CIR ANNUAL REPORT 2016 by Millimeterpress as

Centre for Immune Regulation

CIR Annual report 2016

CENTRE FOR IMMUNE REGULATION (CIR) ANNUAL REPORT 2016

Vision statement

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

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research groups Bakke group Bogen group Jahnsen group Munthe group Sandlie group Sollid group Qiao group

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about Facts and figures Staff and students Collaboration Education and career development

24 26 28 30

activities The Visiting Professor program Minisymposium Work package (WP) symposia Guest lectures Internal activities

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publications Papers in scientific journals Active patents and patent applications

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dissemination Invited lectures Oral presentations Poster presentations Presentations to a targeted audience and the public Media coverage

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contents

Vision statement Key accomplishments 2016 Directorâ&#x20AC;&#x2122;s comments Scientific currency Innovation and industrialisation

2016 n We have undertaken functional and

transcriptomic analysis of macrophage and dendritic cell subsets sorted from the human gut. n We have demonstrated that gluten

specific effector memory CD4 T cell clonotypes persist in the gut of treated celiac disease patients for decades and will dominate the T-cell response upon reintroduction of dietary gluten. n We have shown transport across human

polarized epithelial cells and found that IgG is transported in an FcRn-dependent manner. Furthermore, we have found that the transport can be enhanced by engineering for improved FcRn binding as well as polymerization. The finding inspires design of future therapeutics targeted for transmucosal delivery. n Full implementation of single-cell

transcriptomics protocols on glutenreactive T cells. We have preliminary results that are in accordance with previous findings of gluten-reactive T cells analysed at population-level or after in vitro culture.

n Autophagy is a major cellular

mechanism and involved in many malignancies. So far there has been no link to the TGN pathway. We have shown that Rab7b, normally regulating retrograde transport, is also a player in macroauthofagy regulating autophagic flux. n To study the importance of BCR-ligation

in Id-driven T-B collaboration, we have successfully generated a conventional VDJH315 knock-in mouse and a VL-gene modified mouse (change of three nucleotides from germline). The latter mouse is a first of its kind. F1 offspring have about 1% of B cells with a predefined specificity, as would be expected. The system will be of great use in studying the importance of BCRligation in Id-driven T-B collaboration. n We have discovered that CD45, as a

master regulator controls a wide array of functions in human B cells, responsible for the break of tolerance in autoreactive, anergic B cells and plays a pivotal role in B cell effector functions.

CENTRE FOR IMMUNE REGULATION (CIR) ANNUAL REPORT 2016

Director’s comments CIR has become a success due to the numerous contributions by many people over almost a decade. The existence of centre is soon coming to an end as we have only a few months of operation left. Regardless, the Centre is still running with high speed. I would like take this opportunity to thank all those who have contributed to activities at CIR in 2016. Last year was another good year for CIR. One of the highlights was the annual retreat for 70 members and invited guests at Geilo in April. Our three international keynote speakers, Michael Dustin from the University of Oxford, Ziv Shulman from the Weizmann Institute of Science, and Hyun-Dong Chang from Deutsches RheumaForschungszentrum Berlin, made excellent contributions. I am also impressed by the good quality of the science presentations by the young researchers and students at CIR.

In 2016, CIR scientists authored or coauthored 47 papers in international peer reviewed journals, and four PhD students defended their thesis; 1 woman and 3 men. Currently, 19 nationalities are represented at the centre, making this a stimulating international environment. Half of our publications include international collaborators, demonstrating that CIR scientists have a broad international scientific network. A number of scientists have visited CIR during the year to give guest lectures. Most of the speakers have been invited as part of a seminar series organised by a postdoctoral committee. These include Michael Sieweke from CIML in Marseille-Luminy, Steffen Jung from the Weizmann Institute in Israel, Lill Mårtensson-Bopp from the University of Gothenburg, and Rajesh Grover from the Scripps Research Institute, La Jolla, California. I thank this committee for their effort. Our Visiting Professor programme had visits from Adrian Hayday from King’s College in London and Gwendalyn Randolph from Washington School of Medicine in Washington.

The final report for CIR is in progress and will be published in the fall, so the annual report for 2016 is a little bit shorter than previous years. It is still early June, and CIR will have a number of activities before the summer break starts. The most important are perhaps David Nemazee being a Guest Professor and Eric Meffre being a Guest Lecturer in the coming days. The activities will continue in the fall. CIR will not stop breathing before November 30, our official last day of operation. Keep up the good spirit!

Photo: ÂŠ UiO/Bente Devik

During the year we have had a lot of fun and excitement. However, there have also been moments of sadness and sorrow. This was particularly so when Professor Per Brandtzaeg passed away on September 11, 2016. Per was a friend and esteemed colleague who made fundamental contributions to the understanding of mucosal immunology. For CIR he was tremendously important, not least by forming the fundament onto which CIR was formed. Per is much missed!

Ludvig M. Sollid, Centre Director

CENTRE FOR IMMUNE REGULATION (CIR) ANNUAL REPORT 2016

Scientific currency Impact factor distribution – CIR publications 2016 6% 15% 43%

34%

<5 5–10 10–20 >20 New journals, No IF

CIR publications with collaborating institutions 2016 13% 34%

38% 15%

International International & national National CIR only

PAPERS CIR scientists authored or co-authored 47 papers in international peer-reviewed journals in 2016. The total number of publications per year remains stable. Of the papers published in 2016, 3 publications reached journals with an impact factor above 20.0, another 7 publications reached an impact factor between 10 and 20, and more than half of the publications were accepted into 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, and 49% of the papers published in 2016 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 2016 are presented on page 40 of this report. National and international collaborators are listed on pages 28-29.

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 until 2016 is 32. Active patents and patent applications are listed at page 43. Read more in the innovation and industrialisation section on page 10. DISSEMINATION OF RESEARCH RESULTS CIR members gave 49 talks as invited speakers at international and national scientific meetings in 2016. In addition, 19 oral presentations and 37 posters were presented by CIR scientists at international and national conferences. Furthermore, CIR staff gave 13 lectures and articles aimed at a targeted audience and the general public. These include 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 Group leader and Deputy Director of CIR, Inger Sandlie, became an honorary member of the Norwegian Society of Immunology (NSI) 2016 for her many scientific contributions to immunological research. This was celebrated at the annual meeting for the Norwegian Society of Immunology November 17th in Oslo. INTERNATIONAL CONFERENCES Cinzia Progida and other CIR scientists in the Cell dynamics team (within Bakke’s group), organized the international "Cells on the move" conference at Blindern, Oslo June 9-10. The meeting brought together some of the most renowned experts in fields of intracellular membrane traffic and cell migration. Topics covered included cytoskeleton functions and dynamics, intracellular transport, signalling regulating cell motility, and cell migration in an interdisciplinary perspective with a special focus on cutting-edge imaging technologies. The conference gathered more than 100 participants from disciplines spanning physics, biology, chemistry, pharmacy, dentistry and medicine, with a common interest in understanding how cellular processes are regulated in space and time.

Centre for Immune Regulation (CIR) 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 minisymposia 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. Centre staff is involved in the education and supervision of basic scientists and clinicians at all levels. CIR scientists have organised or lectured at several graduate courses in molecular cell biology and immunology offered by the University of Oslo.

Two honorary members of NSI. Professor Inger Sandlie (2017) together with Professor Emeritus Morten Harboe. Photo: Lise Kveberg

The Federation of Clinical Immunology Societies (FOCIS) Centers of Excellence (FCE) network creates a community of researchers and clinicians that provides an effective translational training environment by promoting interdisciplinary innovation. www.focisnet.org

n tr e fo

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 Department of Pathology offering services within confocal laser scanning microscopy. The Proteomics Core Facility at the Department of Immunology was previously headed by CIR scientist Gustavo DeSouza. Since 2016, the core facility is headed by an associated member of CIR, Dr. Tuula A. Nyman. The facility offers advanced analysis of proteins and peptides by mass spectrometry.

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 FCEâ&#x20AC;&#x2122;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.

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CENTRE FOR IMMUNE REGULATION (CIR) ANNUAL REPORT 2016

Innovation and industrialisation EXTENDING IN VIVO HALF-LIFE OF 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 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, less side effects and the need for less frequent dosing. Together with Inven2, they have signed agreements with Novozymes Biopharma, and together with Novozymes, established a very successful research program. So far, six patent families have been filed by Novozymes based on the results of the collaborative research. 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 differ from normal albumin at one or a few amino acid positions. They bind the neonatal Fc receptor with a range of different affinities, and when tested in rats and rhesus monkeys show greatly altered halflife. 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. During 2015 new albumin variants were designed with increased half-life beyond that of earlier versions. The first drug to use the Veltis® half-life extension technology was launched by GlaxoSmithKline in 2014

as Tanzeum® (US) and Eperzan® (EU). Tanzeum® is a GLP-1 fusion to recombinant albumin for once weekly treatment of type 2 diabetic patients. During 2016, Novozymes established a new company, Albumedix A/S, which aims to develop new drugs based on the Veltis® technology. 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. The muscle 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 VB10.16, as well as a license agreement with the Phibro Animal Health Corporation, covering vaccines for poultry. The company has made significant progress with VB10.16, a therapeutic vaccine against cervical pre-cancerous lesions, and initiated its first clinical trial in 2015. Results from the

interim analysis in the first phase showed excellent safety and tolerability, induction of strong T cell responses and promising early signs of lesion regression. In addition, Vaccibody is dedicated to develop individualized cancer vaccines based on mutation-derived neoantigens (VB10.NEO). A clinical trial application will be submitted in 2017 for evaluating VB10.NEO in patients with melanoma, non-small cell lung cancer, kidney, bladder and head and neck cancer at three centers in Germany.

NEXTERA AS Phage display is the dominating technology for discovery and refinement of novel protein-based diagnostics and therapeutics. A significantly improved version of phage display, termed SSIp display, has been developed by the Sandlie group at CIR, and commercialized by a spin-out company, Nextera AS. Nextera was established by the key inventor, CIR scientist Geir Åge Løset, and Biomedical Innovation AS in 2009, with Geir Åge Løset as its Chief Scientific Officer. Additional jointly developed IPR was acquired from Affitech AS in 2012, and Nextera furthermore holds the rights to

innovations related to MHC class II expression that were jointly developed by the Sandlie and Bogen groups at CIR, and commerzialised as Phagemers. The technology platform thus has a broad patent protection separated into five patent families granted in all major markets. The core activity of the company is focused on discovery of disease relevant antigens presented on MHC class II and development of therapeutic leads towards these targets. Nextera performs joint research with the Sollid and Sandlie groups at CIR with the aim of validating and expanding the use of the Phagemer. In 2015, Nextera entered into a research agreement with Janssen Biotech, Inc., one of the Janssen Pharmaceutical Companies of Johnson & Johnson, to determine the applicability of its Phagemer technology within rheumatoid arthritis (RA). Janssen funds the research program, and has an option for an exclusive worldwide license to the technology platform within RA. In addition, the company has a drug development program within hematological cancer in collaboration with CIR member Professor Ludvig A. Munthe.

research groups

CENTRE FOR IMMUNE REGULATION (CIR) ANNUAL REPORT 2016

Bakke group Our group has since the early nineties aimed to understand the endocytic pathway and how peptide loading of the MHC class I and II complexes (MHC II) is regulated in the endosomal pathway. 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, Wälchli et al., 2014).

OVERVIEW OF RESEARCH IN THE GROUP 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, Kucera et al. 2016). The Bakke group also runs the NFR supported NorMIC-Oslo national imaging facility specialising on microscopy of live cells. KEY PROJECT SUMMARIES The group is focusing on the properties of the endosomal pathway and the implications of this specific pathway in immune regulation. The projects can be divided into four sub themes: • Endosomal sorting and trafficking of immune molecules in model cell lines and in dendritic cells. • Searching for new players in regulatory role of vesicular transport between the Golgi network, endosomes and the autophagosomal pathway. • Studying the endosomal progression as an effect of endosomal maturation and its specific role in the formation of the “immunoendosome”. • The binding dynamics of endosomal associated proteins and their regulatory role in receptor signalling.

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 foundation to better understand vaccination regimes and protocols for immune therapy of cancers, autoimmune-, and infectious diseases. Our main strategy employs a wide array of advanced live cell imaging technologies, supplemented by biochemistry, immunological assays and DNA/RNA techniques. The group collaborates in studies within CIR, where we provide the cell biological outlook and essential microscopy expertise. 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)

Bogen group 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).

OVERVIEW OF RESEARCH IN THE GROUP Immunoglobins (Ig, antibodies) are extremely diverse. The heterogeneity is localized to their variable (V) regions. Bogen and co-workers showed more than 25 years ago that Ig is partially broken down inside B 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. 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 can result in immune dysregulation, autoimmunity and B lymphoma development. To study Id-driven T-B collaboration in even more detail, we have now 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. Id-driven T-B collaboration is now being 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 Idspecific CD4+ T cells and macrophages results in activation of macrophages that in turn kill the tumor cells. Ongoing experiments focus on the molecular mechanisms by which M1-like macrophages, activated by Id-specific Th1 cells, 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 (>30) collaborators worldwide. Using this model, we have ourselves recently demonstrated that CD4+ T cells can kill multiple myeloma cells growing in the bone marrow. We have also knocked out MHC class II molecule (I-Ed) expression in the MOPC315.BM cell line, nevertheless Id-specific CD4+ T cells reject these MHCIIdeficient cells. This study conclusively demonstrates that CD4+ T cells in a collaboration with macrophages can kill tumor cells that lack expression of MHC class II molecules.

CENTRE FOR IMMUNE REGULATION (CIR) ANNUAL REPORT 2016

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

OVERVIEW OF RESEARCH IN THE GROUP We are currently studying: 1) the function and longevity of immune cells in the intestine and lungs under non-inflammatory conditions and 2) the immunopathology of allergic rhinitis and allergic asthma. KEY PROJECT SUMMARIES Mucosal surfaces in the gut and the airways are constantly bombarded by a large variety of antigens from the outside world, including both harmful pathogens such as virus and bacteria and harmless antigens such as foods and pollen. Understanding how the mucosal immune system can maintain homeostasis under such extremely challenging environment is of paramount importance as a basis to restore homeostasis in pathological reactions.. By isolating immune cells from surgical specimens and endoscopic biopsies (cancer surgery and transplanted patients) we have been able to perform detailed functional characterization of immune-cell subsets (monocytes, macrophages, dendritic cells, and B and T cells) in the human small intestine. We find that monocytes constantly migrate to the gut mucosa and differentiate into two distinct subsets of macrophages. The half-life of macrophages are <20 weeks. Functional studies and transcriptomic analysis show that monocytes rapidly downregulate their proinflammatory capacity when entering the tissue and differentiate into macrophages with phagocytic and antigen presenting capacity. Dendritic cells are highly dynamic cells with short transit time in the tissue. They comprise several

subsets with complementary capacities to regulate T-cell responses. Of particular interest we find that both T cells and plasma cellsin the gut are long-lived. In fact, by measuring the integration carbon-14 in DNA of sorted plasma cells we demonstrate they can live for over 20 years. This finding fundamentally changes our view on humoral immunity. We show that CD8+ T cells consist of long-lived cells that produce high levels of cytokines whereas short-lived cells are more cytotoxic. That gut plasma cells and T cells are long-lived may have important implications in the search for efficient vaccination strategies as well as identifying new targets in the treatment of chronic inflammatory diseases. Our studies of monocytes and macrophages show that alveolar macrophages are longlived (>2 years). This demonstrates that macrophages in various tissues are different and most likely shaped by their local environment. We find that proinflammatory monocytes accumulate rapidly in both an experimental model of allergic rhinitis and in tissue obtained from children with fatal allergic asthma. By transcriptomic profiling we find that mononuclear phagocytic cells in the challenged nasal mucosa produce several Th2-associated chemokines during the inflammatory reaction. Our findings thus suggest that monocytes are central players in both allergic rhinitis and allergic asthma and it should be explored whether these cells can be targets for anti-inflammatory therapy.

CENTRE FOR IMMUNE REGULATION (CIR) ANNUAL REPORT 2016

Munthe group 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 now extend these results to Multiple Myeloma. We will extend our autoimmunity research on Th and B cell collaboration to the study of Immune thrombocytopenic purpura (ITP) patients. We define the mechanisms of Ikaros regulation of B cell development and leukemogenesis, and how Th cells can alter B cell signalling pathways. KEY PROJECT SUMMARIES We have the following research questions: • How can Idiotype-specific Th cells drive autoimmune B cell responses? • What is the molecular basis of Th cell regulation of B cell responses, signalling and anergy? • How can Th cells drive the proliferation of human lymphoma? • 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? • How do Th cells regulate B cell signalling and CD45 activity? • What is the function of Ikaros family transcription factors in B cell development and differentiation?

KEY PUBLICATIONS IN 2016 Chen JQ, Papp G, Szodoray P, Zeher M. The role of microRNAs in the pathogenesis of autoimmune diseases. Autoimmun Rev. 2016 Dec;15(12):1171-1180. Szodoray P, Stanford SM, Molberg O, Munthe LA, Bottini N, and Nakken B. T-helper Signals Restore B-cell Receptor Signaling in Autoreactive Anergic B-cells by upregulating CD45 phosphatase activity. J Allergy Clin Immunol. 2016 Apr 4. Li, S., Heller, J. J., Bostick, J. W., Lee, A., Schjerven, H., Kastner, P., Chan, S., Chen, Z. E. and Zhou, L. Ikaros Inhibits Group 3 Innate Lymphoid Cell Development and Function by Suppressing the Aryl Hydrocarbon Receptor Pathway. Immunity. 2016;45(1):185-197.

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

OVERVIEW OF RESEARCH IN THE GROUP We focus on two projects: A) Studies of the interaction between Fc receptors, and in particular TRIM21 and FcRn, with antibodies and albumin. Key questions are how binding to the receptors elicits antibody effector functions and regulates biodistribution and serum half-life. B) Using bioinformatics tools and phage display, we select antibodies with specificity for antigenic peptide-MHC molecule complexes (pMHC), and we utilize the antibodies to characterize the nature of antigen presenting cells. 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 mechanisms depend on their interaction with FcRn, as it is crucial to understand how FcRn rescues IgG and albumin, and to transfer long half-life to therapeutics, utilizing the same mechanisms. We have used our knowledge of the interactions to design both albumin and antibody variants with stronger binding and longer half-lives. FcRn is broadly expressed in different cell types of the body and mediates both recycling and transcytosis across cellular barriers. To gain new insights into how FcRn acts as a transporter, we establish robust in vitro human cell assays where both processes can be studies in great detail using both natural ligands and engineered variants. Such assays can predict the behavior of designed FcRn-binding molecules in vivo in animal models. Furthermore, new animal models are established for the study of FcRn mediated vaccine and drug delivery across cellular barriers. Surprisingly, IgG and

albumin are not sorted in the same manner by the placenta, and we study how cells can distinguish between the two ligands, even if both bind FcRn. FcRn shares binding site on IgG with TRIM21, an intracellular Fc receptor. We study how different antibody classes and subclasses differ in their ability to interact with TRIM21 and induce protection against viruses and intracellular bacteria. To ask questions regarding the location and nature of the antigen presenting cell in patients with celiac disease, detection molecules are needed, and specific antibodies are new tools for such studies. We use the protein engineering method “phage display” to generate specific antibodies. Our best characterized antibody shows a remarkable ability to distinguish between highly similar pMHCs, and we have detected disease associated pMHC complexes on B cells and plasma cells in celiac disease patient biopsies taken from inflamed intestinal mucosa. We work to make the antibodies even more sensitive. We have found that phages can display pMHC class II complexes, and we call such phages “Phagemers”. Phagemers bind to and detect specific T cells via their pMHC portion, and we explore the use of Phagemers as diagnostics for coeliac disease. Furthermore, the spin-out company Nextera AS, commercialises and develops the Phagemer technology and utilizes large libraries of Phagemers to search for disease causing protein sequences.

CENTRE FOR IMMUNE REGULATION (CIR) ANNUAL REPORT 2016

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

OVERVIEW OF RESEARCH IN THE GROUP CD is caused by an inappropriate immune response to cereal gluten proteins in genetically predisposed individuals. Gluten induces disease specific immune responses both in the CD4+ T-cell and B-cell compartments, and a hallmark of the disease is antibody production towards gluten and the autoantigen transglutaminase 2 (TG2). Fundamental disease mechanisms have been defined and characterised by isolating disease relevant adaptive immune cells from patient derived gut biopsies. We are increasingly taking advantage of the fact that the identities of the antigens recognised by these immune cells are known. This allows us to selectively enrich for and isolate cells of a given specificity both in bulk and at the single cell level. We can characterise their phenotype directly thereby avoiding bias introduced by tissue culture, and we can follow their dynamics both at clonal and population level at different stages of disease both in gut and blood. This setting likely will give us unprecedented insight into the disease specific, adaptive immune response. Our recent interest in understanding the autoimmune B-cell response towards TG2 not only encompasses the B cell, but also the antigen, TG2. We aim to understand how the exogenous antigen gluten drives autoantibody production towards TG2. We believe that lessons from CD are relevant for other MCH class II associated autoimmune diseases.

KEY PROJECT SUMMARIES • The B-cell response: –– Phenotypic characterization and high throughput DNA sequencing of disease specific plasma cells from blood and gut, both in bulk and at single cell level. Characterize VH/VL gene usage, pairing preferences, mutation rate, clonal expansion and memory formation. –– Established the relationship between disease specific gut and serum antibody responses by immunoglobulin sequencing on protein and mRNA level –– Established the structural basis for recognition of deamidated gluten by two canonical disease specific B-cell receptors • The T-cell response: –– Longevity of T-cell effector memory compartment and clonal relationship between gut and blood as addressed by sequencing of disease specific T-cell receptors from bulk or single cell. MHC tetramers are key tools in these studies. –– Understand TCR gene usage and bias of disease specific T-cell receptors. MHC tetramers are key tools in these studies. • In vivo models for autoantibody production: –– Assessment of B-cell tolerance to TG2 –– Analysis of mechanisms for activation of autoreactive TG2-specific B cells –– Development of models for T-cell and B-cell interaction

Qiao group We use cuttingedge technologies to analyse at the single-cell level the transcriptional profile of immune cells from human inflammatory conditions.

OVERVIEW OF RESEARCH IN THE GROUP The main focus of our group is T-cell receptor analysis and transcriptional analysis of antigen-specific CD4+ T cells. When performed on the single-cell level, transcriptional profiles can be compared within and across expanded T-cell clones. CD4+ T cells are important players in the adaptive immunity. Antigen stimulation leads to clonal expansion of the few T cells that express the specific T-cell receptors. The transcriptional profiles of CD4+ T cells have been studied in detail albeit only on the population-level until very recently. In order to fully understand the transcriptional adaptions of CD4+ T cells in responses to antigen stimulation, we focus our study on antigen-specific CD4+ T cells. Due to the scarcity of the antigen-specific T cells, single-cell transcriptomics techniques are required. Our group has adapted two different single-cell transcriptomics protocols for the study of antigen-specific single CD4+ T cells, acquired by tetrameraided single-cell sorting. We study glutenspecific CD4+ T cells from celiac disease patients as a model system for pathogenic T cells in a human inflammatory disease. For conditions where the disease-causing antigens are not yet defined, we use high throughput single-cell transcriptomics to characterise the CD4+ T-cell response. By profiling tens thousands of single T cells at time, we hope to pinpoint the disease-specific T cells that are involved in pathogenesis.

KEY PROJECT SUMMARIES • Use Smart-seq2 protocol for single-cell transcriptomics on gluten-reactive CD4+ T cells. • Development of bioinformatics pipeline for analysis of single-cell transcriptomics data of antigen-specific CD4+ T cells • Comparison of transcriptional profiles of clonally related and –unrelated antigenspecific CD4+ T cells by single-cell analysis. • Optimisation of Drop-seq protocol for high throughput single-cell transcriptional analysis of tens thousands of cells at time • Apply Drop-seq on T cells from inflammatory diseases

about

CENTRE FOR IMMUNE REGULATION (CIR) ANNUAL REPORT 2016

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 November 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 the Oslo University Hospital. Centre staff is employed at the Department of Biosciences, the Department of Immunology and the Department of Pathology. 98 persons, producing 61,7 person years, are involved in research at CIR.

The overall gender balance at CIR is 61% females/39% males with an overweight of female members among PhD students, master students and technicians, and an overweight of male members among group leaders and senior researchers. THE RESEARCH GROUPS CIR consists of seven research groups headed by professors Ludvig M. Sollid, Inger Sandlie, Oddmund Bakke, Bjarne Bogen, Frode L. Jahnsen, Ludvig A. Munthe, and Associate Professor Shuo-Wang Qiao. 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.

CIR actively recruits international talents and currently 19 nationalities are represented at the centre.

FUNDING (1000 NOK)

2016

CENTRE PERSONNEL 2016 30

Research Council of Norway (RCN) â&#x20AC;&#x201C; CoE 1 11050 University of Oslo (UiO) 16483 2

Oslo University Hospital (OUS) 3 8730 Other funding from RCN

15609

South-Eastern Norway Regional Health

14428

Private funding 4 5673

International funding 2963 5

Total funding

74936

Centre of Excellence grant. Including value of personnel funded by UiO and indirect costs of infrastructure. Including value of personnel funded by OUS and indirect costs of infrastructure. Including grants from the Norwegian Cancer Society, and others. Including ERC advanced grant, EU grants, and others.

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ro G

Compared to 2015, the total funding is increased in 2016.

ad er s

1 2 3 4 5

The Director has the daily responsibility for project management, administration and delivery. 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. • Lars Eide, Head of research, Division of Laboratory Medicine and Division Radiology and Nuclear Medicine, University of Oslo/Oslo University Hospital

• 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. • Head physician Knut E. Lundin (chair, gastroenterologist, OUS and UiO). • Professor II Geir E. Tjønnfjord (haematologist, OUS and UiO). • Professor Knut Dahl-Jørgensen (paediatrician, OUS and UiO).

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.

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

SCIENTIFIC ADVISORY BOARD Until September 2015, CIR had a scientific advisory board (SAB) consisting of European world-class scientists. The SAB’s mandate was to critically evaluate and advice on the centre’s scientific performance and progress. Their effort was highly appreciated.

• 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.

CIR STAFF DEVELOPMENT

GENDER BALANCE STAFF

120

GENDER DISTRIBUTION

100 15 80

39% 10

61%

5 20

ch er fe Po llo st w do + s w cs re / s. fe P PhD llo h w D s st w ud /o . Ph D St ud en t Te ch ni ci an Ad m in is tra tio n

Man years

* Head count includes unpaid MSc/ MD students and staff that left or joined CIR during 2016.

Head count

ro up

20 16

20 15

20 14

20 13

20 12

20 11

20 10

20 09

20 08

Female Male

CENTRE FOR IMMUNE REGULATION (CIR) ANNUAL REPORT 2016

Staff and students GROUP LEADERS Name Position Funding* Employer* Oddmund Bakke Professor UiO UiO Bjarne Bogen Professor UiO/OUS UiO/OUS Frode L. Jahnsen Professor UiO/OUS UiO/OUS Ludvig A. Munthe Professor UiO UiO Shuo-Wang Qiao Associate Professor UiO UiO Inger Sandlie Professor UiO UiO Ludvig M. Sollid Professor RCN-CIR UiO SENIOR RESEARCHERS Name Position Funding* Employer* Jan Terje Andersen Researcher RCN/RCN-CIR OUS/UiO Espen Bækkevold Researcher S-EN RHA/RCN-CIR OUS/UiO Ole-Audun Haabeth Researcher NCS OUS Denis Khnykin Researcher S-EN RHA OUS Knut E.A. Lundin Professor UiO UiO Geir Åge Løset Researcher RCN-CIR UiO Cinzia Progida Researcher NCS/NFR UiO Hilde Schjerven Researcher RCN-CIR UiO Jorunn Stamnæs Researcher UiO UiO Peter Szoroday Researcher/resident physician OUS OUS Keith Thompson Researcher UiO UiO Anders A. Tveita Researcher NCS OUS Per Brandtzæg

Professor emeritus

Passed away in 2016

TECHNICIANS Name Position Funding* Employer* Hege Eliassen Senior Executive Officer OUS UiO Kathrine Hagelsteen Biomedical Laboratory Scientist UiO UiO Kjersti Thorvaldsen Hagen Biomedical Laboratory Scientist OUS OUS Linda Haugen Senior engineer UiO UiO Carina Hinrichs Biomedical Laboratory Scientist OUS OUS Marie K Johannesen Senior engineer UiO UiO Heidrun Elisabeth Lode Research Technician RCN OUS Bruno Mainnemard Research Technician NCS OUS Martin McAdam Research Technician RCN OUS Sylvi Morth Staff engineer UiO UiO Camilla V. Myklebust Staff engineer UiO UiO Hilde Omholt Senior engineer RCN UiO Bjørg Simonsen Staff engineer RCN OUS Sathiyaruby Sivaganesh Staff engineer RCN OUS Frode M. Skjeldal Senior engineer UiO UiO Linda I. Solfjell Biomedical Laboratory Scientist OUS OUS Maria Ekman Stensland Staff engineer S-EN RHA OUS Merete Storflor Staff engineer UiO-CIR UiO ADMINISTRATION Name Position Funding* Employer* Lise Kveberg Senior advisor RCN-CIR UiO POSTDOCS AND RESEARCH FELLOWS WITH PHD Name Funding* Employer* Jana Blazevski ERC UiO Sudhir Kumar Chauhan EU-SF/UiO-CIR UiO Asbjørn Christophersen RCN/EU-SF/UiO UiO Stian Foss RCN OUS Dominik Michael Frei RCN-CIR/RCN UiO Ramakrishna Prabhu Gopalakrishnan RCN-CIR UiO Noemi Guadagno RCN UiO Kristin S. Gunnarsen S-EN RHA OUS Catherine Heyward UiO UiO Peter C. Huszthy RCN UiO Rasmus Iversen ERC UiO Johanne Jacobsen RCN OUS Ida Jonson NCS OUS Ine Jørgensen RCN/Nextera AS OUS Ole J.B. Landsverk S-EN RHA OUS Peng Lei RCN UiO Elettra Marini NCS UiO Britt Nakken S-EN RHA/RCN-CIR OUS/UiO Ralf Stefan Neumann RCN-CIR UiO Niladri Bhusan Pati RCN-CIR/RCN UiO Fleur du Pré S-EN RHA/ERC OUS/UiO Lisa M. Richter RCN-CIR UiO Bishnudeo Roy ERC UiO Sandra Espada Serrano NCS UiO Omri Snir S-EN RHA UiO Dong Wang RCN-CIR/S-EN RHA UiO/OUS Asima Zia RCN-CIR UiO

CIR Centre for Immune Regulation ERC European Research Council, Advanced grant EU-SF EU Scientia Fellows ImmusanT Biotechnology company, UK NCS Norwegian Cancer Society Nextera AS Biotechnology company, NO OUS Oslo University Hospital Regeneron Pharmaceutical company, US RCN Research Council of Norway S-EN RHA South-Eastern Norway Regional Health Authority UiO University of Oslo The list of CIR staff and students include both members that left and joined the Centre during 2016. Several CIR members have changed employer, position and funding body during 2016. The listed funding body, position and employer refer to the status per December 2016.

CENTRE FOR IMMUNE REGULATION (CIR) ANNUAL REPORT 2016

PHD STUDENTS AND RESEARCH FELLOWS WITHOUT PHD Name Funding* Employer* Karin Christina Ballke RCN-CIR UiO Malin C. Bern RCN/UiO-CIR UiO Anna Bujko RCN-CIR UiO Inês Cardoso UiO-CIR/S-EN RHA UiO/OUS Raquel Bartolomé Casado S-EN RHA OUS Marita Borg Distefano UiO UiO Linn Margrethe Eggesbø RCN-CIR UiO Marte Fauskanger S-EN RHA OUS Rahel Frick S-EN RHA OUS Ibon Eguiluz Gracia S-EN RHA OUS Algirdas Grevys UiO/RCN UiO/OUS Kathrin Hnida RCN-CIR/S-EN RHA UiO/OUS Lene Støkken Høydahl RCN-CIR UiO Ingrid Kjos RCN UiO Shiva Dahal Koirala S-EN RHA OUS Ida Lindeman UiO UiO Stine Rosenqvist Lund UiO ImmusanT/ Regeneron Duarte Nunes De C Mateus UiO UiO Jeannette Nilsen RCN OUS Nicolay Rustad Nilssen S-EN RHA OUS Louise Risnes S-EN RHA OUS Kine Marita K. Sand UiO UiO Vikas K. Sarna S-EN RHA OUS Ying Yao RCN-CIR UiO Anders Theodor Aasebø S-EN RHA OUS STUDENTS Name Study Kjartan Hennig Med Ina Hodnebrug MSc Camilla Myklebust MSc Hanna Noordzij MSc Huma Rehmat MSc Sowmya Subbanna MSc Katharina Marie Vestre MSc Marius Sigurdsson Østrøm MSc

Collaboration 2016 NATIONAL 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, University of Oslo and Oslo University Hospital Ralph Dollner, Department of Otorhinolaryngology, Oslo University Hospital Nikolai Engedal, Centre for Molecular Medicine, University of Oslo Terje Espevik, Norwegian University of Science and Technology, Trondheim Alexander Fosså, Dept of Oncology, University of Oslo and Oslo University Hospital Tobias Gedde-Dahl, Dept. of Haematology, Oslo University Hospital Waleed Ghanima, Dept of Medicine Sykehuset i Østfold Bjørn Tore Gjertsen, Haukeland Univ Hospital Einar Gran, Lovisenberg Hospital, Oslo Krzysztof Grzyb, Dept. of Pathology, Oslo University Hospital Guttorm Haraldsen, Dept. of Pathology, University of Oslo and Oslo University Hospital Christine Henriksen, Institute of Basic Medical Sciences, University of Oslo Are Holm, Dept. of Respiratory Medicine, Oslo University Hospital Pål Andre Holme, Dept of Haematology, OUH-Rikshospitalet and UiO Harald Holte, Dept. of Oncology, Oslo University Hospital Ole Høie, Department of Medicine, Sykehuset Sørlandet Jørgen Jahnsen, Department of Medicine, Akershus University Hospital Knut-Dahl Jørgensen, Dept. of Pediatrics, Oslo University Hospital Mari Kaarbø, Dept. of Microbiology, University of Oslo and Oslo University Hospital Trond Leren, Dept. of Medical Genetics, Oslo University Hospital Benedicte A. Lie, Dept. of Medical Genetics, Oslo University Hospital Fridtjof Lund-Johansen, Department. of Immunology, Oslo University Hospital Geir Åge Løset, Nextera AS, Oslo Innovation Centre Terje E. Michaelsen, School of Pharmacy, Dept. of Pharmaceutical Chemistry, University of Oslo Karsten Midtvedt, Dept. of Internal Medicine, Oslo University Hospital Øyvind Molberg, Dept of Reumatology, Oslo University Hospital and University of Oslo Tom Eirik Mollnes, Dept. of Immunology, University of Oslo J. Preben Morth, Centre for Molecular Medicine, University of Oslo June Myklebust, Dept of Cancer Immunology, Oslo University Hospital and University of Oslo Geir Kjetil Sandve, Dept of Informatics, University of Oslo Anne Simonsen, Institute of Basic Medical Sciences, University of Oslo Ingebjørg Skrindo, Department of Otorhinolaryngology, Ahus

Erlend Smeland, Dept of Cancer Immunology, Oslo University Hospital and University of Oslo Anne Spurkland, Institute of Basic Medical Sciences, University of Oslo Harald Stenmark, Centre for Cancer Biomedicine, Oslo University Hospital and University of Oslo Kjetil Tasken, Centre for Molecular Medicine, University of Oslo Geir Tjønnfjord, Dept. of Haematology, Oslo University Hospital Dag Undlien, Norwegian Sequencing Centre, Oslo University Hospital and University of Oslo Sébastien Wälchli, Institute for Cancer Research, Oslo University Hospital Marit Bragelien Veierød, Institute of Basic Medical Sciences, University of Oslo Anders Waage, St Olavs Hospital and NTNU Sheraz Yaqub, Dept. of Surgery, Oslo University Hospital Ole Øyen, Dept. of Surgery, Oslo University Hospital Lars Aabakken, Dept. of Gastroenterology, Oslo University Hospital Einar-Martin Aandahl, Dept. of Surgery, Oslo University Hospital Researchers at Nextera AS, Oslo Innovation Centre

INTERNATIONAL

William Agace, Lund University, SE Christian Brix Andersen, Aarhus University, DK Claus Andersen, Rigshospitalet, Copenhagen University, DK Robert Anderson, ImmusanT, Cambridge, US Govind Baghat, Columbia University, US Robert Barker, Aberdeen University, UK Richard S. Blumberg, Harvard Medical School, US Anthony Bosco, Telethon Institute of Child Health Research, AU Nunzio Bottini, La Jolla Institute Division of Cellular Biology, CA, US Robert Bremel, Jane Homan, IO Genetics, Madison, WI, US Cecilia Bucci, University of Salento, IT Simone Bürgler, University Children's Hospital, Zurich, CH Søren Buus, University of Copenhagen, DK Jo Caers, Centre Hospitalier Universitaire de Liège, BE Jason Cameron, Novozymes Biopharma Ltd., UK Inhak Choi, University of Busan, KR Matthew Collin, Institute of Cellular Medicine, Newcastle University, UK Marc Dalod, Centre d'Immunologie de MarseilleLuminy, FR Mark Davis, Stanford University, US Tatiana Efimova, Washington University School of Medicine, US Peter M. Elias, University of California, US Donald Forthal, University of California, US Georg Georgiou, University of Texas, US Peter Gibson, Monash University, AU Andrew Godkin, School of Medicine, Cardiff University, UK Mariano Grasselli, Universidad Nacional de QuilmesIMBICE, AR Peter Green, Columbia University, US Martin Hills, Zedira Gmbh, DE Patrick Holt, Telethon Institute of Child Health Research, AU Ann Hosmalin, Cochin Institute, FR Bertrand Huard, University of Geneva, CH Michael Inoyue, University of Melbourne, AU

Martin Iversen, Rigshospitalet, Copenhagen University, DK Bana Jabri, University of Chicago, US Leo C. James, Medical Research Council Laboratory of Molecular Biology, UK Arwyn Jones, Cardiff University, UK Franziska Jundt, University hospital Würzburg, DE Thomas J.D. Jørgensen, University of Southern Denmark, DK Chaitan Khosla, Stanford University, US Chu-Young Kim, University of Texas at El Paso, US Frits Koning, Leiden University Medical Center, NL Ilma Korponay-Szabo, University of Debrecen Medical School, HU Daniel Kowalewski, University of Tübingen, DE Jose E. Kroll, Federal University of Rio Grande do Norte, BR Wayne Lencer, Harvard Medical School, US Ana-Maria Lennon-Dumenil, Institut Curie, FR Wiebke Ludwig-Peitsch, Klinik für Dermatologie, DE Nils Lycke, University of Gothenburg, SE Markku Mäki, University of Tampere, FI Bernard Malissen, Centre d'Immunologie de MarseilleLuminy, FR Kristiina Malmstrøm, Helsinki University, FI Rudolf Manz, University of Lubeck, DE Line Mathiesen: University of Copenhagen, DK Bertrand Meresse, Université Paris Descartes-Sorbonne Paris Cité, FR Jeffery Miner, Washington University School of Medicine, US Jane Muir, Monash University, AU Jacques Neefjes, Netherlands Cancer Institute, NL Morten S. Nielsen, University of Aarhus, DK Richard Pleass, Liverpool School of Tropical Medicine, UK Andreas Plückthun, University of Zurich, CH Cornelis J.H. Pronk , Lund University, SE Hans-Georg Rammensee, University of Tübingen, DE Hugh Thomson Reyburn, Spanish National Center for Biotechnology, ES Paul Roche, NIH, Bethesda, US Derry C. Roopenian, The Jackson Laboratory, US Jamie Rossjohn, Monash University, AU Daniele Sblattero, University of Piemonte, IT Hans Henrik Lawaetz Schultz, Rigshospitalet, Copenhagen University, DK Juliane Stickel, University of Tübingen, DE Sarah Teichmann, University of Cambridge, UK Gestur Vidarsson, Sanquin Research, University of Amsterdam, NL Cisca Wijmenga, University Medical Center Groningen, NL Patrick C. Wilson, University of Chicago, US Jenny Woof, University of Dundee, UK Gur Yaari, Bar-Ilan University , IS Hideo Yagita, Jutendo University, JP Yuguang Zhao, Oxford University, UK Dov Zipori, Weizmann Institute, IS

CENTRE FOR IMMUNE REGULATION (CIR) ANNUAL REPORT 2016

Education and career development PHD A large number of PhD students have graduated from CIR. The ambition was to educate 35 new PhDs. A total of 42 PhD students have already successfully defended their thesis so this goal is achieved. In 2016, one female and three male students defended their thesis: IBON EGUÍLUZ-GRACIA, “Studies of monocytes and macrophages in the respiratory tract with focus on airway allergy”. Supervisor: Frode L. Jahnsen STIAN FOSS, “Intracellular Fc receptors: Role in transcytosis and protection against human”. Supervisors: Inger Sandlie and Jan Terje Andersen FREDRIK HELLEM SCHJESVOLD, “CD4+ T cell-induced macrophage cytotoxicity against tumor cells”. Supervisor: Bjarne Bogen KRISTIN AAS-HANSSEN, “Idiotype driven T cell-B cell collaboration in a mouse model of systemic autoimmune disease”. Supervisor: Ludvig A. Munthe MSC In 2016, 5 graduated master students from the University of Oslo performed their scientific work at CIR. • • • • •

Amalie Grenov Ina Hodnebrug Camilla V. Myklebust Hanna Noordzij Heidrun Elisabeth Lode

CAREER DEVELOPMENT AND OPPORTUNITIES Gender equality program: At CIR and generally in molecular biomedical research, you find 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. CIR has obtained earmarked funding from the Research Council of Norway (RCN) to launch a gender equality program. 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. Following an evaluation of applicants by the centre’s scientific advisory board, financial support was granted two selected talents for two years (Cinzia Progida and Shuo-Wang Qiao). This was a big success as both candidates are now employed as Associate Professors by the University of Oslo. They were both recruited through an open process in strong competition from many excellent national and international candidates. New career development grants for female scientists were announced in the end of 2014, and after an evaluation of the applications by our Scientific Advisory Board, Jorunn Stamnæs and Britt Nakken were selected to receive the grants for 2015 and 2016.

FOCIS assisted opportunities: CIR is member of Federation of Clinical Immunology Societies (FOCIS) and is as FOCIS Centre of Excellence. The FCE status provides an opportunity for CIR to strengthen translational immunology activities and to build an interdisciplinary translational immunology community at our institution. The FCE provides interdisciplinary training programs for students, fellows and continuing education of physicians. Amalie Grenov

Camilla V. Myklebust

Hanna Noordzij

Heidrun Elisabeth Lode

Ina Hodnebrug

Fredrik Hellem Schjesvold

Ibon Eguíluz-Gracia

Kristin Aas-Hanssen

Stian Foss

CIR members can apply to attend the course “Entrepreneurs in Clinical Academia”. The course is delivered by INSEAD, a pioneer of international business education, and the goal is to give researchers insight, knowledge and necessary skills to take their pioneering research from the laboratory into the pharmaceutical market place. 21 candidates from around the world are accepted to the course each year. Two candidates from CIR were accepted in 2015, and one candidate in 2016. Advanced Course in Basic & Clinical Immunology is a course arranged twice a year, and the travel expenses and registration are partly covered by FOCIS and CIR. Three PhD students from CIR attended the course in 2016. The Annual FOCIS Meeting highlights the best science of clinical immunology in the field. In addition, the FOCIS meeting is an incubator for developing scientists and practitioners alike to meet with one another and representatives of the relevant biotech and pharmaceutical industry whose combined support is invaluable to the success of the field of clinical immunology. CIR partly covers travel expenses for two candidates a year. One candidate attended in 2016. Researcher exchange program: CIR provides financial support to facilitate researcher mobility. CIR partly covers travel expenses for centre scientists going abroad, as well as visiting scientists coming to the centre. This program does not fund long-term stays but rather shorter periods to learn new techniques and establish collaborative projects. In 2016, master student Amalie Grenov received financial support to visit Dr. Ziv Shulman’s laboratory at the Weizmann Institute of Science, Israel, and she is now recruited as a PhD student in his group.

COMPLETED PHD DEGREES PER YEAR 8

20 16

20 15

20 14

20 13

20 12

20 11

20 10

20 09

20 08

PhD students Rahel Frick and Jeannette Nilsen received financial support to go to USA, to Johns Hopkins Hospital and to Derry C. Roopenian’s lab at The Jackson Laboratory respectively.

activities

CENTRE FOR IMMUNE REGULATION (CIR) ANNUAL REPORT 2016

The 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 one or 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 fifteen professors have been included in the Visiting Professor program, and many of them have visited us twice.

Gwendalyn Randolph

In 2016, Gwendolyn Randolph from Washington University School of Medicine, and Adrian Hayday from King's College, London, joined the Visiting Professor program. We are deeply honored by their visits and very grateful for their excellent scientific contributions to CIR and the immunological research environment in Oslo. We are very pleased to announce that David Nemazee, The Scripps Research Institute, La Jolla, California, will join the Visiting Professor faculty in 2017 and has accepted to visit CIR in June. We are very much looking forward to his visit.

Adrian Hayday

GWENDALYN RANDOLPH Professor Gwendalyn Randolph is working at the Department of Pathology & Immunology at the Washington University School of Medicine, US. Her main research focus is the fate of monocyte-derived cells after they enter tissue and how dendritic cells emigrate through lymphatics to enter lymph nodes. During her visit in June, Randolph gave a lecture entitled: “Lymphatic transport and chronic inflammatory disease”, and contributed with a lecture to the minisymposium “100 years of phagocytes” entitled “Exploring mononuclear phagocytes in mouse and man”.

ADRIAN HAYDAY Professor Adrian Hayday is a Kay Glendinning Professor at the King's College, London, UK, with a joint appointment at the Francis Crick Institute. His research seeks to identify key molecular processes and mechanisms that regulate lymphoid stress surveillance, and to relate them to tissue inflammation and cancer. He is in particular interested in gamma delta T cells and was the first to describe the T cell receptor gamma chain genes. During his visit in October he gave a lecture entitled “The dominant role of body surface epithelia in shaping local T cell immunity”.

Minisymposium "100 YEARS OF PHAGOCYTES" JUNE 24 Gwendalyn Randolph, Washington University School of Medicine: Title: “Exploring mononuclear phagocytes in mouse and man” Anders Tveita, CIR, Oslo University hospital. Title: “Tumor-infiltrating macrophages as mediators of CD4+ T cell immunotherapy” Anna Bujko, CIR, University of Oslo, Oslo University hospital: Title: “CD14+ monocytes differentiate into distinct macrophage subsets in human small intestine” The symposium was hosted by Centre for Immune Regulation (CIR) together with the Norwegian Society of Immunology (NSI)

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 This year CIR arranged two Work Package seminars (WP3 and WP4, see below). The WP3 seminar was open to the whole immunological research community in Oslo and members of the Norwegian Society of Immunology, while the WP4 seminar was a closed arrangement for CIR members and researchers at the Department of Immunology, Oslo University hospital and University of Oslo. PUBLIC CIR WP3-SEMINAR: B CELL DAY SEPTEMBER 29 Speakers: • Lill Mårtensson-Bopp (CIR guest lecture) Title: “Autoreactive B cells; a road to autoimmune disease?” • Kristine Lillebø Holm. Title: “Vitamin A in regulation of DNA-damage induced B cell apoptosis” • Britt Nakken. “Human B cell memory defined by tyrosine phosphatase CD45 activity” • Hilde Schjerven. Title: “Role of the transcription factor Ikaros in B-cell development and disease” • Omri Snir. Title: “Structural basis and repertoire selection underlying stereotyped antibody recognition of an immunodominant and deamidated gliadin B cell epitope in celiac disease”

• Peter Huszthy. “The role of BCR ligation in Id-driven T-B collaboration” • Rune Alexander Høglund. Title: “In silico prediction analysis of immunoglobulindriven T-B cell collaboration in multiple sclerosis” • Alina Tomescu-Baciu. Title: “IgG1 allotypes in multiple sclerosis” • Jana Blazevski. Title: “Characterization of an anti-TG2 mAb knock in mouse” • June Helen Myklebust. Title: “Distinct patterns of B-cell receptor signaling in non-Hodgkins’ lymphomas identified by single cell profiling” • Kanutte Huse. Title: “Follicular lymphoma analyzed by mass cytometry” • Sigrid Skånland. Title: “A phosphoflow based approach for the assistance of clinical decisions in individualized cancer therapy” The seminar was followed by an informal get together with pizza and beverages CIR WP4-SEMINAR: INTERNAL SEMINAR TOGETHER WITH THE DEPARTMENT OF IMMUNOLOGY. NOVEMBER 9 Program: 13 oral presentations, 11 iPad presentations, and two guest lectures by international speakers.

Tilman Schlothauer

TILMAN SCHLOTHAUER gave a talk entitled “Characterization of Next Generation Antibody Therapeutics with designed and engineered Fc regions”. Dr. Schlothauer is a researcher at Roche Innovation Center Munich,Germany. RAJESH GROVER gave a talk entitled “B Cell Lymphoma and Myeloma – Bacterial Origins?”. Grover is an Assistant Professor at the Scripps Research Institute, La Jolla, California.

Rajesh Grover

CENTRE FOR IMMUNE REGULATION (CIR) ANNUAL REPORT 2016

Guest lectures CIR organizes a series of guest lectures. Most lectures are hosted by a postdoc invitation committee. The 2016 committee consisted of Omri Snir, Lisa M. Gruber, Kristin S. Gunnarsen, Dominik Michael Frei, and Peter C. Huszthy. In 2016, CIR organized 5 international public guest lectures:

Michael Sieweke

Lill Mårtensson-Bopp

STEFFEN JUNG visited CIR in April and gave a talk entitled: “Macrophages – development & tissue specialisation”. His research is focused on how mononuclear phagocytes form a body wide network of myeloid immune cells devoted to homeostasis maintenance and immune defense of the organism. The Jung lab studies these monocytes, dendritic cells and macrophages in physiology and pathophysiology using gene expression and epigenome profiling, as well as a combination of conditional mutagenesis, in vivo cell imaging, cell ablation and transfer strategies. Jung is a professor at the Weizmann Institute of Science, Israel. MICHAEL SIEWEKE visited CIR in May and gave a talk entitled: “Title: Beyond stem cells: Macrophage self renewal and identity”. The work of the team of Michael Sieweke is at the interface of immunology and the study of stem cells, cells that can renew themselves and differentiate into many cell types. There are large hopes that stem cells may revolutionize future medicine. These hopes are based on the idea that these immature ‘undecided’ cells can be coaxed into making large numbers of any particular cell type of the body to serve a therapeutic purpose. Sieweke is a Professor at Centre d'Immunologie de MarseilleLuminy, France. JEANETTE LEUSEN visited CIR in September as an opponent for the PhD defense of Stian Foss, and gave a talk entitled: "Inside-out regulation of Fc receptors; consequences for antibody therapy of cancer". Dr. Leusen is the head of the Immunotherapy group at the Laboratory for Translational Immunology at the University Medical Center Utrecht, Netherland , and her research is focused on the working mechanisms of therapeutic antibodies and Fc receptors in cancer, autoimmune disease, and infection.

LILL MÅRTENSSON-BOPP visited CIR in September and gave a talk at the seminar “B cell day”, entitled “Autoreactive B cells; a road to autoimmune disease?”. Her research is focused on the role of pre-B cell receptors role in development of autoimmune disease. Mårtensson-Bopp is a Professor at the Department of Rheumatology and Inflammation Research, University of Gothenburg. RAJESH GROVER visited CIR in November. In addition to giving a lecture at the WP4 seminar, he also gave a guest lecture on the topic “A Battle for Survival: Chronic Bacterial Infections - Unexpected Consequences”. His research interest is the understanding of microbiome mediated molecular interactions with host B cells on bacterial invasiveness and pathogenesis.

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. ANNUAL RETREAT April 4-7, CIR arranged a retreat to Geilo. A total of 70 people attended the conference. Among these, three invited international guests who gave excellent keynote lectures and interacted with students and researchers at the centre during the retreat, giving a very valuable scientific input to the research at CIR. Michael Dustin. Keynote lecture: “T cell signal integration and decision making based on synapses and kinapses”. Dustin is a Professor at Oxford University, Kennedy Institute of Rheumatology, UK.

Geilo 2016. Photo: Dominik M. Frei.

Ziv Shulman. Keynote lecture: “Dynamic signaling by T follicular helper cells during germinal center B cell selection”. Dr. Shulman is a group leader at The Weizmann Institute of Science, Israel. Hyun-Dong Chang. Keynote lecture: “Adaptation of proinflammatory Th lymphocytes to chronic inflammation”. Dr. Chang is a researcher at Deutsches Rheuma-Forschungszentrum Berlin, a Leibniz Institute, Germany. In addition to the keynote lectures there were 16 oral presentations and 25 poster presentations by centre members. Masterstudent Hanna Noordzij won the prize for best oral presentation, and Peter

Szodoray for the best poster presentation. The candidates were evaluated by a committee consisting of our international guest lecturers and researchers at CIR.

Michael Dustin

Some of our international members and guests had never tried cross country skiing before, or were beginners to the sport, and got to learn the basics by professional skiing instructors in our leisure time. The more experienced skiers enjoyed the slopes in the mountain. The organising committee did an excellent job putting together an interesting scientific program, and consisted of Raquel Bartolomè Casado, Marte H. Fauskanger, Dominik Michael Frei, Kristin S. Gunnarsen, Louise F. Risnes, and Lise Kveberg.

Ziv Shulman

Hyun-Dong Chang

publications

CENTRE FOR IMMUNE REGULATION (CIR) ANNUAL REPORT 2016

Papers in scientific journals

Chen JQ, Szodoray P, Zeher M (2016). Toll-Like Receptor Pathways in Autoimmune Diseases Clin Rev Allergy Immunol, 50 (1), 1-17 PubMed 25687121 DOI 10.1007/s12016-015-8473-z

Andersen AN, Landsverk OJ, Simonsen A, Bogen B, Corthay A, Øynebråten I (2016). Coupling of HIV-1 Antigen to the Selective Autophagy Receptor SQSTM1/p62 Promotes T-Cell-Mediated Immunity Front Immunol, 7, 167 PubMed 27242780 DOI 10.3389/fimmu.2016.00167

Christophersen A, Risnes LF, Bergseng E, Lundin KE, Sollid LM, Qiao SW (2016). Healthy HLADQ2.5+ Subjects Lack Regulatory and Memory T Cells Specific for Immunodominant Gluten Epitopes of Celiac Disease J Immunol, 196 (6), 2819-26 PubMed 26895834 DOI 10.4049/jimmunol.1501152

Ardouin L, Luche H, Chelbi R, Carpentier S, Shawket A, Montanana Sanchis F, Santa Maria C, Grenot P, Alexandre Y, Grégoire C, Fries A, Vu Manh TP, Tamoutounour S, Crozat K, Tomasello E, Jorquera A, Fossum E, Bogen B, Azukizawa H, Bajenoff M, Henri S, Dalod M, Malissen B (2016). Broad and Largely Concordant Molecular Changes Characterize Tolerogenic and Immunogenic Dendritic Cell Maturation in Thymus and Periphery Immunity, 45 (2), 305-18 PubMed 27533013 DOI 10.1016/j.immuni.2016.07.019 Ballke C, Gran E, Baekkevold ES, Jahnsen FL (2016). Characterization of Regulatory T-Cell Markers in CD4+ T Cells of the Upper Airway Mucosa PLoS One, 11 (2), e0148826 PubMed 26866695 DOI 10.1371/journal.pone.0148826 Bartee E, Bartee MY, Bogen B, Yu XZ (2016). Systemic therapy with oncolytic myxoma virus cures established residual multiple myeloma in mice Mol Ther Oncolytics, 3, 16032 PubMed 27933316 DOI 10.1038/mto.2016.32 Bauer J, Bakke O, Morth JP (2016). Overview of the membrane-associated RING-CH (MARCH) E3 ligase family N Biotechnol PubMed 27988304 DOI 10.1016/j.nbt.2016.12.002 Bottermann M, Lode HE, Watkinson RE, Foss S, Sandlie I, Andersen JT, James LC (2016). Antibody-antigen kinetics constrain intracellular humoral immunity Sci Rep, 6, 37457 PubMed 27881870 DOI 10.1038/srep37457 Cardoso I, Østerlund EC, Stamnaes J, Iversen R, Andersen JT, Jørgensen TJ, Sollid LM (2016). Dissecting the interaction between transglutaminase 2 and fibronectin Amino Acids PubMed 27394141 DOI 10.1007/s00726-016-2296-y Chen JQ, Papp G, Szodoray P, Zeher M (2016). The role of microRNAs in the pathogenesis of autoimmune diseases Autoimmun Rev PubMed 27639156 DOI 10.1016/j.autrev.2016.09.003

Dahal-Koirala S, Risnes LF, Christophersen A, Sarna VK, Lundin KE, Sollid LM, Qiao SW (2016). TCR sequencing of single cells reactive to DQ2.5-glia-α2 and DQ2.5-glia-ω2 reveals clonal expansion and epitope-specific V-gene usage Mucosal Immunol, 9 (3), 587-96 PubMed 26838051 DOI 10.1038/mi.2015.147 Deloizy C, Bouguyon E; Fossum E; Sebo P; Osička R; Bole A; Pierres M; Biacchesi S; Dalod M; Bogen B; Bertho N; Schwartz-Cornil I (2016). Expanding the tools for identifying mononuclear phagocyte subsets in swine: Reagents to porcine CD11c and XCR1. Developmental and Comparative Immunology;Volum 65. s. 31-40. DOI 10.1016/j.dci.2016.06.015 Dørum S, Steinsbø Ø, Bergseng E, Arntzen MØ, de Souza GA, Sollid LM (2016). Gluten-specific antibodies of celiac disease gut plasma cells recognize long proteolytic fragments that typically harbor T-cell epitopes Sci Rep, 6, 25565 PubMed 27146306 DOI 10.1038/srep25565 Eguíluz-Gracia I, Bosco A, Dollner R, Melum GR, Lexberg MH, Jones AC, Dheyauldeen SA, Holt PG, Bækkevold ES, Jahnsen FL (2016). Rapid recruitment of CD14(+) monocytes in experimentally induced allergic rhinitis in human subjects J Allergy Clin Immunol, 137 (6), 1872-1881.e12 PubMed 26851967 DOI 10.1016/j. jaci.2015.11.025 Eguíluz-Gracia I, Schultz HH, Sikkeland LI, Danilova E, Holm AM, Pronk CJ, Agace WW, Iversen M, Andersen C, Jahnsen FL, Baekkevold ES (2016). Long-term persistence of human donor alveolar macrophages in lung transplant recipients Thorax PubMed 27329043 DOI 10.1136/thoraxjnl-2016-208292 Fløisand Y, Lundin KE, Lazarevic V, Kristiansen JD, Osnes LT, Tjønnfjord GE, Reims HM, Gedde-Dahl T (2016). Targeting Integrin α4β7 in Steroid-Refractory Intestinal Graft-versus-Host Disease Biol Blood Marrow Transplant PubMed 27777142 DOI 10.1016/j.bbmt.2016.10.009

Foss S, Watkinson RE, Grevys A, McAdam MB, Bern M, Høydahl LS, Dalhus B, Michaelsen TE, Sandlie I, James LC, Andersen JT (2016). TRIM21 Immune Signaling Is More Sensitive to Antibody Affinity Than Its Neutralization Activity J Immunol, 196 (8), 3452-9 PubMed 26962230 DOI 10.4049/jimmunol.1502601 George R, Santhanam, S, Samuel R, Chapla A, Hilmarsen HT, Braathen GJ, Reinholt FP, Jahnsen FL, Khnykin D (2016). Ichthyosis prematurity syndrome caused by a novel missense mutation in FATP4 gene - a case report from India. Clinical Case Reports; Volum 4.(1) s. 87-89 Guilliams M, Dutertre CA, Scott CL, McGovern N, Sichien D, Chakarov S, Van Gassen S, Chen J, Poidinger M, De Prijck S, Tavernier SJ, Low I, Irac SE, Mattar CN, Sumatoh HR, Low GH, Chung TJ, Chan DK, Tan KK, Hon TL, Fossum E, Bogen B, Choolani M, Chan JK, Larbi A, Luche H, Henri S, Saeys Y, Newell EW, Lambrecht BN, Malissen B, Ginhoux F (2016). Unsupervised High-Dimensional Analysis Aligns Dendritic Cells across Tissues and Species Immunity, 45 (3), 669-84 PubMed 27637149 DOI 10.1016/j. immuni.2016.08.015 Haabeth OA, Tveita A, Fauskanger M, Hennig K, Hofgaard PO, Bogen B (2016). Idiotype-specific CD4+ T cells eradicate disseminated myeloma. Leukemia May 30(5): 1216-20 Oct 9 PMID: 26449664 DOI 10.1038/leu.2015.278 Henriksen EK, Jørgensen KK, Kaveh F, Holm K, Hamm D, Olweus J, Melum E, Chung BK, Eide TJ, Lundin KE, Boberg KM, Karlsen TH, Hirschfield GM, Liaskou E (2016). Gut and liver T cells of common clonal origin in primary sclerosing cholangitis-inflammatory bowel disease J Hepatol PubMed 27647428 DOI 10.1016/j. jhep.2016.09.002 Hnida K, Stamnaes J, du Pré MF, Mysling S, Jørgensen TJ, Sollid LM, Iversen R (2016). Epitope-dependent Functional Effects of Celiac Disease Autoantibodies on Transglutaminase 2 J Biol Chem, 291 (49), 25542-25552 PubMed 27784785 DOI 10.1074/jbc.M116.738161 Hære P, Høie O, Schulz T, Schönhardt I, Raki M, Lundin KE (2016). Long-term mucosal recovery and healing in celiac disease is the rule - not the exception Scand J Gastroenterol, 1-8 PubMed 27534885 DOI 10.1080/00365521.2016.1218540

Høydahl LS, Nilssen NR, Gunnarsen KS, Pré MF, Iversen R, Roos N, Chen X, Michaelsen TE, Sollid LM, Sandlie I, Løset GÅ (2016). Multivalent pIX phage display selects for distinct and improved antibody properties Sci Rep, 6, 39066 PubMed 27966617 DOI 10.1038/srep39066 Jørgensen SF, Reims HM, Frydenlund D, Holm K, Paulsen V, Michelsen AE, Jørgensen KK, Osnes LT, Bratlie J, Eide TJ, Dahl CP, Holter E, Tronstad RR, Hanevik K, Brattbakk HR, Kaveh F, Fiskerstrand T, Kran AB, Ueland T, Karlsen TH, Aukrust P, Lundin KE, Fevang B (2016). A Cross-Sectional Study of the Prevalence of Gastrointestinal Symptoms and Pathology in Patients With Common Variable Immunodeficiency Am J Gastroenterol PubMed 27527747 DOI 10.1038/ajg.2016.329 Krogvold L, Wiberg A, Edwin B, Buanes T, Jahnsen FL, Hanssen KF, Larsson E, Korsgren O, Skog O, Dahl-Jørgensen K (2016). Insulitis and characterisation of infiltrating T cells in surgical pancreatic tail resections from patients at onset of type 1 diabetes. Diabetologia ;Volum 59.(3) s. 492-501 Kucera A, Bakke O, Progida C (2016). The multiple roles of Rab9 in the endolysosomal system Commun Integr Biol, 9 (4), e1204498 PubMed 27574541 DOI 10.1080/19420889.2016.1204498 Kucera A, Borg Distefano M, Berg-Larsen A, Skjeldal F, Repnik U, Bakke O, Progida C (2016). Spatiotemporal Resolution of Rab9 and CI-MPR Dynamics in the Endocytic Pathway Traffic, 17 (3), 211-29 PubMed 26663757 DOI 10.1111/ tra.12357 Kulkarni U, Karsten CM, Kohler T, Hammerschmidt S, Bommert K, Tiburzy B, Meng L, Thieme L; Recke A, Ludwig RJ, Pollok K, Kalies K, Bogen B, Boettcher M, Kamradt T, Hauser AE, Langer C, Huber-Lang M, Finkelman FD, Köhl J, Wong DM, Manz, RA (2016). IL-10 mediates plasmacytosis-associated immunodeficiency by inhibiting complement-mediated neutrophil migration. Journal of Allergy and Clinical Immunology;Volum 137.(5) s. 1487-1497e6. Lambert L, Kinnear E, McDonald JU, Grødeland G, Bogen B, Stubsrud E, Lindeberg MM, Fredriksen A, Tregoning JS (2016). DNA vaccines encoding antigen targeted to MHC class II induce influenza-specific CD8+ T cell responses, enabling faster resolution of influenza disease. Frontiers in Immunology;Volum 7:321. DOI 10.3389/fimmu.2016.00321.

CENTRE FOR IMMUNE REGULATION (CIR) ANNUAL REPORT 2016

Lorvik KB, Hammarstrom C, Fauskanger M, Haabeth OA, Zangani M, Haraldsen G, Bogen B, Corthay A (2016). Adoptive transfer of tumorspecific Th2 cells eradicates tumors by triggering an in situ inflammatory immune response Cancer Res PubMed 27634753 DOI 10.1158/00085472.CAN-16-1219 Luda KM, Joeris T, Persson EK, Rivollier A, Demiri M, Sitnik KM, Pool L, Holm JB, Melo-Gonzalez F, Richter L, Lambrecht BN, Kristiansen K, Travis MA, Svensson-Frej M, Kotarsky K, Agace WW (2016). IRF8 Transcription-Factor-Dependent Classical Dendritic Cells Are Essential for Intestinal T Cell Homeostasis Immunity, 44 (4), 860-74 PubMed 27067057 DOI 10.1016/j. immuni.2016.02.008 Ludvigsson JF, Agreus L, Ciacci C, Crowe SE, Geller MG, Green PH, Hill I, Hungin AP, Koletzko S, Koltai T, Lundin KE, Mearin ML, Murray JA, Reilly N, Walker MM, Sanders DS, Shamir R, Troncone R, Husby S (2016). Transition from childhood to adulthood in coeliac disease: the Prague consensus report. Gut. Aug;65(8):1242-51. doi: 10.1136/gutjnl-2016-311574 Marstad A, Landsverk OJB, Strømme O, Otterlei M, Collas P, Sundan A, Brede G (2016). A-kinase anchoring protein AKAP95 is a novel regulator of ribosomal RNA synthesis. The FEBS Journal 2016 ;Volum 283.(4) s. 757-770 Michaelsen TE, Emilsen S, Sandin RH, Granerud BK, Bratlie D, Ihle O, Sandlie I (2016). Human secretory IgM antibodies activate human complement and offer protection at mucosal surface Scand J Immunol PubMed 27864913 DOI 10.1111/sji.12508 Papp G, Horvath IF, Gyimesi E, Barath S, Vegh J, Szodoray P, Zeher M (2016). The assessment of immune-regulatory effects of extracorporeal photopheresis in systemic sclerosis: a long-term follow-up study Immunol Res, 64 (2), 404-11 PubMed 26168768 DOI 10.1007/s12026-015-8678-5 Parente-Ribes A, Skånland SS, Bürgler S, Os A, Wang D, Bogen B, Tjønnfjord GE, Taskén K, Munthe LA (2016). Spleen tyrosine kinase inhibitors reduce CD40L-induced proliferation of chronic lymphocytic leukemia cells but not normal B cells. Haematologica. Feb;101(2):e59-62. PMID: 26589914 DOI: 10.3324/haematol.2015.135590

Progida C, Bakke O (2016). Bidirectional traffic between the Golgi and the endosomes - machineries and regulation J Cell Sci, 129 (21), 3971-3982 PubMed 27802132 DOI 10.1242/jcs.185702 Rentka A, Harsfalvi J, Szucs G, Szekanecz Z, Szodoray P, Koroskenyi K, Kemeny-Beke A (2016). Membrane array and multiplex bead analysis of tear cytokines in systemic sclerosis. Immunol Res. Apr;64(2):619-26. DOI 10.1007/ s12026-015-8763-9. PMID: 26687127 Schrøder M, Melum GR, Landsverk OJ, Bujko A, Yaqub S, Gran E, Aamodt H, Bækkevold ES, Jahnsen FL, Richter L (2016). CD1c-Expression by Monocytes - Implications for the Use of Commercial CD1c+ Dendritic Cell Isolation Kits PLoS One, 11 (6), e0157387 PubMed 27311059 DOI 10.1371/journal.pone.0157387 Skodje GI, Henriksen C, Salte T, Drivenes T, Toleikyte I, Lovik AM, Veierød MB, Lundin KE (2016). Wheat challenge in self-reported gluten sensitivity: a comparison of scoring methods Scand J Gastroenterol, 1-8 PubMed 27797273 DOI 10.1080/00365521.2016.1244705 Spencer J, Sollid LM (2016). The human intestinal B-cell response Mucosal Immunol, 9 (5), 1113-24 PubMed 27461177 DOI 10.1038/mi.2016.59 Stamnæs J, Cardoso I, Iversen R, Sollid LM (2016). Transglutaminase 2 strongly binds to an extracellular matrix component other than fibronectin via its second C-terminal beta-barrel domain FEBS J, 283 (21), 3994-4010 PubMed 27685605 DOI 10.1111/febs.13907 Szodoray P, Stanford SM, Molberg Ø, Munthe LA, Bottini N, Nakken B (2016). T-helper signals restore B-cell receptor signaling in autoreactive anergic B cells by upregulating CD45 phosphatase activity J Allergy Clin Immunol, 138 (3), 839-851.e8 PubMed 27056269 DOI 10.1016/j. jaci.2016.01.035 Tveita A, Fauskanger M, Bogen B, Haabeth OA (2016). Tumor-specific CD4+ T cells eradicate myeloma cells genetically deficient in MHC class II display Oncotarget PubMed 27626487 DOI 10.18632/oncotarget.11946 Zhang R, Alam SM, Yu JS, Scearce R, Lockwood B, Hwang KK, Parks R, Permar S, Brandtzaeg P, Haynes BF, Liao HX (2016). Novel Monoclonal Antibodies for Studies of Human and Rhesus Macaque Secretory Component and Human J-Chain Monoclon Antib Immunodiagn Immunother, 35 (4), 217-26 PubMed 27386924 DOI 10.1089/mab.2016.0014

Zhou P, Chionh YT, Irac SE, Ahn M, Jia Ng JH, Fossum E, Bogen B, Ginhoux F, Irving AT, Dutertre CA, Wang LF (2016). Unlocking bat immunology: establishment of Pteropus alecto bone marrowderived dendritic cells and macrophages Sci Rep, 6, 38597 PubMed 27934903 DOI 10.1038/ srep38597

Fusion proteins for the treatment of allergic disease. US9005630 B2. Priority date 01.11.2012. Dooper M, Bogen B, and Myrset HR. Homodimeric protein constructs, JP2016202185. Priority date: 25.06.2010. Ruffini PA, Fredriksen A, and Bogen B (filed by Vaccibody AS)

Active patents and patent applications

Invariant chain-TGFbRII constuct for cancer vaccination. PCT/EP2015/062933. Priority date 10.04.2014. Walchli SP, Gregers TF, Inderberg EMS, Gaudernack G, Kvalheim G, and Bakke O.

A humanized antibody against CD14. PCT/ IB2014/001276. Priority date: 21.03.2014. Espevik T, Mollnes TE, Sandlie I, Lau C, Gunnarsen KS.

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

Albumin derivatives and variants. PCT/ EP11/055577. Priority date: 09.04.2010. Andersen JT and Sandlie I (with Novozymes).

Multivalent phage display. PCT/ IB2010/002465. Priority date: 25.09.2009. Løset GÅ and Sandlie I.

Albumin variants fused to immunogens (AlbuVax) for improved transcellular delivery. PCT/IB2014/003002. Priority date: 01.11.2013. Sandlie I, Andersen JT, and Bern M.

Novel human albumin mutants with improved FcRn binding and extended half-life. Priority date: 22.11.2016. Sandlie I, Andersen JT, and Nilsen J.

Albumin variants. PCT/EP10/066572. Priority date: 30.10.2009. Andersen JT and Sandlie I (with Novozymes).

Pharmacokinetic animal. PCT/ EP2014/052944. Priority date: 16.02.2013. Andersen JT and Sandlie I (with Novozymes).

Albumin variants. PCT/EP2011/069188. Priority date: 01.11.2010. Andersen JT and Sandlie I (with Novozymes).

pVII phage display. WO2009024591. Løset GÅ.

Albumin variants. PCT/EP2012/058206. Priority date: 04.05.2011. Andersen JT and Sandlie I (with Novozymes). Albumin variants. PCT/EP2013/073426. Priority date: 08.11.2012. Andersen JT and Sandlie I (with Novozymes). DQ2-restricted effector memory T-cells for diagnosis of coeliac disease. PCT/ IB2014/001803. Priority date 14.05.2013. Sollid LM, Qiao SW, Christophersen A, and Lundin KEA. Fc-engineered IgG1 and IgG3 variants with altered anti-viral effector functions. PCT/ IB2017/000314. Priority date 14.03.2016. Sandlie, I, Andersen JT, Foss S, James L. Fc-engineered IgG1 and IgG3 variants with improved FcRn binding. PCT/IB2017/000327. Priority date: 14.03.2016. Sandlie I, Andersen JT, Foss S.

Signal sequence-independent pIX phage display. PCT/EP2010/052344. Priority date 25.02.2009. Løset GÅ. Stabilized recombinant MHC class II. PCT/ GB2011/050325. Priority date: 18.02.2010. Løset GÅ, Sandlie I, Frigstad T, Bogen B. Targeting of vaccine antigen to an intracellular compartment. PCT/ IB2016/001017. Priority date: 22.06.2015. Bogen B, Andersen AN, Øynebraaten I. Vaccine molecules that target human HLAII molecules in all individuals. Priority date: 21.06.2016. Bogen B, Fredriksen AB, Grødeland G.

dissemination

CENTRE FOR IMMUNE REGULATION (CIR) ANNUAL REPORT 2016

Invited lectures Andersen JT: “Human IgG3 Is a Superior Mediator of Intracellular Anti-Viral Immunity”. Gordon Conference in Antibody Biology & Engineering, March 20-25, Texas, US (invited speaker). Andersen JT: “The neonatal Fc receptor (FcRn) – not just for kids!”. Seminar, University of Ferrara, November 25, Italy (invited speaker). Andersen JT: “Targeting of FcRn for invasive and non-invasive delivery”. Albumedix AS, Workshop on albumin, October 2, Nottingham, UK (invited speaker). Andersen JT: “The neonatal Fc receptor (FcRn) – not just for kids!”. Biotechnology course on strategies for half-life extension of drugs, University of Ferrara, November 24, Italy (invited speaker). Andersen JT: “Designed Antibodies as Weapons against Infectious Diseases”. Oslo Life Science Conference - exploring how we can create a leading Nordic Life Science hub for research, education and business in Oslo, February 16, Oslo (invited speaker). Andersen JT: “Engineering Intracellular Antibody Immunity”. IBC Antibody Engineering and Therapeutics meeting, December 14, San Diego, US (invited speaker). Bækkevold ES: “Human mucosal dendritic cells (DCs)”. EU COST Action Mye-EUNITER ECI Workshop, April 11-12, Stockholm, Sweden (invited speaker). Bækkevold ES: “Rapid recruitment of CD14+ monocytes in experimentally-induced allergic rhinitis in humans”. 10th World Immune Regulation Meeting (WIRM), March 16 – 19, Davos, Switzerland (invited speaker). Bakke, O: “From live imaging to super resolution. An overview of light microscopy imaging today”. The Scandinavian Physiological Society Annual Meeting, August 26– 28, Oslo (invited speaker) Bakke, O: “Activation of EGF receptor; recruitment of effectors and effect on endosomal EPS15 and HRS”. Cells on the move. At the intersection of intracellular transport and cell migration. International cell biology meeting, CIR-IBV University of Oslo, Oslo (invited speaker).

Bogen B: “Crosstalk of Tumorinfiltrating Leucocytes in Tumor Immunity”. 43rd Annual Meeting of the Scandinavian Society of Immunology, May 10-13, Turku, Finland (invited speaker). Bogen B: “Crosstalk of Tumorinfiltrating Leucocytes in Tumor Immunity”. The Finnish Cancer Institute meeting June 15-17, Jyvaskyla, Finland (invited speaker). Bogen B: “Crosstalk of Tumorinfiltrating Leucocytes in Tumor Immunity”. 8th symposium and annual meeting of Croatioan society for Medical oncology and 10th meeting of oncology pharmacy section, October 21-23, Trakoscan, Zagreb, Croatia (invited speaker). Frick R: “Isolation and characterization of HLA-DQ2.5:DQ2.5-glia-α2 binding antibodies by use of phage display”. Department for Chemical & Biomolecular Engineering at Johns Hopkins University, March 21, Baltimore, Maryland, USA (invited speaker). Jahnsen FL: “Studies of longevity of macrophages and plasma cells in the human gut”. 34th Annual Meeting of the Norwegian Society for Immunology (NSI), November 17, Oslo (invited lecture). Lundin K: “Coeliac disease – state of the art and unmet clinical needs”. Seminar at Institute of Nutrition, March 30th, Oslo (invited speaker). Lundin K: “Non coeliac gluten sensitivity”. Nordic Nutrition Conference, June 22, Gothenburg, Sweden (invited speaker). Lundin K: “Oats in coeliac disease”. Coeliac UK research meeting, March 9, London, UK (invited speaker). Munthe L: “Autoimmunity and immunotherapy”. Spring Conference in Medical Immunology (NITO), April 17, Norway (invited speaker). Munthe L: “Immunotherapy”. Seminar series, The Norwegian Medical Association. Practical Medical and Immunological Diagnostics, May 24, Oslo (invited speaker). Munthe L: “Immunotherapy: Immunological mechanisms and potentials”. Norwegian Society of Pharmacology, February 28, Beitostølen (invited speaker). Munthe L: “Microenvironment and the antitumor response”. Cancer Immunotherapy conference, October 21-22, Kleivstua (invited speaker).

Nakken B: “Human B cell memory defined by tyrosine phosphatase CD45 activity”. 3rd Meeting of Middle-European Societies for Immunology and Allergology, December 1- 3, Budapest, Hungary (invited speaker).

Sollid LM: “Antigen receptors of disease-relevant T cells and B cells in celiac disease”. KI Inflammation and Immunology network Retreat, October 13-14, Sånga Säby, Sweden (invited speaker).

Rosenqvist-Lund, S: “Detection of anti-TG2 antibodies with AlphaLISA”, Perkin Elmer Alpha Lisa seminar, Forskningsparken, September 20, Oslo (invited speaker).

Sollid LM: “B cells and antibody synthesis in coeliac disease”. 5º Congreso Nacional de la Sociedad Española de Enfermedad Celíaca, November 17-19, Barcelona, Spain (invited speaker).

Sandlie I: “Building a culture for Innovation”, Norway Day in Brussel, June 22, Brussel, Belgium (invited speaker). Sandlie I: “New perspective on IgG function”. Department of Immunology and Microbiology, California Campus, The Scripps Research Institute, California, US (invited speaker). Sandlie, I: ”My favourite molecules”. 34th Annual Meeting of the Norwegian Society for Immunology (NSI), November 17, Oslo (honorary lecture). Sollid, LM: “Immunological tools in measuring treatment outcome”. Tampere Celiac Disease Symposium November 25, Tampere, Finland (invited speaker). Sollid LM: KG Jebsen Coeliac Disease Research Centre K.G. Jebsen Samling, October 25-26, Bekkjarvik, Norway (invited speaker). Sollid LM: “Plasma cell and T-cell repertoires involved in celiac disease”. Antibody Engineering & Therapeutics 2016, December 10-14, San Diego. USA (invited speaker). Sollid LM: “TG2 autoantibody response in celiac disease”. Gordon Research Conference (transglutaminase), July 10-15, Girona, Spain (invited speaker). Sollid LM: “Antigen receptors of adaptive immune cells in celiac disease”. European Mucosal Immunology Group Meeting 2016, October 19-21, Copenhagen, Denmark (invited speaker). Sollid LM: “Antigen receptors of diseaserelevant T cells and B cells in celiac disease”. Immungenomics 2016, September 26-28, Huntsville (AL), USA (invited speaker). Sollid LM: “Antigen receptors of disease-relevant T cells and B cells in celiac disease”. Seminar for Committee on Immunology, University of Chicago. October 3, Chicago, USA (invited speaker).

Sollid LM: “Celiac disease pathogenesis”. Seminar Protagonist Theraputics Inc, September 23, Milpitas (CA), USA (invited speaker). Sollid LM: “Celiac disease”. Opening seminar KG Jebsen Centre, August 18, Oslo, Norway. Sollid LM: “Celiac disease”: An adverse reaction to the environment. 43rd Annual Scandinavian Immunology Meeting, May 11, Turku, Finland (invited speaker). Sollid LM: “Coeliac disease” - from genetic and immunological studies to clinical applications. 5º Congreso Nacional de la Sociedad Española de Enfermedad Celíaca, November 17-19, Barcelona, Spain (invited speaker). Sollid LM: “Gene - environment interactions in inflammatory disease other than MS: the model of celiac disease”. Eur Committee for Treatment and Research in MS (ECTRIMS) focused workshop 2016, March 3, Florence, Italy (invited speaker). Sollid LM: “Immunopathogenesis of celiac disease”. EFIS-EIAS Summer School on Autoimmunity, June 8, Tartu, Estonia (invited speaker). Sollid LM: “Pathogenesis and specificity of immunity in celiac disease”. Immune Tolerance workshop. Be The Cure, May 19-22, Sigtuna, Sweden (invited speaker). Sollid LM: «Sykdomsmekanismen ved cøliaki». Bioingeniørkongressen 2016, June 3, Oslo (invited speaker). Sollid LM: “Therapeutic advances in coeliac disease”. Coeliac UK’s Research Conference 2016, March 9, London, United Kingdom (invited speaker). Sollid LM: “Tracking down antigen-specific T and B cells to dissect autoimmunity”. Seminar Cambridge Immunology, University of Cambridge, March 11, Cambridge, United Kingdom (invited speaker).

CENTRE FOR IMMUNE REGULATION (CIR) ANNUAL REPORT 2016

Sollid LM: “Why do celiac patients react to gluten?”. GI Research Conference, University of Chicago. September 22, Chicago, USA (invited speaker).

Khnykin D: “Keratinocytes stress and skin inflammation”. EU COST action TD1206 "Standerm", WG1 meeting, February, Hamburg, Germany (oral presentation).

Sollid LM: “Why do celiac patients react to gluten?”. Seminar Molecular Nutrition Unit, University of Oslo, March 30, Oslo (invited speaker).

Khnykin D: “Keratinocytes stress predisposes to development of allergic disorders”. Latvian Biomedical Research and Study Center, October,Riga, Latvia (oral presentation).

Szodoray P: “T helper signals restore B cell receptor signaling in autoreactive anergic B cells by upregulating CD45 phosphatase activity. Implications for SLE”. 3rd Meeting of Middle-European Societies for Immunology and Allergology, December 1- 3, Budapest, Hungary (invited speaker).

Khnykin D: Stem cells therapy in dermatology. Invited speaker at 2nd Annual Reproductive, Genetic & Biotechnology Conference, October, Riga, Latvia (oral presentation)

Oral presentations Bakke O: “How Invariant Chain (CD74) delays endosomal maturation”. Unconventional protein and membrane traffic meeting, Lecce, Italy, October 4-10 (oral presentation). Eguíluz-Gracia I: “The mononuclear phagocyte system in experimentally-induced Allergic Rhinitis in humans”. 14th EAACI Immunology Winter School Basic Immunology Research in Allergy and Clinical Immunology, February 4 – 7, Cortina d'Ampezzo, Italy (oral presentation). Frei DM: “Invariant chain-mediated regulation of endosomal fusion and maturation” Bridging Nordic Imaging symposium at Gothenburg, Sweden April 14-15, 2016 (oral presentation) Huszthy P: “The role of BCR ligation in Id-driven T-B collaboration”. Seminar, Department of Immunology, November 9, Ullevål Stadion, Oslo (oral presentation). Høydahl LS: “Discovery of gluten-pMHC-specific antibodies for studies of antigen presentation in celiac disease”. Seminar, Department of Biosciences, UiO, December 8, UiO (oral presentation). Iversen R: “Relatedness between serum antibodies and gut plasma cells in celiac disease”. 34th Annual Meeting of the Norwegian Society for Immunology (NSI), November 17, Oslo (oral presentation).

Lode HE: “Antibody-antigen kinetics constrain intracellular humoral immunity”. 34th Annual Meeting of the Norwegian Society for Immunology (NSI), November 17, Oslo (oral presentation). Nakken B: “Human B cell memory defined by tyrosine phosphatase CD45 activity”. International Congress of Immunology (ICI), August 21-26, Melbourne, Australia (oral presentation). Noordzij H: “Transport of the FcRn ligands, IgG and albumin, through the human placenta”. Seminar, Department of Immunology, November 9, Ullevål Stadion, Oslo (oral presentation). Progida C: “An siRNA screening approach to identify unconventional functions of Rab proteins”. Unconventional protein and membrane traffic meeting, Lecce, Italy, October 4-10 (oral presentation) Risnes LF: “HLA-DQ Signature on T-cell receptor repertoire in celiac disease”. 30th European Immunogenetics and Histocompatibility Conference (EFI2016), 11-14 May Kos Island, Greece (oral presentation) Sand K: “The neonatal Fc receptor (FcRn)-mediated recycling of IgG and albumin in endothelial cells”. Contact meeting, Norwegian Biochemical Society, 22 January, Tromsø (oral presentation). Sand K: “Unraveling the FcRn albumin interaction. Opportunities and challenges for design of albumin-based therapeutics”. Seminar, Department of Biosciences, UiO, April 28, Oslo (oral presentation). Snir O: “Selection and structures of stereotyped anti-gluten antibody responses in celiac disease”. 34th Annual Meeting of the Norwegian Society for Immunology (NSI), November 17, Oslo (oral presentation).

Szodoray P: “T helper signals restore B cell receptor signaling in autoreactive anergic B cells by upregulating CD45 phosphatase activity”. International Congress of Immunology (ICI), August 21-26, Melbourne, Australia (oral presentation). Szodoray P: “B-cell signaling and CD45 phosphatase activity in T-dependent and T-independent humoral memory”. Seminar, Department of Immunology, November 9, Ullevål Stadion, Oslo (oral presentation).

Poster presentations Bartolomé Casado R: “Intriguing role of tissue resident memory T cells in the immunity of the small intestine”. 14th EAACI Immunology Winter School Basic Immunology Research in Allergy and Clinical Immunology, 4 – 7 February, Cortina d'Ampezzo, Italy (poster presentation). Bartolomé Casado R: “Persistence of resident memory CD8 T cells in the human small intestine”. 10th European Mucosal Immunology Group Meeting, October 19-21, Copenhagen, Denmark (poster presentation). Blazevski J: “Characterization of an anti-TG2 mAb knock in mouse”. Seminar, Department of Immunology, November 9, Ullevål Stadion, Oslo (iPad presentation). Bujko A: “CD14+ monocytes differentiate into distinct macrophage subsets in human small intestine”. 10th European Mucosal Immunology Group Meeting, October 19-21, Copenhagen, Denmark (poster presentation). Dahal-Koirala S: “Study of Gluten-specific T Cell Repertoire in Blood and Gut During Gluten Challenge in Celiac Disease Patients”. FOCIS meeting, June 22 – 25, Boston, MA, USA (poster presentation). Distefano MB: “Dendritic cell migration is regulated by the small GTPase Rab7b”. Building the cell meeting, September 28-30, Paris, France (poster presentation). Distefano MB: “The small GTPase Rab7b regulates dendritic cell migration”. European Cytoskeletal Forum - Cell Adhesion and Migration: Robinson College, University of Cambridge, June 20-23, Cambridge, UK (poster presentation).

duPre F: “Characterization of an anti-TG2 mAb knock in mouse”. Seminar, Department of Immunology, November 9, Ullevål Stadion, Oslo (iPad presentation). Frei DM: “Invariant chain-mediated regulation of endosomal fusion and maturation”. Gordon Research Conference "Lysosomes and Endocytosis" Proctor Academy, June 12-17, Andover, NH, US (poster presentation). Frick R: “Affinity maturation of gluten peptide:MHC binding antibodies using computational modeling and phage display”. Seminar, Department of Immunology, November 9, Ullevål Stadion, Oslo (iPad presentation). Gopalakrishnan RP: “Id-driven T-B collaboration in inducing autoimmunity”. 43rd Scandinavian Society for Immunology meeting, May 10-13, Turku, Finland (poster presentation). Gopalakrishnan RP: “Idiotype specific T-B colloboration in development of Autoimmune disease”. Seminar, Department of Immunology, November 9, Ullevål Stadion, Oslo (iPad presentation). Grenov A: “The invariant chain provides strong CD4+ T cell activation in addition to activation of CD8+ T cells and may be an optimal vector for antigen loading in cancer vaccines”. 34th Annual Meeting of the Norwegian Society for Immunology (NSI), November 17, Oslo (oral presentation). Gunnarsen K: “Characterization of the T cell response against immunodominant DQ2.5 epitopes in celiac disease”. Seminar, Department of Immunology, November 9, Ullevål Stadion, Oslo (iPad presentation). Huszthy, PC: “The role of BCR ligation in Id-driven T-B collaboration”. 43rd Scandinavian Society for Immunology meeting, May 10-13, Turku, Finland (poster presentation). Høydahl LS: “Discovery of gluten-pMHC-specific antibodies for studies of antigen presentation in celiac disease”. Seminar, Department of Immunology, November 9, Ullevål stadion, Oslo (iPad presentation). Iversen, R: “Relationship between serum and gut antibody responses”. Keystone Symposia Conference: B Cells at the Intersection of Innate and Adaptive Immunity, May 29-June 2, Stockholm, Sweden (poster presentation).

CENTRE FOR IMMUNE REGULATION (CIR) ANNUAL REPORT 2016

Iversen R: “Relatedness between serum antibodies and gut plasma cells in celiac Disease”. Seminar, Department of Immunology, November 9, Ullevål stadion, Oslo (iPad presentation). Jahnsen FL: “Monocytes constantly replenish macrophages and dendritic cells in the human small intestine”. Cell Symposia, 100 years of phagocytes. September 19-22, Sicilia (poster presentation). Kjos I: “Identification of Rab proteins involved in cell migration using an siRNA screening approach”. European Cytoskeletal Forum - Cell Adhesion and Migration: Robinson College, University of Cambridge, June 20-23, Cambridge, UK (poster presentation). Kjos I: “The small GTPase Rab7b negatively regulates autophagy”. Building the cell meeting, September 28-30, Paris, France (poster presentation). Landsverk OJB: “Human gut contains long-lived plasma cells”. Keystone Symposia Conference, "B Cells at the Intersection of Innate and Adaptive Immunity", May 29 - June 2, Stockholm, Sweden (poster presentation). Lode HE: “Antibody-antigen kinetics constrain intracellular humoral immunity”. Seminar, Department of Immunology, November 9, Ullevål Stadion, Oslo (iPad presentation). McAdam MB: “IgG engineering improves FcRn mediated rescue of IgG”. 2nd Annual BMB Retreat, September 9, Voksenåsen, Oslo (poster presentation). Mester S: “Design of IgG and albumin variants with altered FcRn-mediated transport properties”. 2nd Annual BMB Retreat, September 9, Voksenåsen, Oslo (poster presentation). Mester S: “Design of IgG and albumin variants with altered FcRn-mediated transport properties”. 34th Annual Meeting of the Norwegian Society for Immunology (NSI), November 17, Oslo (poster). Mester S: “Design of IgG and albumin variants with altered FcRn-mediated transport properties”. Seminar, Department of Immunology, November 9, Ullevål Stadion, Oslo (iPad presentation).

Nakken B: “Human B cell memory defined by tyrosine phosphatase CD45 activity”. Keystone symposium: B Cells at the Intersection of Innate and Adaptive Immunity (E3) May 29-June 2, Stockholm, Sweden (poster). Nilsen J: “A novel mouse model for evaluation of human IgG and albumin based therapeutics”. Seminar, Department of Immunology, November 9, Ullevål Stadion, Oslo (iPad presentation). Roy B: “Analysis of Transglutaminase-2 reactive antibody repertoire”. Gordon Research Conference (transglutaminases) July 10-15, Girona, Spain (poster presentation). Sand K: “Unraveling the FcRn albumin interaction: Opportunities and challenges for design of albumin-based therapeutics”, 2nd Annual BMB Retreat, September 9, Voksenåsen, Oslo (poster presentation). Sarna VK: “A study of morphological and immunological responses to a 14 day gluten challenge in adults with treated celiac disease”. Seminar, Department of Immunology, November 9, Ullevål Stadion, Oslo (iPad presentation). Skjeldal F: “EGFR regulated differential recruitment of Cbl and Grb2”. Keystone Symposia, January 31-February 4, Keystone Resort, Keystone, Colorado, USA (poster presentation). Stamnæs J: “On extracellular transglutaminase 2 in relation to celiac disease”. Seminar, Department of Immunology, November 9, Ullevål Stadion, Oslo (iPad presentation). Szodoray P: “T helper signals restore B cell receptor signaling in autoreactive anergic B cells by upregulating CD45 phosphatase activity”. Keystone symposium: B Cells at the Intersection of Innate and Adaptive Immunity (E3) May 29-June 2, Stockholm, Sweden (poster presentation). Vestre K: “Characterization of Rab proteins involved in cell migration”. Building the cell meeting. September 28-30, Paris, France (poster presentation). Wang D: “Autologous bone marrow Th cells can support multiple myeloma cell proliferation in vitro and xenografted mice”. International Congress of Immunology (ICI), August 21-26, Melbourne, Australia (poster presentation).

Presentation to a targeted audience and the public Christophersen A: Ny blodprøve kan forenkle diagnostikk av cøliaki. Tidsskr Nor Laegeforen. 2016 Apr 5;136(6):555 (article). Christophersen A: “Foredrag om ny cøliaki test. Nasjonalt møte om funksjonelle tarmsykdommer”. Norsk Gastromedisinsk Forening, February 14, Oslo (invited speaker). Kveberg L: «Gjesteprofessorprogrammet ved Det medisinske fakultetet». NFRs forskerkonferanse om psykisk helse og rus: Forskning på psykisk helse og rus – muligheter og utfordringer, February 1-3, Oslo (invited speaker).

Sandlie I: En kultur for innovasjon, Patenstyret 200 år, Litteraturhuset i Oslo, 29 april (invited speaker). Sollid LM: “Glutenallergi: Myter og fakta”. Eldre Legers Forening - Høstmøte 2016, November 7, Oslo, Norway (invited speaker).

Media Coverage Geir Åge Løset. Interview with UiO;Life science. January 25, 2016. http://www.uio.no/english/ research/strategic-research-areas/life-science/ news-and-events/research-news/2016/societybenefits-treatment-inflammatory-diseases.html Jan Terje Andersen, Kine Sand and Stian Foss. Interview in Titan February 9, 2016. https://titan. uio.no/node/1345

Lundin K: “Celiac disease – clinical aspects and research”. Support group meeting, Norwegian Celiac Disease Association February 16, Kirkenes (invited speaker).

Shuo-Wang Qiao. Interview “På vei mot en kur for cøliaki” Adresseavisen April 7, 2016. www. adressa.no/pluss/nyheter/2016/04/.../På-veimot-en-kur-for-cøliaki-12566608.ece

Lundin K: “Celiac disease – clinical aspects and research”. Support group meeting, Norwegian Celiac Disease Association Finnmark, February 17th, Vadsø (invited speaker).

Ludvig Sollid. Blog «Gluten – gift eller god mat» at forskning.no. Februar 18, 2016. http:// forskning.no/blogg/forskningssykehuset/glutengift-eller-god-mat.

Lundin K: “Celiac disease – clinical aspects and research”. Support group meeting, Norwegian Celiac Disease Association Buskerud, February 23rd, Hokksund (invited speaker).

Ludvig Sollid. Interview with Allers GLUTENfritt, nr 3, 2016.

Munthe L: “Cancer drug Sensitivity and patient data”. National Lymphoma Day, Norwegian lymphoma Association, September 15, Oslo (invited speaker). Qiao SW: “En cøliakifremtid med gluten”. Norsk Cøliakiforenings årsmøte, April 22 (invited speaker). Sarna VK: “Indremedisineren” nr.3 – 2016, Fagtidskriftet for Norsk Indremedisinsk Forening. (article). Sand K: Tailoring the lifespan of tomorrow's biotherapeutics, UiO festivalen 23 april (invited speaker). Sand K: Proteiner i vår egen kropp inspirerer fremtidens supermedisiner, Innovasjon i lunsjen, February 9, Realfagsbiblioteket, UiO, Oslo (invited speaker).

Per Brandtzæg. Ammedebatten på riktig spor. Aftenposten April 14, 2016. http://www. aftenposten.no/meninger/Ammedebatten-pariktig-spor--Per-Brandtzag-53644b.html Ludvig Sollid. Interview with Norsk Cøliaki Forening glutenFRI, nr 4, 2016 Jan Terje Andersen. Interview with the Norwegian Research Council. June 14, 2016. http://www.forskningsradet.no/prognettbiotek2021/Nyheter/Min_optimaliseringshistorie__Malsokende_antistoffer/1254018945614/ p1253970728192 Ludvig M. Sollid. “Åpnet nytt senter for cøliakiforskning». Dagens medisin, August 26, 2016. https://www.dagensmedisin.no/ artikler/2016/08/26/apnet-nytt-senter-forcoliakiforskning/

CENTRE FOR IMMUNE REGULATION (CIR) ANNUAL REPORT 2016

Geir Åge Løset. Interview with NRK. September 29, 2016. https://www.nrk.no/sognogfjordane/ trur-pa-ei-presis-kreftbehandling-utanbiverknadar-1.13154568 Cinzia Progida. Interview in Khrono, October 21, 2016. https://khrono.no/2016/10/vil-ha-flerekvinnelige-forskere-og-ledere-pa-fakultetet Lise Kveberg. Commentary in KK, November, 2016. http://www.kk.no/helse-kosthold-trening/ cirka-fem-prosent-av-verdens-befolkningutvikler-autoimmun-sykdom-og-av-disse-er78-prosent-kvinner-41337 Britt Nakken and Peter Szodoray. Interview at Forsking.no. November 17, 2016. http://forskning.no/2016/11/kunstenvekke-en-celle/produsert-og-finansiert-av/ universitetet-i-oslo Cinzia Progida, interview on Titan. Cellene vandrer rundt i kroppen, men hvordan det skjer vet vi lite om. https://titan.uio.no/node/2035. Cinzia Progida: “På besøk hos vinner av forskningsprisen”. http://labnorge.no/nyheter/ pa-besok-hos-vinner-av-forskningsprisen/ Bjarne Bogen: Article about Bogens work with BCR anti-Id knock-in mouse at Ozgene.com. Anti-Id matters. http://www.ozgene.com/publication/ newsletter/24-newsletters/215-ozgene-newsfebruary-2016?utm_source=Feature&utm_ medium=email&utm_campaign=16-02Newsletter

Editor: Lise Kveberg, UiO Photos:ÂŠUiO/Ă&#x2DC;ystein H. Horgmo Design: Millimeterpress

CENTRE FOR IMMUNE REGULATION (CIR) ANNUAL REPORT 2016

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

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