstrated a novel pathway for expansion and support of chronic lymphocytic leukemia (CLL) cells from patients, Bürgler et al, The Journal of Immunology 2014. CLL patients have T helper (Th) cells of the Th1, IFN-g secreting type that are specific for CLL cell antigen. When mixed, we show that Th1 cells activate CLL cells in an IFN-g dependent manner and that IFNg activates the T-Bet transcription factor in CLL cells. With ChIP-analysis and qPCR we identify T-Bet consensus sites in intron I of the CD38 gene, demonstrating a IFNG-JAK- T-bet -CD38 axis. Blocking IFNG-g in xenograft experiments abrogated proliferation of cancer cells.

We thereby link Th cell activation, cytokine profile and CLL cell response to the CD38 marker that is important for prognosis in the patient group. We also demonstrated that Th cells activate CLL cells to secrete pro-inflammatory chemokines, further attracting CLL cells.

CENTRE FOR IMMUNE REGULATION (CIR)

Ludvig A. Munthe

• We extended the network of sample collection to South Eastern Norway, adding to our biobank collection.

• We published with the Bogen group on the utility of Vaccibodies in CLL (Ruffini et al, J Transl Med, 2014), on Id-dependent Th B cell collaboration (Jacobsen et al, The Journal of Immunology 2014) and on FAM46 gene variants predisposing to M tuberculosis (Etokebe et al, PlosOne 2014).

We contributed to papers to be published in early 2015.

• We published 8 clinical immunology papers (Bazso et al., 2014; Bodolay et al., 2014; Laczik et al., 2014; Nakken et al., 2014; Senolt et al., 2014; Szodoray et al., 2014; Vincze et al., 2014; Zold et al., 2014) • We obtained funding from the Health Region South East to initiate a Personalized Medicine initiative for CLL and myeloma in 2015 (Kjetil Tasken, Geir Tjønnfjord; Miljøstøtte, 9 million NOK).

• We achieved long term culture of CLL cells ex vivo from patients, implemented multiplexed phosphoflow in our analyses • We initiated collaborations with two biotech companies.

• We will define how a small molecular pathway inhibitor can have effect on CLL cells and not normal B cells, pinpointing a treatment strategy in this disease.

• We will demonstrate how primary mye­ loma cells from patients can be stimulated to proliferate in vitro and in vivo.

• We will succeed in establishing ex vivo culture of human primary myeloma cells.

• We will define how EBV infection may play a part in disease progression in CLL. • We will initiate a high throughput drug screen for CLL (ex vivo culture).

AMBITIONS FOR 2015 • We will characterize allelic inclusion, exclusion and exchange of VL and VH of anti-dsDNA B cells in Lupus mice.

• We will present bioinformatics analyses of Th cell antigens in murine Lupus.

• We will define the mechanism for how B cell anergy is reversed in human anergic B cells, suggest novel druggable targets.

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CENTRE FOR IMMUNE REGULATION (CIR)

25

SANDLIE GROUP

26

The Sandlie group studies the structure and function of antibodies and T-cell receptors, the specific detecting molecules of the adaptive immune system. The purpose of the work is to engineer antibodies and antibody derived molecules to be used in therapy and as research reagents.

OVERVIEW OF RESEARCH IN THE GROUP Furthermore, one antibody receptor, the neonatal Fc receptor (FcRn), also binds albumin, and we study how FcRn binding regulates the serum half life and biodistribution of albumin and molecules bound to albumin.

We focus on two projects: A) Studies of the interaction between Fc receptors, and in particular FcRn, with IgG subclasses and albumin. Key questions are how ligand binding elicits antibody effector functions and regulate biodistribution and serum half-life. B) Selection of antibodies for the detection of complexes between antigenic peptides and HLA molecules, as well as peptide – HLA complexes for detection of specific T-cell receptors. The focus is on engineering to increase stability and affinity for molecules that are characteristic of disease models in groups at CIR.

KEY PROJECT SUMMARIES Proteins in blood are short lived and normally degrade within a few hours or days, but the two most abundant proteins, IgG and albumin, are rescued from degradation and have half-lives of three weeks. The rescue mechanism depends on their interaction with the neonatal Fc receptor (FcRn), and it is crucial to understand how FcRn rescues IgG and albumin, and to transfer long half-life to therapeutics, using the same mechanism. We have worked in collaboration with Novozymes Ltd, UK, who has filed several patent applications and developed the Veltis® technology, a set of human albumin variants designed by us with greatly increased binding affinity for FcRn. Biopharmaceuticals fused to a new albumin

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variant can have half-life of months, which will decrease dose, dozing frequency and toxic side effects. In 2014, we reported on the fine mapping of the albumin FcRn interaction.

To ask questions regarding the nature of the antigen presenting cell, the location and rate of antigen presentation and the interaction with T cells, specific detection molecules are needed. Specific antibodies and soluble T-cell receptors are new tools for such studies in health and disease. We have explored how phage display may be used to improve the affinity of antibodies and the stability and affinity of soluble T-cell receptors and MHC class II molecules. We have displayed not only soluble T cell receptors, but also MHC class II molecules, so-called “Phagemers”, which will be used as diagnostics for coeliac disease. Furthermore, a spin-out company, Nextera AS, commercialises and develops the new phage display- and Phagemer technologies, and utilizes libraries of Phagemers to search for disease causing proteins that drive pathological T cell activation in autoimmune diseases and chronic infections.

CENTRAL PUBLICATIONS IN 2014 Hallstensen RF, Bergseth G, Foss S, Jæger S, Gedde-Dahl T, Holt J, Christiansen D, Lau C, Brekke OL, Armstrong E, Stefanovic V, Andersen JT, Sandlie I, Mollnes TE. Eculizumab treatment during pregnancy does not affect the complement system activity of the newborn. Immunobiology. 2014 Nov 13. pii: S0171-2985(14)00228-9. doi: 10.1016/j. imbio.2014.11.003.

CENTRE FOR IMMUNE REGULATION (CIR)

Inger Sandlie

Sand KM, Bern M, Nilsen J, Dalhus B, Gunnarsen KS, Cameron J, Grevys A, Bunting K, Sandlie I, Andersen JT. Interaction with both domain I and III of albumin is required for optimal pH-dependent binding to the neonatal Fc receptor (FcRn). J Biol Chem. 2014 Dec 12;289(50):34583-94. doi: 10.1074/jbc.

M114.587675. Epub 2014 Oct 24.

Sand KM, Dalhus B, Christianson GJ, Bern M, Foss S, Cameron J, Sleep D, Bjørås M, Roopenian DC, Sandlie I, Andersen JT. Dissection of the neonatal Fc receptor (FcRn)-albumin interface using mutagenesis and anti-FcRn albumin-blocking antibodies. J Biol Chem.

2014 Jun 13;289(24):17228-39. doi: 10.1074/ jbc.M113.522565. Epub 2014 Apr 24.

Andersen JT, Dalhus B, Viuff D, Ravn BT, Gunnarsen KS, Plumridge A, Bunting K, Antunes F, Williamson R, Athwal S, Allan E, Evans L, Bjørås M, Kjærulff S, Sleep D, Sandlie I, Cameron J. Extending serum halflife of albumin by engineering neonatal Fc receptor (FcRn) binding. J Biol Chem. 2014 May 9;289(19):13492-502. doi: 10.1074/jbc.

M114.549832. Epub 2014 Mar 20.

ACHIEVEMENTS IN 2014 • Increased our understanding of the interaction between the serum half-life regulating receptor, FcRn, and albumin.

Designed and characterized novel albumin variants with increased binding to FcRn that will be used as carriers of biopharmaceuticals to increase their serum half-life.

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• Demonstrated that the interaction is hydrophobic, and the binding site for FcRn on albumin overlaps with a high affinity binding site for fatty acids. Thus, ligands bound to albumin may well affect its interaction with FcRn, which is important for transport and deposition of ligands at different body sites.

• Selected antibodies that bind specifically to HLA DQ2.5 in complex with gluten peptide.

AMBITIONS FOR 2015 • Design improved molecular trackers for specific peptide – MHC complexes to be used in studies of antigen presentation.

• Design molecular trackers for specific T-cell receptors characteristic for gluten specific T cells to be used in diagnostic tests.

• Analyse the fine specificity of the T cell response in coeliac disease.

• Understand basic mechanisms that govern transcytosis and recycling of albumin and IgG, and how both processes are altered by ligand binding.

• Describe structural features of the constant regions of the human IgG subclasses that are important for their effector functions, and characterize how IgG bound to certain pathogens directs them to intra­ cellular degradation and initiate signalling that alerts the cell to convert to fighting the infection.

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CENTRE FOR IMMUNE REGULATION (CIR)

27

SOLLID GROUP

28

Our group is trying to dissect the interplay of environmental and genetic factors in chronic autoimmune disorders. We are concentrating on coeliac disease as a model to understand the molecular mechanisms leading to chronic inflammatory disease.

OVERVIEW OF RESEARCH IN THE GROUP This disorder, caused by an inappropriate immune response to cereal gluten proteins, is characterised by a strong HLA association and presence of autoantibodies specific for TG2. We have generated a large panel of CD4+ T-cell lines and clones cultured from intestinal biopsy specimens from coeliac disease patients. Characterisation of how these T cells recognise gluten protein has led to interesting findings such as the importance of protein structure on antigen processing, how enzyme mediated posttranslational protein modification increases antigenicity and how HLA binding specificity and peptide-MHC stability influence T-cell priming. This knowledge reveals general principles of immune regulation that are applicable to other autoimmune and chronic inflammatory diseases. Currently we have taken up a strong interest in characterising the autoantibody response of coeliac disease.

This is the focus of an ERC Advanced Grant project we undertake.

gen-specific cells: High throughput DNA sequencing is implemented to monitor and follow adaptive immune responses.

KEY PROJECT SUMMARIES Structure and function of TG2: We are trying to understand where and how TG2 is active in the intestinal coeliac lesions.

Christophersen A, Ráki M, Bergseng E, Lundin KE, Jahnsen J, Sollid LM, Qiao SW (2014) Tetramer-visualized gluten-specific CD4+ T cells in blood as a potential diagnostic marker for coeliac disease without oral gluten challenge. United. European. Gastroenterol.

J., 2(4):268-78.

Gluten-reactive T cells: We are studying TCR specificity and function of glutenreactive T cells. MHC tetramers are key tools in these studies.

B cells and plasma cells: We are studying the specificity of human recombinant antibodies cloned from immunoglobulin genes of single TG2-specific or gluten-specific plasma cells isolated from gut biopsies.

Characterisation of BCR and TCR of anti-

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ANNUAL REPORT 2014

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CENTRAL PUBLICATIONS IN 2014 Qiao SW, Christophersen A, Lundin KE, Sollid LM (2014) Biased usage and preferred pairing of – and -chains of TCRs specific for an immunodominant gluten epitope in coeliac disease. Int. Immunol., 26(1):13-9.

Iversen R, Mysling S, Hnida K, Jørgensen TJ, Sollid LM (2014) Activity-regulating structural changes and autoantibody epitopes in transglutaminase 2 assessed by hydrogen/ deuterium exchange. Proc. Natl. Acad. Sci. U. S. A., 111(48):17146-51.

Dørum S, Bodd M, Fallang LE, Bergseng E, Christophersen A, Johannesen MK, Qiao SW, Stamnaes J, de Souza GA, Sollid LM (2014) HLA-DQ molecules as affinity matrix for identification of gluten T cell epitopes. J. Immunol., 193(9):4497-506.

Steinsbø Ø, Henry Dunand CJ, Huang M, Mesin L, Salgado-Ferrer M, Lundin KE, Jahnsen J, Wilson PC, Sollid LM (2014) Restricted VH/VL usage and limited mutations in gluten-specific IgA of coeliac disease lesion plasma cells. Nat. Commun., 5:4041.

CENTRE FOR IMMUNE REGULATION (CIR)

Ludvig M. Sollid

Amundsen SS, Viken MK, Sollid LM, Lie BA (2014) Coeliac disease-associated poly­morphisms influence thymic gene expression. Genes. Immun., 15(6):355-60.

Sollid LM, Pos W, Wucherpfennig KW (2014) Molecular mechanisms for contribution of MHC molecules to autoimmune diseases.

Curr. Opin. Immunol., 31:24-30.

Lundin KE, Sollid LM. Advances in coeliac disease (2014) Curr. Opin. Gastroenterol., 30(2):154-62.

ACHIEVEMENTS IN 2014 • Monoclonal antibodies were cloned from single gluten-specific plasma cells isolated from coeliac lesions (Nat Comm 2014).

Gluten-specific IgA were found to have restricted VH/VL usage and limited numbers of mutations.

• Completed studies using hydrogen/ deuterium exchange to assess structural changes induced by Ca2+, GTP, cysteine oxidation and by the binding of transglutaminase 2 (TG2) autoantibodies of coeliac disease patients on TG2 (PNAS 2014). Binding of Ca2+ and GTP stabilised distinct regions in the catalytic core and C-terminal domains of TG2 and oxidation prevented the Ca2+-induced changes.

Binding of TG2 autoantibodies resulted in pronounced allosteric effects on TG2 structure.

• Used proteomics to characterise the endogenous peptide ligands of HLADQ2.5, HLA-DQ2.2 and HLA-DQ7.5 (Immunogenetics 2015) and to identify (novel) gluten T-cell epitopes that selectively bind to HLA-DQ2.5 and HLA-DQ2.2 (J Immunol 2014). The binding motifs of

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ANNUAL REPORT 2014

HLA-DQ2.5 and HLA-DQ2.2 were found to be different where position P3 was a major anchor site only in HLA-DQ2.2.

This data fit with the finding that the three known HLA-DQ2.2-restricted gluten epitopes all harbour serine at P3.

• Measured frequency of gluten-reactive T cells in blood of coeliac disease patients and healthy controls by HLA tetramer staining (United European Gastroenterol J 2014). Showed proof-of principle that the enumeration of gluten-tetramer binding effector memory T cells in blood may be used in coeliac disease diagnosis.

AMBITIONS FOR 2015 • Continue with high throughput sequencing of B-cell receptors (BCR) and T-cell receptors (TCR) as well as undertaking paired BCR VH–VL and TCR Va–Vb sequencing from single cells. Complete the study on paired TCR repertoire analysis of DQ2.5glia-2 and DQ2.5-glia-2-reactive T cells.

• Complete the structural studies of TG2specific autoantibodies of coeliac disease, and in complex with TG2.

• Perform blinded study on using tetramerstaining of gluten-reactive T cells in blood as potential diagnostic tool in differentiating coeliac disease patients on gluten-free diet and healthy controls.

• Perform in vitro studies to investigate cooperation between TG2-specific B cells and gluten-reactive T cells.

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CENTRE FOR IMMUNE REGULATION (CIR)

29

30

ABOUT

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CENTRE FOR IMMUNE REGULATION (CIR)

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CENTRE FOR IMMUNE REGULATION (CIR)

FACTS AND FIGURES 32

FACTS AND FIGURES Centre for Immune Regulation (CIR) was established in December 2007 as a Centre of Excellence appointed by the Research Council of Norway. Following a successful midterm evaluation, CIR will continue to operate as a CoE till the end of 2017. CIR is also a FOCIS (Federation of Clinical Immunology Societies) Center of Excellence.

Our host institution is the University of Oslo. Oslo University Hospital is an equal consortium partner. The centre is organised directly under the Faculty of Medicine and the centre Director reports to the Dean. CIR comprises research groups from the Faculty of Mathematics and Natural Sciences, the Faculty of Medicine and from Oslo University Hospital. Centre staff is employed at the Department of Biosciences, the Department of Immunology and the Department of Pathology.

THE RESEARCH GROUPS CIR consists of six research groups headed by professors, Ludvig M. Sollid, Inger Sandlie, Oddmund Bakke, Bjarne Bogen, Frode L. Jahnsen and Ludvig A. Munthe. Professor Ludvig A. Munthe joined CIR as a new group leader in January, 2014. Sollid’s group includes the group of Gustavo de Souza, head of the proteomics core facility and projects.

Bakke’s group includes the group of Alexandre Corthay and Sandlie’s group includes the group of Jan Terje Andersen.

107 persons, producing 60.5 person years, are involved in research at CIR.

THE CIR BOARD The governing board of CIR has four members; two from the University of Oslo (UiO) and two from Oslo University Hospital (OUS). The board is appointed by UiO. • Hilde I. Nebb (chair), Dean of Research, Faculty of Medicine, UiO. • Svein Stølen, Dean of Research, Faculty of Mathematics and Natural Sciences, UiO. • Erlend B. Smeland, Director of Research, Innovation and Education, OUS.

CIR actively recruits international talents and currently 20 nationalities are represented at the centre.

The overall gender balance at CIR is 37/63 with an overweight of female members among postdocs, PhD students, master students and technicians.

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ANNUAL REPORT 2014

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MANAGEMENT The centre is headed by Director Ludvig M. Sollid and Deputy Director Inger Sandlie.

The centre management is supported by an administrative coordinator, Lise Kveberg.

The Director has the daily responsibility for project management, administration and delivery.

CENTRE FOR IMMUNE REGULATION (CIR)

• John Torgils Vaage, Head of the Department of Immunology, OUS. The authority of the board is to ensure that the intentions and terms of contract described in the Centre of Excellence agreement are fulfilled. Furthermore, the board approves the annual budget and ensure that centre activities are completed as outlined in the project description and funding plan, within the adopted time frame.

SCIENTIFIC ADVISORY BOARD CIR has a scientific advisory board (SAB) consisting of European world-class scientists.

The SAB’s mandate is to critically evaluate and advice on the centre’s scientific performance and progress.

• Professor Søren Buus, University of Copenhagen, Denmark.

• Professor Rikard Holmdahl, Karolinska Institutet, Stockholm, Sweden.

• Professor Sirpa T. Jalkanen, University of Turku, Finland.

FOCIS COE CLINICAL ADVISORY BOARD AND LAY ADVISORY BOARD As a Federation of Clinical Immunology Societies (FOCIS) Centre of Excellence (FCE), CIR has established two advisory boards.

The clinical advisory board is responsible for facilitating translational research at CIR.

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ANNUAL REPORT 2014

• Head physician Knut E. Lundin (chair, gastro­enterologist, OUS).

• Professor II Geir E. Tjønnfjord (haematologist, OUS and UiO).

• Professor Knut Dahl-Jørgensen (paediatrician, OUS and UiO).

• The lay advisory board focuses on strategic development, fundraising and community outreach.

• The Director of the Norwegian Coeliac Society.

• The Secretary General of the Norwegian Asthma and Allergy Association.

• The Secretary General of the Norwegian Diabetes Association.

33

FUNDING (1000 NOK)

2014

Research Council of Norway (RCN) – CoE 1

11050

University of Oslo (UiO) 2

19686

Oslo University Hospital (OUS) 3

9086

Other funding from RCN

7323

South-Eastern Norway Regional Health

12811

Private funding 4

2857

International funding 5

7749

Total funding 1 Centre of Excellence grant.

2 Including value of personnel funded by UiO and indirect costs of infrastructure.

3 Including value of personnel funded by OUS and indirect costs of infrastructure.

4 Including grants from the Norwegian Cancer Society, and others.

5 Including ERC advanced grant, EU grants, and others.

Compared to 2013, the total funding is increased in 2014.

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CENTRE FOR IMMUNE REGULATION (CIR)

70562

STAFF AND STUDENTS GROUP LEADERS Name

Position

Oddmund Bakke

Professor

Funding* Employer* UiO

UiO

Bjarne Bogen

Professor

UiO/OUS

UiO/OUS

Frode L. Jahnsen

Professor

UiO/OUS

UiO/OUS

Inger Sandlie

Professor

UiO

UiO

Ludvig M. Sollid

Professor

RCN-CIR/ERC

UiO

Ludvig A. Munthe

Professor

UiO

UiO

RESEARCH SCIENTISTS

34

Name

Position

Per Brandtzæg

Professor emeritus

Funding* Employer*

Espen Bækkevold

Researcher

S-EN RHA

OUS

Alexandre Corthay

Researcher

RCN

OUS

Gerbrand Koster

Researcher

RCN

UiO

Knut E.A. Lundin

Consultant

S-EN RHA

OUS

Geir Åge Løset

Researcher

RCN

UiO

Ingrid Olsen

Researcher

RCN

UiO

Shuo-Wang Qiao

Researcher

UiO

UiO

Gustavo de Souza

Researcher

UiO

UiO

Keith Thompson

Researcher

UiO

UiO

Inger Øynebråten

Researcher

S-EN RHA

OUS

Jan Terje Andersen

Researcher

RCN

OUS

CENTRE PERSONNEL 2014

CIR STAFF DEVELOPMENT

35

140

29

30

120

25

100

20

20 15

18

80

18

60

13

10

40

6 5

20

1

ANNUAL REPORT 2014

0

2008

2009

2010

2011

2012

2013

2014

tra

tio

n

ns

is

ic

m in Ad

hn

en t |

Te c

ud st D

/M Sc M

|

ia

s

s ud en

s

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td oc Po s

ch se ar Re

Ph

G

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0

Man years Head count

CENTRE FOR IMMUNE REGULATION (CIR)

* Headcount includes unpaid MSc/ MD students and staff that left or joined CIR during 2014.

Peter Szoroday

Researcher

OUS

OUS

Dong Wang

Researcher

RCN-CIR

UiO

Name

Position

Funding* Employer*

Frode M. Skjeldal

Senior engineer

UiO

UiO

Linda Haugen

Senior engineer

UiO

UiO

TECHNICIANS

Kahsai Beraki

Senior engineer

Ingrid Kjos

Staff engineer

Hilde Omholt

Senior engineer

Marte Fauskanger

Research assistent

UiO

UiO

RCN-CIR

UiO

NCS

OUS

S-EN RHA

OUS

Aaste Aursjø

Senior engineer

UiO

UiO

Kathrine Hagelsteen

Biomedical Laboratory Scientist

UiO

UiO

Linda I. Solfjell

Biomedical Laboratory Scientist

OUS

OUS

Kjersti Thorvaldsen Hagen

Biomedical Laboratory Scientist

S-EN RHA

OUS

Hege Eliassen

Senior Executive Officer

UiO/OUS

UiO/OUS

Sara Halmøy Bakke

Staff engineer

UiO

UiO

Sathiyaruby Sivaganesh

Staff engineer

UiO

UiO

Marie K Johannesen

Senior engineer

UiO

UiO OUS

Bjørg Simonsen

Staff engineer

S-EN RHA

Maria Ekman Stensland

Staff engineer

S-EN RHA

UiO

Martin McAdam

Research Technician

RCN

OUS

Stine Rosenqvist Lund

Engineer

S-EN RHA

OUS

CIR – Centre for Immune Regulation ERC – European Research Council, Advanced grant EU – European Union S-EN RHA – South-Eastern Norway Regional Health Authority NCS – Norwegian Cancer Society OUS – Oslo University Hospital RCN – Research Council of Norway ImmusanT – Biotechnology company, UK UiO – University of Oslo UEG – United European Gastroenterology The list of CIR staff and students include both members that left and joined the Centre during 2014. Several CIR members have changed employer, position and funding body during 2014. The listed funding body, position and employer refer to the status per December 2014.

ADMINISTRATION Name

Position

Funding* Employer*

Lise Kveberg

Senior advisor

RCN-CIR

UiO

POSTDOCS Name

Funding* Employer*

Cinzia A. M. Progida

RCN/CIR/UiO/NCS

UiO

Cathrine Hayward

UiO

UiO

Anders A Tveita

NCS

OUS

Johanne Jacobsen

S-EN RHA

OUS OUS

Ole-Audun W. Haabeth

S-EN RHA

Peter C. Huszthy

RCN

UiO

Lisa M. Gruber

S-EN RHA

OUS

Ole J.B. Landsverk

S-EN RHA

OUS

Kristin Gunnarsen

S-EN RHA

OUS

GENDER BALANCE STAFF

GENDER DISTRIBUTION

20 18 16 14 12 10

37%

8

63%

6 4 2

n tio tra

is

de nt tu

Ad m

rs te

as |

Male

in

n ia ic hn

en t

Te c

ud

St

M

G

ro

up

le

ad er Re se ar ch er Po st do c Ph D st ud en t

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ANNUAL REPORT 2014

Female

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CENTRE FOR IMMUNE REGULATION (CIR)

35

Peng Lei

RCN

UiO

Elin Bergseng

RCN

UiO

Jorunn Stamnæs

ERC

UiO

Siri Dørum

RCN-CIR

UiO

Fleur du Pre

S-EN RHA

OUS

Omri Snir

ERC/S-EN RHA

UiO

Bishnuedo Roy

ERC

UiO

Xi Chen

S-EN RHA

OUS

Rasmus Iversen

ERC

UiO

Britt Nakken

S-EN RHA

OUS

Astrid E. V. Tutturen

RCN-CIR

UiO

NATIONAL Magnar Bjørås, Dept. of Microbiology, Oslo Univ. Hosp. and Univ. of Oslo Heidi Kiil Blomhoff, Institute of Basic Medical Sciences, University of Oslo Rune Blomhoff, Institute of Basic Medical Sciences, University of Oslo Bjørn Dalhus, Dept. Medical Biochemistry, Univ. of Oslo and Oslo Univ. Hospital Ralph Dollner, Department of

PHD STUDENTS

36

COLLABORATION

Otorhinolaryngology, Head and Neck Surgery,

Name Funding* Employer*

Oslo University Hospital

Henrik Aamodt

OUS

OUS

Terje Espevik, Norwegian University of Science

Kristin Aas-Hanssen

RCN/S-EN RHA

UiO

and Technology, Trondheim

Axel Berg-Larsen

UiO

UiO

Peter Gaustad, Dept. of Medical Microbiology,

Malin C. Bern

RCN

UiO

University of Oslo and Oslo University Hospital

Anna Bujko

S-EN RHA

OUS

Tobias Gedde-Dahl, Dept. of Haematology,

Inês Cardoso

EU

UiO

Oslo University Hospital

Asbjørn Christophersen

S-EN RHA/ImmusanT/RCN

Marita Borg Distefano

UiO

UiO

Harleen Grewal, Gades Institute, University

Stian Foss

UiO

UiO

of Bergen and Haukeland University Hospital

Ibon Eguiluz Gracia

S-EN RHA

OUS

Krzysztof Grzyb, Dept. of Pathology, Oslo

Algirdas Grevys

UiO

UiO

University Hospital

Kathrin Hnida

EU

UiO

Guttorm Haraldsen, Dept. of Pathology,

Christina Hoffmann

RCN-CIR

UiO

University of Oslo and Oslo University Hospital

Lene Støkken Høydahl

RCN

UiO

Are Holm, Dept. of Respiratory Medicine,

Shiva Dahal Koirala

RCN-CIR

UiO

Oslo University Hospital

Dorota Joanna Konorska

RCN-CIR

UiO

Harald Holte, Dept. of Oncology,

Ana Kucera

UiO

UiO

Oslo University Hospital

Duarte Nunes De C Mateus

UiO

UiO

Jørgen Jahnsen, Department of Medicine,

Guro Reinholt Melum

S-EN RHA

OUS

Akershus University Hospital

Nadia Mensali

OUS/UiO

UiO

Kjetill S. Jacobsen, Centre for Ecological and

Elisabeth Müller

UiO

UiO

Evolutionary Synthesis, University of Oslo

Jeannette Nilsen

RCN

OUS

Knut-Dahl Jørgensen, Dept. of Pediatrics,

Nicolay Rustad Nilssen

S-EN RHA

OUS

Oslo University Hospital

Anna Parente Ribes

NCS/UiO

UiO

Mari Kaarbø, Dept. of Microbiology, University

Louise Risnes

S-EN RHA

OUS

of Oslo and Oslo University Hospital

Kine Marita K. Sand

UiO

UiO

Benedicte A. Lie, Dept. of Medical Genetics,

Vikas K. Sarna

S-EN RHA

OUS

Oslo University Hospital

Fredrik Hellem Schesvold

NCS

OUS

Fridtjof Lund-Johansen, Dept. of Immunology,

Øyvind Steinsbø

UEG/S-EN RHA/OUS

UiO /OUS

UiO /OUS

Einar Gran, Lovisenberg Hospital, Oslo

Oslo University Hospital Trond Leren, Dept. of Medical Genetics, Oslo University Hospital

STUDENTS Name Study

Name Study

Terje E. Michaelsen, School of Pharmacy, Dept.

Astri Frafjord

MSc

Mira Halvorsen Børstad

MSc

of Pharmaceutical Chemistry, University of Oslo

Shuai Guo

MSc

Nora Valeur

MSc

Karsten Midtvedt, Dept. of Internal Medicine,

Heidi Anine Korsmo

MSc

Sofie Navelsaker

MSc

Oslo University Hospital

Álvaro Sahún Español

BSc

Hanna Noordzij

MSc

Tom Eirik Mollnes,

Branislava Stankovic

MSc

Ina Hodnebrug

MSc

Dept. of Immunology, University of Oslo

Merete Storflor

MSc

Rahel Frick

MSc

J. Preben Morth, Centre for Molecular Medicine,

Sanjib Halder

MSc

Heidrun Elisabeth Lode

MSc

University of Oslo

Melanie Manzke

MSc

Camilla Myklebust

MSc

Johanna Olweus, Institute for Cancer Research,

Martine Schrøder

MSc

Sowmya Subbana

MSc

Oslo University Hospital

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ANNUAL REPORT 2014

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CENTRE FOR IMMUNE REGULATION (CIR)

Norbert Roos, Dept. of Molecular Biosciences,

Patrick Holt,

University of Oslo

Telethon Institute of Child Health Research, AU

Anne Simonsen, Institute of Basic Medical Sciences,

Ann Hosmalin, Cochin Institute, FR

University of Oslo

Bertrand Huard, University of Geneva, CH

Ingebjørg Skrindo, Department of

Bana Jabri, University of Chicago, US

Otorhinolaryngology, Ahus

Leo C. James, Medical Research Council Laboratory

Anne Spurkland, Institute of Basic Medical

of Molecular Biology, UK

Sciences, University of Oslo

Franziska Jundt,

Harald Stenmark, Centre for Cancer Biomedicine,

Charite – Universitätsmedizin BerlinDE

Univ. of Oslo and Oslo Univ. Hospital

Thomas J.D. Jørgensen,

Bernt Thiede, Biotechnology Center,

University of Southern Denmark, DK

University of Oslo

John Kappler, National Jewish Health, US

Geir Tjønnfjord, Dept. of Haematology,

Chaitan Khosla, Stanford University, US

Oslo University Hospital

Chu-Young Kim,

Sheraz Yaqub, Dept. of Surgery,

National University of Singapore, SI

Oslo University Hospital

Frits Koning, Leiden University Medical Center, NL

Einar-Martin Aandahl, Dept. of Surgery,

Wayne Lencer, Harvard Medical School, US

Oslo University Hospital

Ana-Maria Lennon-Dumenil,

Ole Øyen, Dept. of Surgery,

Institut Curie, Paris, FR

Oslo University Hospital

Wiebke Ludwig-Peitsch,

Researchers at Nextera AS, Oslo Innovation Centre

Klinik für Dermatologie, DE Bernard Malissen, Centre d’Immunologie de

INTERNATIONAL

Marseille-Luminy, FR

William Agace, Lund University, SE

Kristiina Malmstrøm, Helsinki University, FI

Christian Brix Andersen, Aarhus University, DK

Rudolf Manz, University of Lubeck, DE

Francesco Annunziato, University of Florence, IT

Markku Mäki, University of Tampere, FI

Richard S. Blumberg, Harvard Medical School, US

Jeffery Miner,

Kurt Bommert, University of Würzburg, DE

Washington University School of Medicine, US

Anthony Bosco, Telethon Institute of Child

Jacques Neefjes, Netherlands Cancer Institute, NL

Health Research, AU

Morten Nielsen,

Cecilia Bucci, University of Salento, IT

Technical University of Denmark, DK

Søren Buus, University of Copenhagen, DK

Morten S. Nielsen, University of Aarhus, DK

Jo Caers, Centre Hospitalier Universitaire

Hugh Thomson Reyburn,

de Liège, BE

Spanish National Center for Biotechnology, ES

Jason Cameron, Novozymes Biopharma Ltd., UK

Paul Roche, NIH, US

Inhak Choi, University of Busan, KR

Derry C. Roopenian, The Jackson Laboratory, US

Matthew Collin, Institute of Cellular Medicine,

Daniele Sblattero, University of Piemonte, IT

Newcastle University

Hauke Smidt, Wageningen University, NL

Shaodong Dai, National Jewish Health, US

Dimitri Svergun,

Marc Dalod, Centre d’Immunologie de

European Molecular Biology Laboratory, DE

Marseille-Luminy FR

Mario Vaz, St. Johns Research Institute, IN

Morten Dziegiel, Rigshospitalet –

Gestur Vidarsson, Sanquin Research,

Copenhagen University Hospital, DK

University of Amsterdam, NL

Tatiana Efimova,

Patrick C. Wilson,

Washington University School of Medicine, US

University of Chicago, US

Caroline Ekblad, Affibody AB, SE

Cisca Wijmenga,

Peter M. Elias, University of California

University Medical Center Groningen, NL

San Francisco, US

Jenny Woof, University of Dundee, UK

Laszlo Fesus, University of Debrecen, HU

Anna Wu, University of California

Mattias Forsell, Karolinska Institutet, SE

Los Angeles, US

Donald Forthal, University of California,

Kai W. Wucherpfennig,

California, US

Dana-Farber Cancer Institute, US

Johan Garssen, University of Utrecht and Danone

Hideo Yagita, Jutendo University, JP

Research Centre for Specialised Nutrition, NL

Gur Yaari, Bar-Ilan University , IS

Georg Georgiou, University of Texas, US

Dov Zipori, Weizmann Institute, IS

Mariano Grasselli, Universidad Nacional de Quilmes-IMBICE, AR

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EDUCATION AND CAREER DEVELOPMENT PHD A large number of PhD students have graduated from CIR. The ambition has been to educate 35 new PhDs during this 10 years period. A total of 33 PhD students have already successfully defended their thesis so this goal is almost achieved.

In 2014, two female students defended their thesis:

38

ASTRID ELISABETH VOORHAM TUTTUREN, “Enrichment and identification of citrullinated proteins in biological samples”.

Supervisor: Ludvig M. Sollid.

SYNNE JENUM, “Mycobacterium tuberculosis infection and disease – a contribution to the understanding of immunological diagnostics in children”. Supervisor: Frode Jahnsen.

COMPLETED PHD DEGREES AT CIR PER YEAR FROM 2008 TO 2014 8 7 6 5

MSC In 2014, 5 CIR master students graduated from the University of Oslo. Two foreign students performed their work for MSc degree at CIR and graduated in Italy and Netherland respectively.

Jeanette Nilsen Astri Frafjord Heidi Anine Korsmo Mira Halvorsen Børstad Martin Mc Adam Jeta Sadikaj Brenda van Dieren Álvaro Sahún Español did a project at CIR for a BSc degree in Spain.

GENDER EQUALITY PROGRAM At CIR and generally in molecular bio­ medical research there is a high proportion of female PhD students and postdocs, while the majority of the senior scientists and group leaders are male. CIR and the University of Oslo value gender diversity and aim to increase the number of female researchers in senior scientist positions.

Women, more so than men, leave academia during their postdoctoral engagements and transition to independent researchers.

CIR acknowledges that the centre, our host institution and other academic institutions nationally and abroad are at risk of losing many talents, possessing valuable and highly specialised competency.

4 3 2 1 0

2008

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2009

2010

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2011

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2012

2013

2014

In 2013, in line with the gender diversity strategy of the University of Oslo, CIR provided two development grants to support the career of female scientists. CIR has obtained earmarked funding from the Research Council of Norway (RCN) to

CENTRE FOR IMMUNE REGULATION (CIR)

launch this program. Following an evaluation of applicants by the centre’s scientific advisory board, financial support was granted for two years to two selected talents.

This has been a big success. The candidates either received career grants for 2015 or scored at the top range in the evaluation of their applications.

The gender equality program will be continued in 2015 and 2016 and the new career development grants for female scientists were announced in the end of 2014.

CAREER DEVELOPMENT AND OPPORTUNITIES CIR continues to support the career develop­ ment of our talents. In 2014 the Medical Faculty has through the “phasing in scheme” announced an associate professor­ ship for a junior faculty member within CIR. The selection board has now submitted their recommendation, and we hope the position will be filled before the summer of 2015.

39

Two young CIR scientists, Cinzia Progida and Anders Tveita, received career grants from the Norwegian Cancer Society and Progida also received a “Young researcher career grant” from the Research Council of Norway.

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ACTIVITIE

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CENTRE FOR IMMUNE REGULATION (CIR)

VISITING PROFESSOR PROGRAM One of the core activities at CIR is the Visiting Professor program. CIR scientists have an extensive international network which has made it possible to attract some of the world’s most important scientists in medical sciences to Oslo. The invited professors stay for one week at CIR. During this week they engage in scientific discussions with researchers, supervision of CIR students and give two public lectures for the whole scientific environment at the University of Oslo and the Oslo University hospital. These visits have resulted in fruitful collaborations resulting in joint publications, researcher mobility and new ideas. A total of twelve professors have been included in the Visiting Professor program, and many of them have visited us twice.

42

Susan K. Pierce

Mark M. Davis

In 2014, Susan K. Pierce (NIAID, NIH, USA) revisited CIR for her second time in June and Mark M. Davis (Stanford University, USA) joined the Visiting Professor program in August.

We are very pleased to announce that Mark M. Davis and Bana Jabri (University of Chicago, USA) will revisit CIR in 2015, and Bernhard Malissen (Centre d’Immunologie de Marseilles-Luminy, France) will join the Visiting Professor faculty in 2015 and has accepted to visit CIR in June. We are very much looking forward to their visits.

New Visiting Professors are nominated by CIR staff and will be invited to CIR in the future.

SUSAN K. PIERCE Dr. Pierce works at the National Institute of Allergy and Infectious Diseases, NIH, US. Pierce focuses her work on B-cell receptor signaling and trafficking as well as on the acquisition and maintenance of immunological memory in B cells. Her group studies the regulation of these processes during immune responses to infections and vaccination and has a special interest in the immunological memory response to the malaria parasite. During her visit in June, Pierce gave two guest lectures entitled “Regulating the initiation of antigen-driven B cell responses" and “The acquisition of immunity in malaria”.

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MARK M. DAVIS Dr. Davis works at the Stanford University in California, US. His focus is to understand the characteristics of a healthy humane immune system. Davis and his research group are trying to define what a normal immune response look like at the molecular and cellular level. There is no easy test to look for normal function of a patient’s immune system, and one goal of Davis’ research is to generate a simple battery of tests to be performed on a blood sample that can give information about the health status of your complex immune system. The future aim is to be able to give optimal treatment to patients and customized vaccines to older people. During his visit at CIR in August, Davis gave two lectures. One was entitled “Immunology taught by humans” and the other was part of a minisymposium on T cells in health and disease and was entitled “Molecular aspects of T cell recognition and applications to human responses”.

MINISYMPOSIUM T CELLS IN HEALTH AND DISEASE / AUG 27 Contributors and titles: Mark M. Davis, Stanford University, USA. “Molecular aspects of T cell recognition and applications to human responses”.

Yueh-Hsiu Chien, Stanford University, USA. “Gamma delta T cells: First line of defense and beyond”.

Shuo-Wang Qiao, Centre for Immune Regulation, University of Oslo. “The CD4+ T-cell response to gluten in celiac disease.

Geir Åge Løset, Centre for Immune Regulation, University of Oslo and Nextera AS. “CD4+ TH-cell epitope discovery using MHC class II displayed on filamentous bacteriophages”.

CENTRE FOR IMMUNE REGULATION (CIR)

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WORK PACKAGE (WP) SYMPOSIA In CIRs research plan for the last five years (2013-2017) we introduced a new strategy to enhance scientific interaction between the research groups. Projects were organized into four work packages (WP) with common research focus. The WPs bridge disease models and cross lab-boundaries and will hopefully enhance sharing of knowledge and skills between the scientists and students. The four main themes for the WPs are: WP1 – Function of APCs in autoimmunity and allergy WP2 – T-cell repertoire in autoimmunity and allergy WP3 – Pathogenic T-B collaboration WP4 – Pathogenic and regulatory antibodies

WP1 SYMPOSIUM / MAY 27 Goal: Establishment of a competence/ technology “database”.

Program: Introduction by the WP coordinator Espen S. Bækkevold, short presentations by attendees, and discussion of future WP-activities.

WP4 SYMPOSIUM / OCT 16 Title: Generation of recombinant antibodies and derived fragments Program: Introduction by the WP coordinator Jan Terje Andersen.

Stian Foss: “Antibody production using the HEK293E cell line” Bjørg Simonsen: “Antibody production using the HEK293E/F cell lines” Xi Chen: “Eukaryotic expression of antibody fragments and characterization” Kristin S. Gunnarsen/Lene Støkken Høydahl: “Prokaryotic expression of antibody fragments and characterization”

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CENTRE FOR IMMUNE REGULATION (CIR)

GUEST LECTURES CIR organizes a series of guest lectures.

Most lectures are hosted by a postdoc invitation committee. The 2014 committee consisted of Omri Snir, Lisa M. Gruber, Cinzia Progida, Kristin S. Gunnarsen and Peter C. Huszthy.

Matthew Collin

Ralf Küppers

IN 2014, CIR ORGANIZED 8 GUEST LECTURES: Jacques Neefjes, a former member of the CIR Visiting Professor faculty from the Netherlands Cancer Institute in Amsterdam, visited us in June and gave a lecture entitled "How Salmonella causes cancer and the epidemics of gallbladder carcinoma in India". Professor Neefjes is a cell biologist who has made large contributions to the detailed understanding of antigen presentations by MHC molecules.

Ana-Maria Lennon-Dumenil

Kunchithapadam Swaminathan visited CIR in June and gave a lecture entitled “Happy marriages among biophysical techniques”. Professor Swaminathan is a structural biologist which heads a research group at the National University of Singapore. His research is focused on cell signaling and gene regulation in human diseases and in his talk he introduced us to the strength and limitations to some of the contemporary biophysical techniques.

44

Matthew Collin visited CIR in June and gave a lecture entitled “Human dendritic cells in health and disease”. Professor Collin heads a research group at the Newcastle University and the Director of adult bone marrow transplantation at the Northern Centre for bone marrow transplantation. The focus of his research is to understand the origin and function of human dendritic cells.

Gur Yaari

Gabriel D. Victora

Patrick Holt visited CIR in June and gave a lecture entitled "Treg-mediated control of IgE-mediated acute phase responses??”.

Professor Holt is the head of the Division of Cell Biology at the Telethon Institute and University of Western Australia in Perth, and heads a research group with focus on the pediatric immune system in relation to asthma and allergy.

Ralf Küppers visited CIR in September and gave a lecture entitled “Generation and function of human memory B cells and

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ANNUAL REPORT 2014

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aspects of CLL pathogenesis”. Professor Küppers heads a research group at the Institute of Cell Biology (Cancer Research) at University of Duisburg-Essen in Essen, Germany. Their research aims at understanding the pathogenesis of B cell tumors by comparing the gene expression profile of the B cell lymphomas or leukemias with the B cell subsets they originate from.

Ana-Maria Lennon-Dumenil visited CIR in October and gave a lecture entitled “Coordinating cell migration with function: the example of dendritic cells”. Dr. LennonDumenil heads a research group at the Institut Curie in Paris, France, which aims to identify the molecular mechanisms involved in the space and time-related control of the function of antigen-presenting cells.

Gur Yaari visited CIR in November and gave a lecture entitled: “Mining B cell repertoire dynamics from next-generation sequencing studies”. Dr. Yaari heads a research group at the Bar-Ilan University in Israel which develops computational and statistical tools to process and analyze high-throughput biological data in order to obtain meaningful biological insights into the adaptive immune system.

Gabriel D. Victora visited CIR in December and gave a lecture entitled: “Darwin in miniature: antibody evolution in germinal centers”. Dr. Victora is a young scientist from the Whitehead Institute for Biomedical Research, MIT, Cambridge, MA, US. He presented several cutting edge techniques used in his laboratory to study the generation of germinal centers in lymph nodes. His studies are important to understand the dynamics and regulation of germinal center B cells and have implications for how vaccines work, but also for the development of allergies, autoimmune diseases and lymphomas.

In collaboration with the KG Jebsen Centre for Research on Influenza Vaccines (JIV) and Norwegian Society for Immunology (NSI) we arranged a guest lecture by: Simon J. Draper from the Blood-Stage Malaria Group Jenner Institute at the University of Oxford, UK. Title: “Develop­ ment of broadly-neutralising vaccines against the blood-stage infection of human malaria”.

CENTRE FOR IMMUNE REGULATION (CIR)

INTERNAL ACTIVITIES PROJECT MEETINGS Once a month, all CIR members participates in a project meeting where research projects are presented to other colleagues within CIR. This is a great opportunity to have scientific discussions, critical review of recent data, and initiate new collaborations.

It also provides a friendly venue where less experienced junior scientists can practice presentation of experimental data. The project meeting is one of the key events which gather all CIR members, and it is important for building centre identity. After the project presentation pizza and soft drinks are served, and the scientific discussions continue in a more relaxed atmosphere.

RETREAT August 18-19 2014, CIR arranged a retreat to Soria Moria in Oslo. A total of 80 people attended the conference. Attendants were the members of CIR and the scientific advisory board. Members of the CIR centre board were also present during parts of the program. Two international keynote speakers were invited. Rudolf Valenta (Medical University of Vienna) presented “From allergen genes to new forms of diagnosis and therapy of allergy”, and Rikard Holmdahl (Karolinska Institutet, Stockholm), member of the CIR scientific advisory board, gave a talk entitled “From genes to oxidation inflammation pathways”. The talks of the keynote speakers were excellent and were followed by 15 very good selected oral presentations and 23 poster presentations by young CIR scientists.

The program was divided into seven sessions which were chaired by researchers at CIR: Keynote lectures (Wang Dong and Alexandre Corthay), “Immune cells and their responses in the gut” (Inger Øynebråten), “T and B cells and extracellular molecules in celiac disease” (Anders Tveita), “Protein engineering and approaches to regulate immune responses” (Shuo-Wang Qiao), “Immune cells and responses in tumor pathogenesis” Espen Bækkevold), and “Anti-tumor responses, and “Transport and signalling pathways” (Jan Terje Andersen). The organizing committee did an excellent job and consisted of Wang Dong, Fleur De Pré, Marte Hotvedt Hauskanger, Ibon Eguiluz Gracia, Elisabeth Müller, Nicolay Rustad Nilssen and Anders Sandvik.

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Centre for Immune Regu lation

(CIR)

CIR Retreat 2014

Program and abstracts August 18–19, 2014 Soria Moria Hotel, Oslo

This material is confide ntial and is only for internal use at the Centre for Immune Regulation

CIR_Abstract_book_201

4.indd 1 12.08.14 11:22

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CENTRE FOR IMMUNE REGULATION (CIR)

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PUBLICATI

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CENTRE FOR IMMUNE REGULATION (CIR)

IONS

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CENTRE FOR IMMUNE REGULATION (CIR)

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PAPERS IN SCIENTIFIC JOURNALS

Borg M, Bakke O, Progida C (2014) A novel interaction between Rab7b and actomyosin reveals a dual role in intracellular transport and cell migration. J Cell Sci, 127 (22), 4927-39

Aas-Hanssen K, Funderud A, Thompson KM, Bogen B, Munthe LA (2014) Idiotype-specific Th cells support oligoclonal expansion of antidsDNA B cells in mice with lupus. J Immunol, 193 (6), 2691-8 Amundsen SS, Viken MK, Sollid LM, Lie BA (2014) Coeliac disease-associated polymorphisms influence thymic gene expression.

Genes Immun, 15 (6), 355-60 Andersen JT, Dalhus B, Viuff D, Ravn BT, Gunnarsen KS, Plumridge A, Bunting K, Antunes F, Williamson R, Athwal S, Allan E, Evans L, Bjørås M, Kjærulff S, Sleep D, Sandlie I, Cameron J (2014) Extending serum halflife of albumin by engineering neonatal Fc receptor (FcRn) binding. J Biol Chem, 289 (19), 13492-502 Bagherifam S, Skjeldal FM, Griffiths G, Mælandsmo GM, Engebråten O, Nyström B, Hasirci V, Hasirci N (2014) pH-Responsive Nano Carriers for Doxorubicin Delivery.

Pharm Res. Oct 7.

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Bakke O, Progida C. (2014). Emerging regulators of endosomal dynamics during mitosis.

Cell Cycle.13(3):, 349-50 Bazso A, Bazso T, Szodoray P, Poor G, Kiss E (2014) Aseptic necrosis at multiple localisations in a lupus patient with lymphoma. Osteoporosis international: a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 25:1415-1417.

Cover page from Borg et al. 2014, Journal of Cellular Science, 127 (22), 49274939. Reproduced with permission.

Binsfeld M, Beguin Y, Belle L, Otjacques E, Hannon M, Briquet A, Heusschen R, Drion P, Zilberberg J, Bogen B, Baron F, Caers J (2014) Establishment of a murine graft-versus-myeloma model using allogeneic stem cell transplantation. PLoS One, 9 (11), e113764 Bodolay E, Prohaszka Z, Paragh G, Csipo I, Nagy G, Laczik R, Demeter N, Zold E, Nakken B, Szegedi G, Szodoray P (2014) Increased levels of anti-heat-shock protein 60 (anti-Hsp60) indicate endothelial dysfunction, atherosclerosis and cardiovascular diseases in patients with mixed connective tissue disease. Immunologic research 60:50-59.

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Christophersen A, Ráki M, Bergseng E, Lundin KE, Jahnsen J, Sollid LM, Qiao SW (2014) Tetramer-visualized gluten-specific CD4+ T cells in blood as a potential diagnostic marker for coeliac disease without oral gluten challenge.

United European Gastroenterol J, 2 (4), 268-78 Corthay A (2014) Does the immune system naturally protect against cancer? Front Immunol, 5, 197 De Luca M, Cogli L, Progida C, Nisi V, Pasco­ lutti R, Sigismund S, Di Fiore PP, Bucci C (2014) RILP regulates vacuolar ATPase through interaction with the V1G1 subunit. J Cell Sci. 127(Pt 12), 2697-708.

Dhanasekaran S, Jenum S, Stavrum R, Ritz C, Kenneth J, Vaz M, Doherty TM, Grewal HM, TB Trials Study Group (Jahnsen FL)(2014) Concordant or discordant results by the tuberculin skin test and the quantiFERON-TB test in children reflect immune biomarker profiles.

Genes Immun, 15 (5), 265-74 Dhanasekaran S, Jenum S, Stavrum R, Wiker HG, Kenneth J, Vaz M, Doherty TM, Grewal HM, TB Trials Study Group (2014) Effect of non-tuberculous Mycobacteria on host biomarkers potentially relevant for tuberculosis management. PLoS Negl Trop Dis, 8 (10), e3243 Dørum S, Bodd M, Fallang LE, Bergseng E, Christophersen A, Johannesen MK, Qiao SW, Stamnaes J, de Souza GA, Sollid LM (2014) HLA-DQ molecules as affinity matrix for identification of gluten T cell epitopes. J Immunol, 193 (9), 4497-506 Etokebe GE, Bulat-Kardum L, Munthe LA, Balen S, Dembic Z (2014) Association of variable number of tandem repeats in the coding region of the FAM46A gene, FAM46A rs11040 SNP and BAG6 rs3117582 SNP with susceptibility to tuberculosis. PLoS One. Mar 13;9(3):e91385.

Fenaroli F, Westmoreland D, Benjaminsen J, Kolstad T, Skjeldal FM, Meijer AH, van der Vaart M, Ulanova L, Roos N, Nyström B, Hildahl J, Griffiths G. Nanoparticles as drug delivery system against tuberculosis in zebrafish

CENTRE FOR IMMUNE REGULATION (CIR)

embryos: direct visualization and treatment (2014) ACS Nano, Jul 22;8(7):7014-26.

Lundin KE (2014) Non-celiac gluten sensitivity - why worry? BMC Med, 12, 86

Haabeth OA, Tveita AA, Fauskanger M, Schjesvold F, Lorvik KB, Hofgaard PO, Omholt H, Munthe LA, Dembic Z, Corthay A, Bogen B (2014) How Do CD4(+) T Cells Detect and Eliminate Tumor Cells That Either Lack or Express MHC Class II Molecules? Front Immunol, 5, 174

Makharia GK, Mulder CJ, Goh KL, Ahuja V, Bai JC, Catassi C, Green PH, Gupta SD, Lundin KE, Ramakrishna BS, Rawat R, Sharma H, Sood A, Watanabe C, Gibson PR, World Gastroenterology Organization-Asia Pacific Association of Gastroenterology Working Party on Celiac Disease (2014) Issues associated with the emergence of coeliac disease in the Asia– Pacific region: a working party report of the World Gastroenterology Organization and the Asian Pacific Association of Gastroenterology.

J Gastroenterol Hepatol, 29 (4), 666-77

Hjelle AM, Apalset E, Mielnik P, Bollerslev J, Lundin KE, Tell GS (2014) Celiac disease and risk of fracture in adults--a review. Osteoporos Int, 25 (6), 1667-76 Iversen R, Mysling S, Hnida K, Jørgensen TJ, Sollid LM (2014) Activity-regulating structural changes and autoantibody epitopes in transglutaminase 2 assessed by hydrogen/ deuterium exchange. Proc Natl Acad Sci U S A, 111 (48), 17146-51 Jabri B, Chen X, Sollid LM (2014) How T cells taste gluten in celiac disease. Nat Struct Mol Biol, 21 (5), 429-31 Jacobsen J, Haabeth OA, Tveita AA, Schjetne KW, Munthe LA, Bogen B (2014) Naive idiotope-specific B and T cells collaborate efficiently in the absence of dendritic cells.

J Immunol, 192 (9), 4174-83 Jenum S, Grewal HM, Hokey DA, Kenneth J, Vaz M, Doherty TM, Jahnsen FL, TB Trials Study Group (2014) The frequencies of IFNγ+IL2+TNFα+ PPD-specific CD4+CD45RO+ T-cells correlate with the magnitude of the QuantiFERON® gold in-tube response in a prospective study of healthy indian adolescents. PLoS One, 9 (7), e101224 Knudsen Sand KM, Landsverk OJ, Berg-Larsen A, Bakke O, Gregers TF (2014) The humanspecific invariant chain isoform Iip35 modulates Iip33 trafficking and function. Immunol Cell Biol, 92 (9), 791-8 Laczik R, Soltesz P, Szodoray P, Szekanecz Z, Kerekes G, Paragh G, Rajnavolgyi E, Abel G, Szegedi G, Bodolay E (2014) Impaired endo­ thelial function in patients with undifferentiated connective tissue disease: a follow-up study. Rheumatology 53:2035-2043.

Lin M, Du L, Brandtzaeg P, Pan-Hammarström Q (2014) IgA subclass switch recombination in human mucosal and systemic immune compartments. Mucosal Immunol 7 (3), 511-20

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ANNUAL REPORT 2014

Melum GR, Farkas L, Scheel C, Van Dieren B, Gran E, Liu YJ, Johansen FE, Jahnsen FL, Baekkevold ES (2014) A thymic stromal lymphopoietin-responsive dendritic cell subset mediates allergic responses in the upper airway mucosa. J Allergy Clin Immunol, 134 (3), 613-621.e7

Cover from Nature Structural & Molecular Biology, Volume 21 No 5. Reproduced with permission

Nakken B, Bodolay E, Szodoray P (2014).

Cytokine Milieu in Undifferentiated Connective Tissue Disease: a Comprehensive Review.

Clinical reviews in allergy & immunology

49

Rahman MA, Kristiansen PE, Veiseth SV, Andersen JT, Yap KL, Zhou MM, Sandlie I, Thorstensen T, Aalen RB (2014) The arabidopsis histone methyltransferase SUVR4 binds ubiquitin via a domain with a four-helix bundle structure. Biochemistry, 53 (13), 2091-100 Sand KM, Bern M, Nilsen J, Dalhus B, Gunnar­ sen KS, Cameron J, Grevys A, Bunting K, Sandlie I, Andersen JT (2014) Interaction with Both Domain I and III of Albumin Is Required for Optimal pH-dependent Binding to the Neonatal Fc Receptor (FcRn). J Biol Chem, 289 (50), 34583-94 Sand KM, Dalhus B, Christianson GJ, Bern M, Foss S, Cameron J, Sleep D, Bjørås M, Roopenian DC, Sandlie I, Andersen JT (2014) Dissection of the neonatal Fc receptor (FcRn)albumin interface using mutagenesis and anti-FcRn albumin-blocking antibodies. J Biol Chem, 289 (24), 17228-39 Schwarzer R, Nickel N, Godau J, Willie BM, Duda GN, Schwarzer R, Cirovic B, Leutz A, Manz R, Bogen B, Dörken B, Jundt F (2014) Notch pathway inhibition controls myeloma bone disease in the murine MOPC315.BM model. Blood Cancer J, 4, e217

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CENTRE FOR IMMUNE REGULATION (CIR)

Cover from Proc Natl Acad Sci U S A, 111 (48). Reproduced with permission

Senolt L, Grassi W, Szodoray P (2014) Laboratory biomarkers or imaging in the diagnostics of rheumatoid arthritis? BMC medicine 12:49.

Skrede S, Steinsland H, Sommerfelt H, Aase A, Brandtzaeg P, Langeland N, Cox RJ, Saevik M, Wallevik M, Skutlaberg DH, Tellevik MG, Sack DA, Nataro JP, Guttormsen AB (2014) Experimental infection of healthy volunteers with enterotoxigenic Escherichia coli wildtype strain TW10598 in a hospital ward.

BMC Infect Dis, 14, 482 Solberg LB, Brorson SH, Stordalen GA, Bækkevold ES, Andersson G, Reinholt FP (2014) Increased tartrate-resistant Acid phosphatase expression in osteoblasts and osteocytes in experimental osteoporosis in rats. Calcif Tissue Int 94 (5), 510-21 Sollid LM, Pos W, Wucherpfennig KW (2014) Molecular mechanisms for contribution of MHC molecules to autoimmune diseases.

Curr Opin Immunol, 31C, 24-30

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Steinsbø Ø, Henry Dunand CJ, Huang M, Mesin L, Salgado-Ferrer M, Lundin KE, Jahnsen J, Wilson PC, Sollid LM (2014) Restricted VH/VL usage and limited mutations in gluten-specific IgA of coeliac disease lesion plasma cells. Nat Commun, 5, 4041 Szodoray P, Hajas A, Toth L, Szakall S, Nakken B, Soltesz P, Bodolay E (2014) The beneficial effect of plasmapheresis in mixed connective tissue disease with coexisting antiphospholipid syndrome. Lupus 23:1079-1084.

Toft-Hansen H, Rasmussen KS, Staal A, Roggen EL, Sollid LM, Lillevang ST, Barington T, Husby S (2014) Treatment of both native and deamidated gluten peptides with an endo-peptidase from Aspergillus niger prevents stimulation of gut-derived gluten-reactive T cells from either children or adults with celiac disease. Clin Immunol, 153 (2), 323-31 Tutturen AE, Fleckenstein B, de Souza GA (2014) Assessing the citrullinome in rheumatoid arthritis synovial fluid with and without enrichment of citrullinated peptides. J Proteome Res, 13 (6), 2867-73 Tveita AA, Haabeth OA, Bogen B (2014) Limitations of bystander killing in Th1/M1 immune responses against a secreted tumor antigen. OncoImmunology, 3 (9), e954953

Tveita AA, Schjesvold FH, Sundnes O, Haabeth OA, Haraldsen G, Bogen B (2014) Indirect CD4+ T-cell-mediated elimination of MHC II(NEG) tumor cells is spatially restricted and fails to prevent escape of antigen-negative cells. Eur J Immunol, 44 (9), 2625-37 Vincze M, Der H, Kerekes G, Szodoray P, Zeher M, Danko K, Soltesz P (2014) Decreased flow-mediated dilatation with increased arterial stiffness and thickness as early signs of atherosclerosis in polymyositis and dermatomyositis patients. Clinical rheumatology 33:1635-1641.

Wong D, Winter O, Hartig C, Siebels S, Szyska M, Tiburzy B, Meng L, Kulkarni U, Fähnrich A, Bommert K, Bargou R, Berek C, Chu VT, Bogen B, Jundt F, Manz RA (2014) Eosinophils and megakaryocytes support the early growth of murine MOPC315 myeloma cells in their bone marrow niches. PLoS One, 9 (10), e109018 Zold E, Bodolay E, Dezso B, Soos G, Nakken B, and Szodoray P (2014) Mixed connective tissue disease associated with autoimmune hepatitis and pulmonary fibrosis. The Israel Medical Association journal: IMAJ 16:733-734.

OTHER PAPERS Moum B, Lundin KE (2014) Biosimilar medicines in inflammatory bowel disease.

Tidsskr Nor Laegeforen, 134 (8), 819-20 Frich J, Lundin KE, Os I (2014) [The grading system--balancing various interests] Tidsskr Nor Laegeforen, 134 (1), 14-5 Frich J, Lundin KE, Os I (2014) [J. Frich and colleagues reply] Tidsskr Nor Laegeforen, 134 (5), 496; discussion 497

BOOKS AND BOOK CHAPTERS Andersen J.T., Hjelstuen O.K. and Sandlie I. Medical technology - meeting tomorrow’s healthcare challenges, edited by John Grue and Anne-Brit Kolstø. Chapter: From basic research to innovation. Novus forlag, 2014.

(ISBN 978-82-7099-791-6).

Brandtzaeg P, Eskeland S. Bevisvurdering og juss eller “vitenskap og galskap”. s. 17-29. I:

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ANNUAL REPORT 2014

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CENTRE FOR IMMUNE REGULATION (CIR)

Festskrift til Fredrik Fasting Torgersen (Red.: Eskeland KO, Mossig H, Os Simonsen Ø, Steen T, Holck P). SpreDet Forlag, Oslo, 2014 (ISBN: 978-82-93277-13-2).

Dooper M, Myrset HR, Bogen B: New fusion proteins for the treatment of allergic diseases (US application/PCT international application no. 13/666,023, Canadian Patent Application No. 2,794,051).

PATENTS

Johansen FE, Sandvik A and Engstad RE: Methods of treating or preventing inflammatory disease of the intestinal tract (PCT/ GB2008/003850).

Andersen JT and Sandlie I (with Novozymes): Albufuse2 Domain III extreme C-terminal (EP11164955.4).

Andersen JT and Sandlie I (with Novozymes): Albumin derivatives and variants (WO2011124718 A1).

Andersen JT and Sandlie I (with Novozymes): Albumin variants (EP10159450.5).

Andersen JT and Sandlie I (with Novozymes): Albumin variants (WO2011051489 A2).

Andersen JT and Sandlie I (with Novozymes): Albumin variants (WO2012059486 A1).

Andersen JT and Sandlie I (with Novozymes): Albumin variants (WO2012150319 A1).

Andersen JT and Sandlie I: Modulation of albumin half-life (EP9174698.2).

Andersen JT and Sandlie I (with Novozymes): Albufuse mutations (EP11164989.3).

Andersen JT and Sandlie I: Albumin combination mutants (EP12177916.9 and EP12191859.9).

Andersen JT, Bern M and Sandlie I: Albumin variants fused to immunogens (AlbuVax) for improved transcellular delivery, US 61/936,442. Filed 06.02.2014 Bogen B and Braathen R: Heterodimeric vaccine molecules (U.S. Provisional Patent Application Serial No. 61/695,639).

Bogen B and Hofgaard PO: A novel mouse model for multiple myeloma (MOPC315.BM) that allows noninvasive spatiotemporal detection of osteolytic disease (U.S. Provisional Patent Application Serial No. 61/708,310).

Bogen B, Fossum E and Grødeland G: Vaccibodies targeted to cross-presenting dendritic cells (US serial no: 61538,186).

Di Niro R, Sollid LM and Wilson PC: Identification of antibodies in mucosal cells (US provisional, US61/352/467).

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ANNUAL REPORT 2014

Løset GÅ and Sandlie I: Multivalent phage display systems and methods (WO2011/036555).

Løset GÅ, Frigstad T, Sandlie I and Bogen B: Disulphide bond-stabilized functional soluble MHC class II heterodimers (WO2011/101681).

Løset GÅ: pVII phage display (WO2009/024591).

Løset GÅ: Signal sequence-independent pIX phage display (WO2010/097411).

Mollnes TE, Espevik T, Sandlie I, Gunnarsen JT, Lau C. A humanized antibody against CD14, PCT/US14/31402. Filed 21.03.2014, Munthe LA, Carlsen H, Blomhoff R and Bogen B: Triple transgenic mouse model of autoimmune disease and NF-kB in vivo imaging (US provisional, US61/262/968).

Reiersen H, Løset GÅ, Hagemann UB and Owen D: Method for screening phage display libraries against each other (WO2010/097589).

Ruffini PA, Fredriksen A and Bogen B: Homodimeric protein constructs (WO2010/61358513, EP10167291.3).

Sandlie I, Andersen JT and Bern M: Albumin variants fused to immunogens (AlbuVax) for improved transcellular delivery (61033-13082US-P).

Sandlie I, Andersen JT and Foss S: A human IgG1 mutant with improved binding to tripartite motif-containing protein 21 (TRIM21) (61500-13035-US-P).

Sandlie I, Andersen JT and Sand KMK: Human albumin mutants with decreased binding to FcRn (2132-13083-US-P).

Sollid LM, Qiao SW, Christophersen A and Lundin KEA: Detection of gluten specific T cells (U.S. Provisional Patent Application Serial No. 61/823,072).

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DISSEMINA

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NATION

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INVITED LECTURES

Koster G: “Membrane nanotube formation by proteins - regulation by force and curvature” University of California Berkeley.

February 20, USA

Andersen, JT. Life Science workshop at Oslo University Hospital, June 10, Oslo, Norway Andersen, JT. CRS Workshop Albumin: The Next Generation Protein Therapeutic at the Controlled Release Society's Annual Meeting and Exposition in Chicago, July 13-16, Illinois, USA

Alexandre Corthay

54

Jan Terje Andersen

Lundin KE: «Controversies about bio­ similars». Annual GEDII meeting, January 17, Lisboa, Portugal Lundin KE: «HLA tetramers in the diagnosis of CDV. Prolamin Working Group meeting, September 26, Nantes, France

Andersen, JT. Seminar October 21. Department of Microbiology, University of Oslo, Oslo University Hospital, Rikshospitalet, Norway

Lundin KE: «Celiac disease. Lecture at Postgrauduate training programme»,22nd European Gastroenterology Week, October 18-22, Vienna, Austria

Andersen, JT: Intracellular antibody sensing in the battle against infection. Norwegian Society for Immunology 32nd annual meeting, November 13, Oslo, Norway

Lundin KE: «Round table discussion - Should asymptomatic CD patients be treated?».

22nd European Gastroenterology Week, October 18-22, Vienna, Austria

Bogen B:” How do CD4+ T cells eliminate tumor cells that lack MHC class II mole­ cules? “. Norwegian Cancer Symposium, June 10-12, Oslo, Norway

Lundin KE: «Celiac disease – state of the art and unmet clinical needs». Gastroenterologi i fokus. November 20, Stockholm, Sweden

Bogen B: “A Novel Mouse Model for Multiple Myeloma (MOPC315.BM)”. Department of Hematology, Mount Sinai Hospital/ Icahn School of Medicine, December 17, New York, USA Brandtzæg P. NSI Honorary Member Lecture: “The advent of immunological research in Norway and NSI as a catalyst”. November 13, Oslo, Norway Corthay A “What is inflammation? An immunologist’s perspective”. Norwegian Inflammation Network seminar “Sufficient options to treat inflammation? Looking at the pipeline of the pharmaceutical industry”, October 29, Oslo, Norway Corthay A “Can tumor-specific Th2 cells be used to treat cancer?”. Norwegian Cancer Symposium 2014 – Harnessing Innate and Adaptive Immunity in Cancer Therapy, June 10-12, Oslo, Norway Corthay A “Cancer prevention by the immune system: role of CD4+ T cells, macrophages, and interleukin-1”. 11th International Conference on Innate Immunity, June 1-6, Olympia, Greece

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ANNUAL REPORT 2014

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Sandlie I: Half-life extension by albumin or Fc-fusion. Gordon Conference on Antibody Biology and Engineering, March 23-28, Tuscany, Italy Sandlie I: Tailoring the Lifespan of Bio­ pharmaceuticals by Targeting the Neonatal Fc Receptor (FcRn), KTH, Royal Institute of Technology, School of Biotechnology, May 23, Stockholm, Sweden Sandlie I: New perspective on IgG function.

December 15. Department of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria Sandlie I: Fra Grunnforskning til Innovasjon.

Det Norske Vitenskapsakademi (January 29) and Cutting Edge Konferansen Oslo Inno­ vation Week October 10, Oslo, Norway Sandlie I: Strategier for å bygge produktive fagmiljøer. Odontologisk fakultets strategiseminar, April 9, Praha, Czech Republic Sollid LM: «Antigen recognition (B and T cell mechanisms». JDRF/Wellcome Trust Frontier Meeting. Common Mechanisms of Autoimmune Diseases, January 27-28, London, UK

CENTRE FOR IMMUNE REGULATION (CIR)

Sollid LM: «Coeliac disease: Food hypersensitivity coupled with autoimmunity». 12th EAACI Immunology Winter School: Basic immunology research in allergy and clinical immunology. January 30-Feb 2, Poiana Brasov, Romania Sollid LM: «Immunopathogenesis of celiac disease». Columbia University Conference: Development of Therapies for celiac disease, March 20-21, New York, USA Sollid LM: « Celiac disease: Interplay of autoimmunity and food hypersensitivity».

Stanford Institute of Immunity, Transplantation and Infection Special Seminar, April 2, Stanford, USA

ORAL PRESENTATIONS Bakke, O. Invariant chain (Ii), a multifunctional molecule, its role in sorting and Ii as a vehicle for antigen loading onto MHC I and MHCII. 8th International Workshop on Antigen Processing and Presentation, June 10-13, Philadelphia, PA, USA Bujko A: Monocytes differentiate into macrophages and lymph node-homing dendritic cells in human gut, World Immune Regulation Meeting VIII-2014, March 19-22, Davos, Switzerland (oral and poster presentation).

Sollid LM: «Celiac disease: When food is the problem». Gordon Research Conference: Immunochemistry & Immunobiology, June 1-6, Newry, USA

Bujko A: Monocytes differentiate into macrophages and lymph node-homing dendritic cells in human gut, 13th International Symposium on Dendritic Cells, September 14-18, Tours, France

Sollid LM: «Immune control of celiac disease». 42nd Annual Meeting of the Scandinavian Society of Immunology, June 11-14, Reykjavik, Iceland

Bækkevold ES: Human airway mucosal DCs respond to TSLP and induce Th2 responses.

8th World Immune Regulation Meeting March 19-22, Davos, Switzerland

Sollid LM: «Transglutaminase 2: auto­ antibody target and generator of T-cell epitopes». Gordon Research Conference: Transglutaminases in Human Disease Processes, June 29-July 4, Barga, Italy

Bækkevold ES: Novel concepts to investigate immunopathology in organ rejection. Medisinsk fakultets 200-års jubileum, September 10, Oslo universitetssykehus Rikshospitalet, Oslo

Sollid LM: «Small bowel, celiac disease and adaptive immunity». Falk Symposium no 193: Celiac Disease and other small bowel disorders, September 5-6, Amsterdam, the Netherlands Sollid LM: «The antibody response of celiac disease». 18th Germinal Centre Conference, September 11-14, Uddevalla, Sweden

Hnida K, Stamnaes J, Chen X, Iversen R and Sollid LM «Functional implications of celiac-autoantibodies-transglutaminase inter­ actions». Gordon-Merck Research Seminar Antibody Biology & Engineering, March 22-23, Barga, Italy

Koster G: “Forces of membrane nanotubes in vitro and in vivo – regulation by physical membrane properties” Norsk biofysikkmøte, March 6, Soria Moria, Oslo, Norway

Sollid LM: «Triggers and Drivers of autoimmunity: Lessons from coeliac disease». 22nd European Gastroenterology Week, October 18-22, Vienna, Austria

Kucera A. “Invariant chain as a vaccination vehicle for loading of MHC I”. Annual meeting, Norwegian Society of Immunology, November 13, Oslo, Norway Stankovic B. “Immune Cell Composition in Human Non-Small Cell Lung Cancer”.

Annual meeting, Norwegian Society of Immunology, November 13, Oslo, Norway

ANNUAL REPORT 2014

Espen Bækkevold

Jenum S: Characterization of Mycobacterium Tuberculosis specific T cells – clues to protective immunity? Årsmøte, Norsk Flowcytometri Forening, April 30, Norway

Sollid LM: «New insights into the pathogenesis of coeliac disease: Glutengene-environmental interactions». 22nd European Gastroenterology Week, October 18-22, Vienna, Austria

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CENTRE FOR IMMUNE REGULATION (CIR)

Kathrin Hnida

Steinsbø Ø. «Binding motifs of gluten-specific antibodies from celiac disease patients».

Annual meeting, Norwegian Society of Immunology, November 13, Oslo, Norway Steinsbø Ø: «Restricted VH/VL usage and limited mutations in gluten-specific IgA of coeliac disease lesion plasma cells”. Award for excellent article published first half of 2014 Oslo University Hospital November 21, Oslo, Norway Wang, D: “Autologous bone marrow Th cells can support multiple myeloma cell proliferation in vitro and in vivo”. Annual Meeting of the Federation of Clinical Immunology Societies (FOCIS), June 25-28, Chicago, USA. (oral and poster presentation, poster prize winner)

POSTER PRESENTATIONS Borg M, Bakke O, Progida C: “A novel Rabactomyosin interaction reveals a dual role in intracellular transport and cell migration”.

14th International Advanced Light Micro­scopy Meeting. May 20-23, Oslo, Norway

56

Borg M, Bakke O, Progida C,: “A novel interaction between Rab7b and actomyosin cytoskeleton reveals multiple functions in intracellular transport and cell migration”.

1st International Meeting “Building The Cell”. September 24-26, Paris, France Marita Borg Stefano

Linda Haugen

Cardoso I, Stamnaes J, Iversen R, Sollid LM. «TG2 interactions with extracellular matrix proteins as probed with celiac disease antibodies». Gordon Research Conference: Transglutaminases in Human Disease Processes, June 29-July 4, Barga, Italy

Gruber LM: Human small intestinal SIRPa+CD103+ dendritic cells display putative immunoregulatory features. 13th Inter­ national Symposium on Dendritic Cells, September 14-18, Tours, France Gruber LM: Human small intestinal SIRPa+CD103+CD1a+ dendritic cells display putative immunoregulatory features. 32nd Annual Meeting of the Norwegian Society for Immunology, November 13, Oslo, Norway Haugen LH, Skjeldal FM, Bergeland T, Bakke O. Growth factor-induced phosphoraylation of Eps15 and Hrs regulates their binding to endosomes and RTK degradation, European Light Microscopy Meeting, May, Oslo, Norway Hnida K, Stamnaes J, Chen X, Iversen R and Sollid LM «Epitope-dependent effect of celiac anti-TG2 hmAbs on preventing TG2 oxidation». Gordon-Merck Research Seminar Anti­ body Biology & Engineering, March 22-23 and Gordon Research Conference, Antibody Biology & Engineering, March 23-28, Barga, Italy Hnida K, Chen X, Iversen R, Graewert MA, Svergun D and Sollid LM « Structural basis for antigen recognition of Transglutaminase 2 specific autoantibodies in celiac disease».

Gordon Research Conference: Transglutaminases in Human Disease Processes, June 29-July 4, Barga, Italy Iversen R: «Gluten, antibodies and TG2: mechanisms for generation of autoantibodies in celiac disease». 18th Germinal Centre Conference, September 11-14, Uddevalla, Sweden McAdam. M. Engineering of novel antibodies for targeted anti-viral therapy. Norwegian Society for Immunology annual meeting, November 13, Oslo, Norway

Eguíluz-Gracia I, Melum GR, Döllner R, Bækkevold ES, Jahnsen FL: Experimentally-induced early recruitment of CD14+ monocytes in human allergic rhinitis. EAACI Winter School on Basic Research in Allergy and Clinical Immunology, January 30February 2, Poiana Brasov, Romania

Nilsen J, Høydahl LS, Gunnarsen KS, Qiao SW, Sollid LM, Sandlie I, Løset GÅ. Affinity maturation of a T cell receptor by use of phage display and deep sequencing. Norwegian Biochemical Society Contact Meeting, January 23-26, Røros, Norway

Algirdas Grevys: Fc-engineering of human IgG1 for altered binding to the neonatal Fc receptor affects Fc effector functions.

Gordon Research Conference (GRC), March 23-28, Lucca (Barga), Italy

Nilsen J, Sand KMK, Bern M, Dalhus B, Sandlie I, Andersen JT. The impact of albumin DI on FcRn cross-species binding.

Norwegian Society for Immunology annual meeting, Nov 13, Oslo, Norway

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CENTRE FOR IMMUNE REGULATION (CIR)

Progida C, Borg M, Koster G, Bakke O: “Rab7b at the intersection of intracellular trafficking and cell migration”. 9th EMBO/ Annaberg Workshop “Protein and lipid function in secretion and endocytosis”.

January 14-19, Goldegg am See, Austria Progida C, Borg M, Bakke O: “Rab7b and the actomyosin cytoskeleton: novel roles in intracellular trafficking and cell migration”.

Conference “The Dynamic Cell 2014”.

September 4-7,Cambridge, UK Snir O, Mesin L, Lundin KE, Yaari G and Sollid LM. «Analysis of celiac disease autoreactive gut-plasma cells and their corresponding memory compartment in peripheral blood using high-throughput sequencing».

18th Germinal Center Conference, September 11-14, Uddevalla, Sweden Steinsbø Ø: «Restricted VH/VL usage and limited mutations in gluten-specific IgA of coeliac disease lesion plasma cells». 18th Germinal Centre Conference, September 11-14, Uddevalla, Sweden

PRESENTATIONS TO A TARGETED AUDIENCE AND THE PUBLIC Christophersen A. «HLA tetramer to understand and diagnose celiac disease. Lecture at the 200-year anniversary seminar of the Faculty of Medicine, September 10, University of Oslo, Norway Lundin KE: «Cøliaki og glutensensitivitet uten cøliaki». Foredrag på årsmøtet for Buskerud NCF, February 18, Hokksund, Norway Lundin KE: «Non coeliac gluten sensitivity».

Lecture at Nordic-baltic AOESC meeting, Scandic KNA Hotel, Oslo, Norway Lundin KE: «Non-coeliac gluten sensitivity».

Foredrag på 40-års jubileum, April 26, Norsk Cøliakiforening, Hotel Bristol, Oslo, Norway

Wang D, Fløisand Y, Tveita A, Thoresen AS, Bürgler S, Parente-Ribes A, Hofgaard P, Bogen B, Tjønnfjord G, Dalgaard J, Munthe L. “Autologous bone marrow Th cells can support multiple myeloma cell proliferation in vitro and in vivo”. 1st International Winter Symposium on Immunobiology: Metabolism, Cancer, Auto immunity and Drug Discovery, October, Seefeld, Austria

Lundin KE: «Cøliaki og fremtiden». Foredrag på 40-års jubileum, June 26, Norsk Cøliakiforening, Hotel Bristol, Oslo, Norway

OTHER

Lundin KE: «Cøliaki». Foredrag på samling for Norsk Cøliakiforenings Ungdommer Hotell Rica Park Hotell, November 22, Drammen, Norway

Andersen, JT. Chair for Gordon Research seminars (GRS), Gordon Research Conference (GRC) pre-seminar for young investigators in Antibody Biology & Engineering: Next-Generation Antibodies: From Biology to Therapeutics, March 23-28, Renaissance Tuscany Il Ciocco Resort, Lucca (Barga), Italy Bakke, O and research group. Main organizer of 14th annual meeting of the European Light Microscopy Initiative (ELMI), Oslo, May 20-23, http://www.mn.uio.no/ibv/forskning/ aktuelt/arrangementer/konferanser/2014/ elmi2014/

ANNUAL REPORT 2014

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Lundin KE: «Glutensensitivitet uten cøliaki», Foredrag på Med Fak 200 års jubileumsseminar, May 24, Gamle Festsal, Oslo, Norway Lundin KE: «Cøliaki». Foredrag på ungdoms leir NCFU, June 23, Elverum, Norway

Progida C; “How do intracellular compartments communicate?” Lab14, October 29, Lillestrøm, Norway Progida C; “How do intracellular compartments communicate?” Lab Norges medlemsmøte, November 27, Oslo, Norway Qiao SW: «Cøliaki – alltid glutenfritt?»

Foredrag på Med Fak 200 års jubileums­ seminar, May 24, Oslo, Norway Qiao SW: «Cøliaki og gluten-intoleranse Er gluten kilden til alt ondt?» Forsknings­ dagene, September 21, Oslo, Norway

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Øyvind Steinsbø

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CENTRE FOR IMMUNE REGULATION (CIR)

Rasmus Iversen

MEDIA COVERAGE

«Cinzia Progida vant Lab Norges forskningspris» at http://messe.no/no/Lab/Nyheter/ Cinzia-Progida-vant-Lab-Norges-forsknings­ pris/

Lundin KE: Paneldeltager i Dagsnytt 18 om glutensensitivitet: http://radio.nrk.no/serie/ dagsnytt-atten/nmag03003714/21-02-2014.

«Mie (10) og Filippa (12) mistet mamma – nå har de samlet inn 600.000 kroner til kreftsaken». TV2 and the Norwegian Cancer Society visited Audun Tveita at his home in relation to his research grant from the Norwegian Cancer Society. http://www.tv2. no/2014/10/28/nyheter/innsamling/kreft/ armband/6170879

Inger Sandlie, Jan Terje Andersen and colleagues. "The Research Race to Make Drugs More Efficient". Wall Street Journal May 6.

Featuring technology developed by CIR in collaboration with Novozymes.

“Jakter på WOW-effekten”. Geir Åge Løset and Inger Sandlie. http://www.mn.uio.no/ forskning/aktuelt/aktuelle-saker/2014/ jakter-pa-wow-effekten.html

Anders Tveita

58

«Lanserte HelseOmsorg21 på OUS Riks­ hospitalet». The Prime Minister Erna Solberg and Minister of Health and Care Services Bent Høie visited CIR. http://www.oslo-universitetssykehus.no/aktuelt_/nyheter_/ Sider/Lanserte-HelseOmsorg21-på-OUSRikshospitalet.aspx “Sykehuset hedrer forskere”. Ludvig Sollid honored with Excellent Researcher Award. http://www.oslo-universitetssykehus.no/ aktuelt_/nyheter_/Sider/forskningspriser-august14.aspx

Cinzia Progida

“Miljonpris til Norges mest citerade forskare”. Per Brandtzæg. Press release at Lunds Universitet on Fernströmstiftelsens Nordiska Pris: http://www.lu.se/article/miljonpris-till-norges-mest-citerade-forskare, and story in Dagens medisin: http://www. dagensmedisin.no/nyheter/per-brandtzaghedres-med-millionpris/ “UiOs mest oppfinnsomme forsker», Inger Sandlie. Uniforum. http://www.uniforum. uio.no/nyheter/2014/10/uios-mest-oppfinnsomme-forsker.html «Synliggjør nanoverdenen». Oddmund Bakke in Finansavisen, Oct 9.

«Nobelpris kjemi», NRK Radio live at Oddmund Bakkes lab, Oct 9. http:// radio.nrk.no/serie/ekko-hovedsending/ MDSP25020114/09-10-2014

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ANNUAL REPORT 2014

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CENTRE FOR IMMUNE REGULATION (CIR)

Annual Report

2010 Centre for Immune Regulation (CIR)

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Redaktør: Lise Kveberg, UiO Foto: Øystein H. Horgmo, UiO Design: Millimeterpress Trykk: Rolf Ottesen

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CENTRE FOR IMMUNE REGULATION (CIR) Visiting address Oslo University Hospital-Rikshospitalet Sognsvannsveien 20 Building A2/A3 N-0027 Oslo Mailing address Centre for Immune Regulation OUS HF, Rikshospitalet P.O.Box 4956 Nydalen N-0424 OSLO Norway Phone (+47) 23 07 35 00 Fax (+47) 23 07 35 10 Email post@cir.uio.no www.cir.uio.no