CIR annual report 2015 by Millimeterpress as

Centre for Immune Regulation

research groups publications dissemination activities about

CIR Annual report 2015

Vision statement

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

ANNUAL REPORT 2015

CENTRE FOR IMMUNE REGULATION (CIR)

2 5 6 8 10 12

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

16 18 20 22 24 26 28

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

32 33 34 36 38

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

42 42 43 44 45

publications Papers in scientific journals Books and book chapters Patents and patent applications

48 50 51

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

54 56 56 57 57

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contents

Vision statement Key accomplishments 2015 Directorâ&#x20AC;&#x2122;s comments Scientific currency Innovation and industrialisation Core competency

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CENTRE FOR IMMUNE REGULATION (CIR)

2015 n Showed that the small GTPase

n In Systemic lupus erythematosus

n We have generated antibodies that

(SLE), we used bioinformatics analyses to demonstrate that diverse and seemingly incompatible suggestions for Th cell antigen drivers for this disease (DNA associated cationic proteins, anti-dsDNA autoantibodies) share high level of identity and can function as peptide mimics

bind one of the immunodominant gluten peptides in complex with HLA DQ2.5. The antibody can detect in vitro peptide-loaded APCs in an antigen-specific manner, a finding that holds promise for its utility in studies of antigen presentation

Rab9 directs vesicular transport from TGN to the endosomal pathway whereas another member of the same protein family, Rab7b, directs vesicular traffic in the opposite direction n Generated an Ig VDJH knock-in

mouse that, when bred with a new V位2315m-modified mouse, establishes a model for an Id+ BCR

of TG2 n Succeeded in adaption of the

n Detailed characterization of

long-lived plasma cells in the human gut

n Explored models for activation

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STRT-seq protocol for single-cell transcriptomics on gluten-reactive CD4+ T cells.

CENTRE FOR IMMUNE REGULATION (CIR)

Director’s comments I will like to take this opportunity thank all the people working at CIR for their fantastic contributions to making CIR a success. Our centre is getting increasing attention for our science. This is the result of small contributions by a large number of CIR members during the years since our centre was formed. The existence of centre is coming to an end though. We were given a life span of maximally ten years and now we have less than two years to go. We should enjoy the time left. For CIR 2015 was a good year. We did a lot of fine science. CIR scientists authored or co-authored 49 papers in international peer reviewed journals. Five PhD students defended their thesis in 2015; 2 women and 3 men. Jan Terje Andersen received the Fridtjof Nansen Award for Young Researchers. Last year was also a good year for me personally. I was awarded the Anders Jahre’s Senior Award for Medical Research together with Rikard Holmdahl, I became an honorary member of the Norwegian Society for Immunology, and my group was selected as one of five world leading research communities at the University of Oslo. I am of course glad and proud of these events. It was an honour to share the Jahre Prize with Rikard who we

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at CIR know very well. He has been a member of our Scientific Advisory Board together with Sirpa Jalkanen and Søren Buus. I feel that these honours are something to build on, not to rest on. Speaking of our Scientific Advisory Board, I would like to thank its three members for the outstanding job they have done. Being unafraid, direct and honest they have given me as Director and the group leaders at CIR very useful advice over the years. Thank you! One of views of the Scientific Advisory Board was that a centre of excellence should be dynamic. The three board members said that over a ten year period the composition of the group leaders should change. We followed their advice. We have recruited two new group leaders, Ludvig Munthe and

CENTRE FOR IMMUNE REGULATION (CIR)

Shuo-Wang Qiao. Shuo-Wang qualified among 10 strong applicants for a permanent academic and CIR group leader position and started her new job at CIR in the summer of 2015. I warmly welcome her. There have been a number of scientists who have visited CIR during the year to give guest lectures. These include Vivianne Malmström and Jenny Mjösberg from Karolinska Institutet in Stockholm, and Sarah Teichmann from EMBL-EBI & WT Sanger Institute in Cambridge. Most of the speakers have been invited as part of a seminar series organised by a postdoctoral committee. I thank this committee for conducting this task. Our Visiting Professor programme had visits from Mark Davis (Stanford University), Bernard Malissen

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(Centre d’Immunologie de Marseille-Luminy) and Bana Jabri (University of Chicago). Their effort coming visiting us is much appreciated. As I said, we should enjoy the time we have left with our Centre. The upcoming retreat at Dr. Holm’s Hotel at Geilo just after Easter will give us an opportunity to indulge in science and recreational activities. I am looking forward to spending time in the high mountains with other CIR members.

Ludvig M. Sollid, Centre Director

CENTRE FOR IMMUNE REGULATION (CIR)

Scientific currency Impact factor distribution – CIR publications 2015 10% 12%

22%

55%

8 <5 5–10 >10 New journals, No IF

CIR publications with collaborating institutions 2015

24%

31%

29%

16%

International International & national National CIR-only

PAPERS CIR scientists authored or co-authored 49 papers in international peer-reviewed journals in 2015. The total number of publications per year remains stable. Of the papers published in 2015, 6 publications reached journals with an impact factor above 10.0 and 1 of 3 publications reached journals with an impact factor above 5.0. In general the quality and visibility of publications from the centre is high. CIR scientists have extensive collaborations with national and international research groups. More than 4 of 10 papers published in 2015 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 2015 are presented on page 48–50 of this report. National and international collaborators are listed on page 36–37. PATENTS Researchers at CIR have a strong interest in, and record of, innovation and securing of intellectual property rights from research. The accumulated number of patents granted or patent applications filed by CIR scientists since CIR commenced operations is 28 (see list on page 51). Read more in the innovation and industrialisation section on page 10, and see a list of active patents on page on page 51. DISSEMINATION OF RESEARCH RESULTS CIR members gave 48 talks as invited speakers at international and national scientific meetings in 2015. In addition, 9 oral presentations and 18 posters were presented by CIR scientists at international and national conferences. Furthermore, CIR staff gave 10 lectures and articles aimed at a targeted audience and the general

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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 Centre director Ludvig M. Sollid received the honorable Anders Jahre’s Awards for Medical Research. This prize honor research of outstanding quality in basic and clinical medicine. The prizes are awarded by the University of Oslo and are among the largest within Nordic biomedical research. The prize was shared with Rikard Holmdahl, Karolinska Institutet. Ludvig M. Sollid’s group was also awarded funding from UiO to develop a worldleading research community within the field of human immunology. The funding was granted over the central government budget and Sollid’s group was one of five research groups at the University of Oslo to receive such funding. Sollid was also appointed «Innovator of the month» by the South-Eastern Norway Regional Health Authority for his two ideas for new diagnostic tools for celiac disease, and an honorary membership in the Norwegian Society of Immunology for his contributions to the immunological community. CIR scientist Jan Terje Andersen was awarded the Fridtjof Nansen Prize for Early Career Achievements and the Oslo University Hospital Early Career Award. PhD students Malin Bern and Kine Marita Knudsen Sand from Sandlie’s group received an innovation award from the Department of Biosciences.

CENTRE FOR IMMUNE REGULATION (CIR)

Photo: Thomas Eckhoff/Det Norske Videnskaps-Akademi

Annual Report

2010

Jan Terje Andersen was awarded the Fridtjof Nansen Prize for Early Career Achievements. Jan Terje Andersen (on the left) and Professor Øyvind Østerud from the Norwegian Academy of Science and Letters (DNVA) board.

Photo: © UiO/Yngve Vogt

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. 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. CIR scientist Gustavo De Souza has until the end of 2015 headed the Proteomics Core Facility at the Department of Immunology. The facility offers advanced analysis of proteins and peptides by mass spectrometry. In 2015, CIR invested 3.3 mill NOK in scientific equipment which will be available for the scientific environment at the Oslo University Hospital and the University of Oslo: • One Attune™ NxT Flow Cytometer will be part of the Flow Cytometry Core facility at the Department of Pathology. This will increase the total capacity of the core facility and the instrument will continue to be a part of the core facility after the lifetime of CIR. • One Biacore T200 instrument at the Department of Immunology. • One automatic cell harvester (Harvester96) at the Department of Immunology.

Centre for Immune Regulation (CIR)

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

FOCIS-COE CIR is a Federation of Clinical Immunology Societies (FOCIS) Centre of Excellence (FCE) (www.focisnet.org). The FCEs represents

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Ludvig M. Sollid received Anders Jahre’s award for medical research. The prize was presented by the university rector Ole Petter Ottersen in the University Aula.

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

CENTRE FOR IMMUNE REGULATION (CIR)

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 techno logy 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® technol-

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ogy. 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 half-life. The best binders have increased and the poorest binder decreased half-life. Now, either genetic fusion (peptide or protein) or chemical conjugation of small drugs to either of these albumin variants will greatly alter the serum half-life of the drug. During 2015 we have designed new albumin variants 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. 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 applica-

CENTRE FOR IMMUNE REGULATION (CIR)

tions. 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 precancerous lesions, and initiated its first clinical trial in 2015. Results from the first phase are expected in 2016. In addition, Vaccibody is dedicated to develop individualized cancer vaccines based on mutationderived neoantigens. Vaccines for other indications within cancer as well as infectious diseases for human and veterinary use are also developed through partnerships with companies and academic groups, and in particular with the Bogen group at CIR. 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.

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11 Through 2013, Nextera was granted patent rights to W02009/024591, WO2010/097411, WO2010/097589, WO2011/036555 and WO2011/101681. The core activity of the company is presently phage display of MHC class II molecules, the socalled Phagemers. Phagemer technology enables antigen-specific CD4+ T cell detection as well as epitope discovery of HLA class II associated antigens. Nextera will use the Phagemer technology to identify unknown disease causing antigens, and utilize the new knowledge to develop targeted drugs. Nextera performs joint research with the Sollid and Sandlie groups at CIR partially funded by a major NRC BIA grant using Phagemers with the aim of developing novel therapeutics for Crohns disease. In 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.

CENTRE FOR IMMUNE REGULATION (CIR)

Core competency at CIR SANDLIE GROUP Structure and ligand binding properties of antibodies and T-cell receptors Phage display Recombinant molecule expression and purification

• A wide variety of cellular and humoral immune assays. • Advanced methods in molecular biology, proteomics and cellular imaging. • Disease models in humans and animals. The models are used to understand the molecular mechanisms of immune regulation and autoimmunity. • Transgenic mouse models. • Functional characterisation of immune cells in human tissue. • Study of immune molecules and their intracellular functions in antigen presenting cells. • Molecular engineering for the development of new therapeutic agents and research reagents. • High-throughput sequencing

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CENTRE FOR IMMUNE REGULATION (CIR)

Interaction studies

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

BOGEN GROUP Cellular immunology Experimental studies in mice Transgenic mice

BAKKE GROUP JAHNSEN GROUP

Live cell Imaging

Human model of airway allergy in vitro and in vivo

Confocal microscopy Characterisation of intracellular trafficking pathways

Mucosal antibody system Dendritic cells Immunohistochemistry

QIAO GROUP

Flow cytometry

Molecular biology

Transfection of cells and the study of binding kinetics of cytosolic molecules

Single cell receptor sequencing Molecular and transcriptional profiling of antigen-specific T cells

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

The centre consists of research groups with complementary scientific expertise. Two groups, headed by Inger Sandlie and Oddmund Bakke, are affiliated with the Department of Biosciences at the Faculty of Mathematics and Natural Sciences. Four research groups, headed by Bjarne Bogen, Ludvig A. Munthe, Shuo-Wang Qiao and Ludvig M. Sollid are affiliated with the Department of Immunology at the Faculty of Medicine. One group, headed by Frode L. Jahnsen, is a member of the Laboratory for Immunohistochemistry and Immunopathology, Department of Pathology, at the Faculty of Medicine.

Flow cytometry

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CENTRE FOR IMMUNE REGULATION (CIR)

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CENTRE FOR IMMUNE REGULATION (CIR)

research groups 15

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CENTRE FOR IMMUNE REGULATION (CIR)

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 group consisted of 2 researchers, 2 postdocs, 2 PhD students, 2 master students and 2 technicians. 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.

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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.

CENTRE FOR IMMUNE REGULATION (CIR)

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. These include: • Uptake and sorting of targeted antigen (Bogen). • B lymphoma cells with complementary BCRs delete each other in vitro (Jacobsen/ Bogen) • Intracellular trafficking of the FcRn receptor (Andersen/ Sandlie) CENTRAL PUBLICATIONS IN 2015 • Øynebråten I, Barois N, Bergeland T, Küchler AM, Bakke O, Haraldsen G. (2015) Oligomerized, filamentous surface presentation of RANTES/CCL5 on vascular endothelial cells. Sci Rep. 5: 9261 • Hansson KA, Døving KB, Skjeldal FM. (2015) Mixed input to olfactory glomeruli from two subsets of ciliated sensory neurons does not impede relay neuron specificity in the crucian carp. J Exp Biol. 218, 3257-63.

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ACHIEVEMENTS IN 2015 • Showed the dynamics of the mannose 6 phosphate receptor from the TGN to the endosomal pathway and redefined the traffic regulation of an important Rab in this pathway, the Rab9 (Traffic, 2016). • Developed a patented and invariant chain based vector for immune therapy against cancer. • The NorMIc Oslo imaging platform led by the Bakke group was ratified as a EuroBioimaging Imaging Node and national funding assured. AMBITIONS FOR 2016 • Decipher the molecular mechanisms for sorting to the intracellular antigen-loading compartment based on high throughput antigen loading screens. • Elucidate how autophagy and biogenesis of autofagosomes are connected to the trans Golgi network. • Characterise endosomal maturation in dendritic cells and the Meljuso model antigen presenting cells. Define a pathway to the MHC II antigen loading compartment.

CENTRE FOR IMMUNE REGULATION (CIR)

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 being localized to their variable (V) regions. Bogen and co-workers showed more than 25 years ago that Ig is partially broken down inside cells and that proteolytic fragments of the V-regions [Idiotypic (Id)-fragments] are presented on Major Histocompatibility Complex (MHC) class II molecules to Id-specific CD4+ T cells. This phenomenon forms the foundation for the CIR-related projects of the research group, outlined below. KEY PROJECT SUMMARIES The basis for Id-driven T-B collaboration is that B cells spontaneously degrade their Ig-receptor for antigen (BCR), and display Id-peptides bound to MHC class II molecules on their cell surface. Such Id/MHCII complexes can be recognized by Id-specific CD4+ T cells. Now, if a B cell happens to recognize a self-antigen with its BCR, and at the same time receives help from an Id-specific CD4+ T cell, the B cell receiving these two distinct signals will be activated, proliferate and differentiate. This may result in immune dysregulation, autoimmunity and B lymphoma development. To study Id-driven T-B collaboration in even more detail, we have generated novel BCR knock-in mice. In one of these strains, a mutated Id-sequence (3 amino acids) have been successfully inserted in a germ-line V gene segment. The latter mouse should represent a close to physiological model for Id-driven T-B collaboration. A project on elucidation of the ternary Id-specific TCR/Id-peptide/MHC class II (I-Ed) molecule is in progress (with Inger Sandlie). Id-driven T-B collaboration is now being extended to human autoim-

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mune disease and lymphoma development in collaboration with Ludvig Munthe (see his report) The basis for the tumor immunological experiments of the group is that Ig secreted by multiple myeloma cells (malignant plasma cells) is processed and presented on MHC class II molecules of tumor-infiltrating macrophages. An interplay between Id-specific CD4+ T cells and macrophages results in activation of macrophages that in turn kill the tumor cells. In 2014 we have published that the above described mechanism does not confer bystander killing of antigen-negative tumor cells. In 2015, we have reported a mechanism by which tumor cells can escape killing by CD4+ T cells Tveita et al. Cancer research 2015). 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 (>20) collaborators world-wide. Our group is doing work in this model, and we have demonstrated that CD4+ T cells can kill multiple myeloma cells growing in the bone marrow (Haabeth et al. Leukemia 2015). 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 (cannot) express MHC class II molecules. Internationally, it is now increasingly recognized that CD4+ T cells play an important role in rejection of tumors, also in humans.

CENTRE FOR IMMUNE REGULATION (CIR)

To study the importance of BCR-ligation in Id-driven T-B collaboration, we have 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 BCR-ligation in Id-driven T-B collaboration. CENTRAL PUBLICATIONS IN 2015 • Fossum E, Grødeland G, Terhorst D, Tveita AA, Vikse E, Mjaaland S, Henri S, Malissen B, Bogen B. Vaccine molecules targeting Xcr1 on cross-presenting DCs induce protective CD8+ T-cell responses against influenza virus. Eur J Immunol 2015;45(2):624-35. • Tveita AA, Schjesvold F, Haabeth OA, Fauskanger M, Bogen B (2015). Tumors Escape CD4+ T-cell-Mediated Immunosurveillance by Impairing the Ability of Infiltrating Macrophages to Indirectly Present Tumor Antigens. Cancer Res, 75 (16), 3268-78. • Haabeth OA, Tveita A, Fauskanger M, Hennig K, Hofgaard PO, Bogen B (2015). Idiotypespecific CD4(+) T cells eradicate disseminated myeloma. Leukemia advance online publication 10 November 2015.

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• Kikuchi J, Koyama D, Wada T, Izumi T, Hofgaard PO, Bogen B, Furukawa Y (2015). Phosphorylation-mediated EZH2 inactivation promotes drug resistance in multiple myeloma. J Clin Invest. 2015;125(12):4375-4390. ACHIEVEMENTS IN 2015 • Generated an Ig VDJH knock-in mouse that, when bred with a new Vl2315mmodified mouse, establishes a model for an Id+ BCR. • Published that the CD4+ T cell/macrophage mechanism can eliminate MHCIInegative tumor cells. • Detected a molecular mechanism by which tumor cells can escape elimination by CD4+ T cells/macrophages. AMBITIONS FOR 2016 • To investigate the importance of BCR-ligation by self-antigen in Idiotype-driven T-B collaboration, using the new BCR knockin mice described above. • To test if chronic Idiotype-driven T-B collaboration can cause development of autoimmune disease • To explore the molecular mechanism by which CD4+ T cells reject tumour cells.

CENTRE FOR IMMUNE REGULATION (CIR)

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. This environment is extremely challenging for the local mucosal immune system and maintenance of homeostasis depends on its ability to be tolerant to harmless antigens and at the same time be able to rapidly mount an effective immune response to incoming pathogenic microbes. However, breakdown of tolerance mechanisms at mucosal sites are not uncommon as exemplified by a dysregulated immune reaction to gluten in the case of celiac disease and reactions to harmless pollen and animal proteins that cause airway allergies. To understand the mechanisms underlying such diseases it is of paramount importance to understand how the mucosal immune system operates under steady-state conditions. By isolating immune cells from surgical specimens and endoscopic biopsies (cancer surgery and transplanted patients) we have been able to perform detailed characterization of immune-cell subsets (monocytes, macrophages, dendritic cells, and B and T cells) in the human small intestine. Studies in mice have shown that tissue macrophages are selfmaintained cells, independent of circulating monocytes. In the human gut, however, we find that monocytes constantly migrate to the gut mucosa as proinflammatory cells. After enter-

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ing the tissue they rapidly downregulate their inflammatory capacity and differentiate into two types of tissue macrophages with a lifespan of 10-20 weeks. Interestingly, whereas the major population of macrophages are located in the villi the other subset is located in the deep part of the lamina propria and the submucosa. Most dendritic cells are readily distinguished from monocytes and macrophages. They consist of two types (resembling their counterparts in blood) that are clearly functionally different in terms of T-cell stimulatory capacity. Both dendritic cell subsets have a high turnover rate in the tissue (<3 weeks) and have markers compatible with their ability to travel to the draining lymph nodes. Interestingly, a minor fraction of monocytes develop into dendritic cells which are phenotypically similar, but functionally different from bona fide dendritic cells. By following the replacement kinetics of T cells and plasma cells in the transplanted gut we have been able to demonstrate that both cell types comprise both very long-lived (>> 1 year) and short-lived cells. The current dogma suggests that plasma cells in the gut are shortlived cells. Our findings are radically changing this view. Moreover, it is also surprising that a high proportion of T cells in the gut are very long-lived. Understanding the underlying mechanisms of longevity by plasma cells and T cells may have important implications in the search for efficient vaccination strategies as well as identifying new targets in the treatment of chronic inflammatory diseases. Studying the turnover of alveolar macrophages in transplanted lungs we find, in contrast to macrophages in the gut, that alveolar macrophages live for more than 2 years. This demonstrates that macrophages in various tissues are different and most likely shaped by their local environment.

CENTRE FOR IMMUNE REGULATION (CIR)

Macrophages and monocytes are functionally different, but they are phenotypically similar and therefore difficult to distinguish by in situ staining methods. Based on our detailed studies of monocytes and macrophages in the gut mucosa we have been able to establish in situ staining methods to distinguish monocytes and macrophages in tissue sections. We find that proinflammatory monocytes accumulate rapidly and robustly in both an experimental model of allergic rhinitis and in tissue obtained from children with fatal allergic asthma. This accumulation was most likely caused by an increased recruitment of circulating monocytes. However, it is also possible that an inflammatory environment keep these cells in an immature proinflammatory state by abrogating their differentiation into regulatory macrophages. By transcriptomic profiling we found that mononuclear phagocytic cells in the challenged nasal mucosa produced 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. CENTRAL PUBLICATIONS IN 2015 • Skrindo I, Ballke C, Gran E, Johansen FE, Baekkevold ES, Jahnsen FL (2015). IL-5 production

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by resident mucosal allergen-specific T cells in an explant model of allergic rhinitis. Clin Exp Allergy, 45 (8), 1296-304 • Bjerkan L, Schreurs O, Engen SA, Jahnsen FL, Baekkevold ES, Blix IJ, Schenck K (2015). The short form of TSLP is constitutively translated in human keratinocytes and has characteristics of an antimicrobial peptide. Mucosal Immunol, 8 (1), 49-56 ACHIEVEMENTS IN 2015 • Identified monocytes as a central component of the inflammatory reaction in allergic asthma • Identified long-lived plasma cells and T cells in the human small intestine. • Identified distinct subsets of macrophages in the gut. • Shown that monocytes differentiate into dendritic cells in the gut. AMBITIONS FOR 2016 • Study the blood monocyte compartment in experimentally-induced celiac disease. • Genomic profiling of monocyte-derived cells in the human small intestine. • Genomic profiling of plasma cells and T cells in the human small intestine. • Functional characterization of T cells in the human gut.

CENTRE FOR IMMUNE REGULATION (CIR)

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. KEY PROJECT SUMMARIES We have the following research questions: • How can Idiotype-specific Th cells drive autoimmune B cell responses? • How can Th cells drive the proliferation of human lymphoma? • What is the drive for myeloma proliferation in human patients? • How can we identify which drugs can abrogate lymphoma and myeloma proliferation? • What allows reversal of B cell anergy in CLL and reversal of anergy in anergic B cell subsets in normals? CENTRAL PUBLICATIONS IN 2015 • Systemic Lupus Erythematosus: Molecular Mimicry between Anti-dsDNA CDR3 Idiotype, Microbial and Self Peptides-As Antigens for Th Cells. Aas-Hanssen K, Thompson KM, Bogen B, Munthe LA. • Front Immunol. 2015 Jul 28;6:382. doi: 10.3389/ fimmu.2015.00382. eCollection 2015. PMID: 26284067 • Inclusion of an IgG1-Fc spacer abrogates efficacy of CD19 CAR T cells in a xenograft mouse model.

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• Almåsbak H, Walseng E, Kristian A, Myhre MR, Suso EM, Munthe LA, Andersen JT, Wang MY, Kvalheim G, Gaudernack G, Kyte JA. Gene Ther. 2015 May;22(5):391-403. doi: 10.1038/gt.2015.4. Epub 2015 Feb 5. PMID: 25652098 • Chronic lymphocytic leukemia cells express CD38 in response to Th1 cell-derived IFN-γ by a T-bet-dependent mechanism. Bürgler S, Gimeno A, Parente-Ribes A, Wang D, Os A, Devereux S, Jebsen P, Bogen B, Tjønnfjord GE, Munthe LA. J Immunol. 2015 Jan 15;194(2):827-35. doi: 10.4049/ jimmunol.1401350. Epub 2014 Dec 10. PMID: 25505279 • 10 clinical immunology papers: Rentka A, et al. Immunol Res., Nakken B, et al. Mediators Inflamm. 2015, Bazsó A, Mediators Inflamm. 2015. Rentka A, et al Mediators Inflamm., Nagy G, et al Mediators Inflamm. Papp G, et al Immunol Res. Bazsó A, et al Immunol Res. Nakken B, et al Clin Rev Allergy Immunol. KEY ACHIEVEMENTS IN 2015 • The specificity of Th cells relevant for SLE disease and the mechanisms of cognate collaboration with anti-dsDNA B cells are unclear. The following Th cell specificities have however been proposed: specificities towards B cell idiotypes, cationic DNA binding self-proteins and DNA-associated cationic proteins from pathogens. We demonstrated that peptides drawn from these three sources could in fact represent a common pool of cationic peptides that could represent peptide mimics for T cells that could drive lupus (Aas-Hanssen K et al Frontiers Immunol). • We demonstrated a novel molecular pathway for expansion and support of chronic lymphocytic leukemia (CLL) cells from patients, Bürgler et al, JI 2015. We thereby link Th cell activation, cytokine profile and

CENTRE FOR IMMUNE REGULATION (CIR)

CLL cell response to the CD38 marker in this cancer that is driven by autoimmune Th cells. • Together with Taskén’s group at Centre of Molecular Medicine (NCMM, Univ. of Oslo), we have initiated a drug sensitivity trial for CLL and MM. The first paper on this topic was Epublished in Nov 15, in print in 2016 (Parente-Ribes A, et al Haematologica). The national trial board for this study is headed by Bjørn Tore Gjertsen, Haukeland Univ. Hospital, Bergen. Discussions have been finalized with SLV (Norwegian Medicines Agency). Ethical approval is now being sought. Together with phosphoflow analysis, and genome analyses, this platform will be used in a Health Region South East-funded pipeline for n-of-1 trial. We will extend and capitalize on a recent breakthrough allowing MM cell expansion from unfractionated bone marrow aspirates, allowing testing of MM cell drug sensitivity assays in a personalized medicine context. • Together with the Biotech company Nextera we have received support from RCN-BIA to develop novel biologics in CLL. AMBITIONS FOR 2016 • We will characterize allelic inclusion, exclusion and exchange of VL and VH of anti-dsDNA B cells in Lupus mice.

ANNUAL REPORT 2015

• We will define the mechanism for how B cell anergy is reversed in human anergic B cells, suggest novel druggable targets. • We will continue to characterize Th cell autospecificity in CLL patients. • We will demonstrate how primary multiple myeloma cells from patients can be stimulated to proliferate in vitro and in vivo in xenografted mice. • We will demonstrate the phenotype and function of Th cells that support MM cell growth in patients, and start characterization of Th cell autospecificities in this disease. • We will demonstrate how to establish ex vivo culture of human primary multiple myeloma (MM) cells and how MM cell culture can be extended to several months. • We will define how EBV infection may play a part in disease progression in CLL. • We will initiate a high throughput drug screen for CLL (ex vivo culture). • We will establish assays to measure Th cell phenotype and function in Immune thrombocytopenic purpura (ITP) patients enrolled in clinical trials together with clinical partners, see Holme et al, Lancet 2015. • We will develop and test lead candidates for novel biologics in CLL.

CENTRE FOR IMMUNE REGULATION (CIR)

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 FcRn, with IgG subclasses and albumin. Key questions are how binding to the receptors elicits antibody effector functions and regulates biodistribution and serum half-life of both IgG and albumin. B) Using bioinformatics tools and phage display, we select antibodies with specificity for antigenic peptide-HLA molecule complexes, and we also select peptide-HLA complexes that bind to specific T-cell receptors. 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. 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 are attractive not only because they reveal how FcRn is regulating the transport of its two ligands, but also from a translational perspective, as they can be used as screening tools to predict the behavior of designed FcRn-binding molecules prior to preclinical studies in animal models. To ask questions regarding the location

ANNUAL REPORT 2015

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 so far distinguishes between highly similar complexes, and thus shows unique fine-specificity. Antibody binding depends on the presence of an amino acid residue in a particular position in the peptide that is also necessary for binding of specific T cells, indicating that the two share binding mode. We now work to make them even more sensitive also aim to increase the number of different antibodies that we can make available to other groups in CIR. We have found that phages can display peptide-HLA class II complexes, given that they are stabilized by mutagenesis. The complexes on phage are named «Phagemers». Phagemers bind to and detect specific T cells, and we explore their use 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 proteins that drive pathological T cell activation in autoimmune diseases and chronic infections. CENTRAL PUBLICATIONS IN 2015 • Bern M, Sand KM, Nilsen J, Sandlie I, Andersen JT (2015). The role of albumin receptors in regulation of albumin homeostasis: Implications for drug delivery. J Control Release, 211, 144-62 • Grevys A, Bern M, Foss S, Bratlie DB, Moen A, Gunnarsen KS, Aase A, Michaelsen TE, Sandlie I, Andersen JT (2015). Fc Engineering of

CENTRE FOR IMMUNE REGULATION (CIR)

Human IgG1 for Altered Binding to the Neonatal Fc Receptor Affects Fc Effector Functions. J Immunol, 194 (11), 5497-508. • Sand KM, Bern M, Nilsen J, Noordzij HT, Sandlie I, Andersen JT (2015). Unraveling the Interaction between FcRn and Albumin: Opportunities for Design of Albumin-Based Therapeutics. Front Immunol, 5, 682. • Løset GÅ, Berntzen G, Frigstad T, Pollmann S, Gunnarsen KS, Sandlie I (2015). Phage Display Engineered T Cell Receptors as Tools for the Study of Tumor Peptide-MHC Interactions. Front Oncol, 4, 378. • Foss S, Watkinson R, Sandlie I, James LC, Andersen JT (2015). TRIM21: a cytosolic Fc receptor with broad antibody isotype specificity. Immunol Rev, 268 (1), 328-39. ACHIEVEMENTS IN 2015 • We have generated antibodies that bind one of the immunodominant gluten peptides in complex with HLA DQ2.5. The antibody can detect in vitro peptideloaded APCs in an antigen-specific manner, a finding that holds promise for its utility in studies of antigen presentation. • We have shown that engineering of IgG for altered binding to FcRn also influences binding to both the classical Fc gamma receptors and complement. This results in changes in their ability to induce antibody

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dependent cell cytotoxicity, phagocytosis and complement mediated lysis. The finding has great implications for the therapeutic efficacy and use of such engineered IgG variants with long half life. AMBITIONS FOR 2016 • Generate a panel of antibodies with specificity for peptide – MHC complexes to be used in studies of antigen presentation in celiac disease patients. • Design molecular trackers for specific T-cell receptors characteristic for gluten specific T cells to be used in diagnostic tests. • Analyse the fine specificity of memory T cells in coeliac disease. • Understand basic mechanisms that govern transcytosis and recycling of albumin and IgG. • Describe structural features of the constant regions of the human IgG subclasses that are important for their effector functions, and characterize how IgG bound to certain pathogens directs them to intracellular degradation and initiate signaling that alerts the cell to fight the infection.

CENTRE FOR IMMUNE REGULATION (CIR)

Group leader Inger Sandlie was on sabbatical leave in US when the group picture was taken.

Sollid group

Our group is trying 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 and expression of disease associated MCH class II molecules is required for disease development. Gluten induces disease specific immune responses both in the CD4+ T cell and B cell compartments, and these responses lead to tissue destruction as well as 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 we know the antigen of recognised by these immune cells. 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 avoiding bias introduced upon 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 gives us unprecedented insight into the disease specific, adaptive immune response and will likely be of future diagnostic value. 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 disease. KEY PROJECT SUMMARIES Plasma cells: phenotypic characterization and high throughput DNA sequencing of disease specific plasma cells from blood and gut, both in bulk and at single cell level. To character-

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ize VH/VL gene usage, pairing preferences, mutation rate, clonal expansion and memory formation. Gluten-reactive T cells: We are studying TCR specificity and function of gluten-reactive T cells. MHC tetramers are key tools in these studies. Utilisation of disease specific antibodies and MHC tetramer for development of novel diagnostic assays Characterisation of models for B- and T-cell cooperation and mechanisms for activation of autoreactive TG2-specific B cells. CENTRAL PUBLICATIONS IN 2015 • Snir O, Mesin L, Gidoni M, Lundin KE, Yaari G, Sollid LM (2015). Analysis of celiac disease autoreactive gut plasma cells and their corresponding memory compartment in peripheral blood using high-throughput sequencing. J Immunol. 15;194(12):5703-5712 • Di Niro R, Snir O, Kaukinen K, Yaari G, Lundin KE, Gupta NT, Kleinstein SH, Cols M, Cerutti A, Mäki M, Shlomchik MJ, Sollid LM (2015). Responsive population dynamics and wide seeding into the duodenal lamina propria of transglutaminase-2-specific plasma cells in celiac disease. Mucosal Immunol. 9(1):254-264 • Steinsbø Ø, Dørum S, Lundin KE, Sollid LM (2015). Serologic assay for diagnosis of celiac disease based on a patient-derived monoclonal antigliadin antibody. Gastroenterology. 149(6):1530-1540 • du Pré MF, Sollid LM (2015). T-cell and B-cell immunity in celiac disease. Best Pract Res Clin Gastroenterol. 29(3):413-423 • Iversen R, Fleur du Pré M, Di Niro R, Sollid LM (2015). Igs as substrates for transglutaminase 2: Implications for autoantibody production in celiac disease. J Immunol 195(11):5159-5168

CENTRE FOR IMMUNE REGULATION (CIR)

• Stamnaes J, Iversen R, du Pré MF, Chen X, Sollid LM (2015). Enhanced B-cell receptor recognition of the autoantigen transglutaminase 2 by efficient catalytic self-multimerization. PLoS One 10(8):e0134922 ACHIEVEMENTS IN 2015 • Characterised the anti-TG2 B-cell response by high throughput sequencing of plasma cells from gut and blood (J Immunol 2015). The response was found to be dynamic and decrease upon removal of dietary gluten (Mucosal Immunol 2015). • Developed novel serological assay based on competition with monoclonal antideamidated gluten antibody cloned from CD patient gut plasma cells (Gastroenterology 2015). • Explored models for activation of TG2specific B cells and cooperation between TG2-specific B cells and gluten-specific CD4+ T cells. Obtained in vitro experimental evidence for two concurrent but not mutually exclusive models: a) the B cell receptor may itself serve as s substrate for TG2 and become cross-linked to gluten epitopes (J Immunol 2015) and b) TG2 may by utilising itself as a substrate to generate multivalent complexes of TG2 and gluten T-cell epitopes (PLoS One2015).

ANNUAL REPORT 2015

AMBITIONS FOR 2016 • Continue with high throughput sequencing of B-cell receptors (BCRs) and T-cell receptors (TCRs) from single cells and as well as undertaking paired BCR VH–VL and TCR Vα–Vβ sequencing from single cells. Complete the study on paired TCR repertoire analysis of DQ2.5-glia-α2 and DQ2.5-gliaω2-reactive T cells. • Characterise epitopes recognised by monoclonal anti-deamidated gluten antibodies established from CD plasma cells by pulldown assays and mass spectrometry. • Compare antibody sequences of serum antiTG2 and anti-deamidated gliadin antibodies with sequences from gut plasma cells to understand the relationship between serum and gut immune responses. • Understand the structural basis for stereotyped antibody recognition of deamidated gluten peptides by high through sequencing of BCRs and by X-ray crystallography of antigen-antibody complexes. • Characterise the development of autoreactive TG2-specific B cells in an immunoglobulin knock-in mouse model based on a CD patient derived anti-TG2 monoclonal antibody. We will utilise this mouse model to address requirement for activation of naïve autoreactive B-cells.

CENTRE FOR IMMUNE REGULATION (CIR)

Qiao group

The main focus of our group is T-cell receptor analysis and transcriptional analysis of antigenspecific CD4+ T cells. When performed on the single-cell level, transcriptional profiles can be compared within and across expanded T-cell clones.

OVERVIEW OF RESEARCH IN THE GROUP 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 tetramer-aided single-cell sorting. KEY PROJECT SUMMARIES • Optimisation of STRT-seq protocol for single-cell transcriptomics on glutenreactive CD4+ T cells. • Analysis of single-cell transcriptomics data from gluten-reactive CD4+ T cells • Optimisation of SMARTseq2 protocol for single-cell transcriptomics. • Comparison of transcriptional profiles of clonally related and –unrelated antigenspecific CD4+ T cells by single-cell analysis.

ANNUAL REPORT 2015

ACHIEVEMENTS IN 2015 • In collaboration with the Sollid group, a study on the T-cell receptor repertoire acquired on the single-cell level from DQ2.5-glia-α2 and DQ2.5-glia-ω2 reactive CD4+ T cells is finalised (Dahal-Koirala et al. Mucosal Immunol 2016). These are two immunodominant gluten epitopes in celiac disease and despite high sequence similarities of these two antigen epitopes, we found that the T-cell receptor repertoires are distinct but bear similar overall characteristics. • Succeeded in adaption of the STRT-seq protocol for single-cell transcriptomics on gluten-reactive CD4+ T cells. AMBITIONS FOR 2016 • Optimise the SMARTseq single-cell transcriptomics protocol for CD4+ T cells. • Submit several single-cell transcriptomics libraries of gluten-reactive CD4+ T cells using either the STRT-seq or the SMARTseq protocols. • Establish a bioinformatics pipeline for data analysis of single-cell transcriptomics data, coupled with T-cell receptor information, in collaboration with GeirKjetil Sandve, an Associate Professor in bioinformatics at the Department of Informatics, University of Oslo. • Establish protocols for isolating CD4+ T cells that are specific for antigens other than gluten.

CENTRE FOR IMMUNE REGULATION (CIR)

ANNUAL REPORT 2015

CENTRE FOR IMMUNE REGULATION (CIR)

ANNUAL REPORT 2015

CENTRE FOR IMMUNE REGULATION (CIR)

about 31

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CENTRE FOR IMMUNE REGULATION (CIR)

Facts and figures

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

Our host institution is the University of Oslo. Oslo University Hospital is an equal consortium partner. The centre is organised directly under the Faculty of Medicine and the centre Director reports to the Dean. CIR comprises research groups from the Faculty of Mathematics and Natural Sciences, the Faculty of Medicine and from Oslo University Hospital. Centre staff is employed at the Department of Biosciences, the Department of Immunology and the Department of Pathology. 112 persons, producing 64.5 person years, are involved in research at CIR. CIR actively recruits international talents and currently 19 nationalities are represented at the centre. The overall gender balance at CIR is 39/61 with an overweight of female members among PhD students, master students and technicians, and an overveight of male members among group leaders and senior researchers.

MANAGEMENT The centre is headed by Director Ludvig M. Sollid and Deputy Director Inger Sandlie. The centre management is supported by an administrative coordinator, Lise Kveberg. The Director has the daily responsibility for project management, administration and delivery.

THE RESEARCH GROUPS CIR consists of seven research groups headed by professors Ludvig M. Sollid, Inger Sand lie, Oddmund Bakke, Bjarne Bogen, Frode L. Jahnsen, Ludvig A. Munthe, and Associate Professor Shuo-Wang Qiao. Shuo-Wang Qiao was recruited as a new group leader in CIR, August 2015.

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.

ANNUAL REPORT 2015

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. • John Torgils Vaage, Head of the Department of Immunology, OUS.

CENTRE FOR IMMUNE REGULATION (CIR)

SCIENTIFIC ADVISORY BOARD CIR has until September 2015 had a scientific advisory board (SAB) consisting of European world-class scientists. The SAB’s mandate has been to critically evaluate and advice on the centre’s scientific performance and progress. • Professor Søren Buus, University of Copenhagen, Denmark. • Professor Rikard Holmdahl, Karolinska Institutet, Stockholm, Sweden. • Professor Sirpa T. Jalkanen, University of Turku, Finland. FOCIS COE CLINICAL ADVISORY BOARD AND LAY ADVISORY BOARD As a Federation of Clinical Immunology Societies (FOCIS) Centre of Excellence (FCE), CIR has established two advisory boards. The clinical advisory board is responsible for facilitating translational research at CIR • Head physician Knut E. Lundin (chair, gastroenterologist, OUS). • Professor II Geir E. Tjønnfjord (haematologist, OUS and UiO). • Professor Knut Dahl-Jørgensen (paediatrician, OUS and UiO).

ANNUAL REPORT 2015

The lay advisory board focuses on strategic development, fundraising and community outreach • The Director of the Norwegian Coeliac Society. • The Secretary General of the Norwegian Asthma and Allergy Association. • The Secretary General of the Norwegian Diabetes Association.

FUNDING (1000 NOK)

2015

Research Council of Norway (RCN) – CoE 1

11050

University of Oslo (UiO) 2

15869

Oslo University Hospital (OUS) 3 Other funding from RCN South-Eastern Norway Regional Health

3733 13062 11918

Private funding 4

3818

International funding 5

1000

Total funding 1 Centre of Excellence grant. 2 Including value of personnel funded by UiO and indirect costs of infrastructure. 3 Including value of personnel funded by OUS and indirect costs of infrastructure. 4 Including grants from the Norwegian Cancer Society, and others. 5 Including ERC advanced grant, EU grants, and others. Compared to 2014, the total funding was reduced with 14% in 2015.

CENTRE FOR IMMUNE REGULATION (CIR)

60450

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 RESEARCHERS Name Position Funding* Employer* Jan Terje Andersen Researcher NFR OUS Per Brandtzæg Professor emeritus Espen Bækkevold Researcher S-EN RHA OUS Alexandre Corthay Researcher RCN UiO/OUS Denis Khnykin Researcher S-EN RHA OUS Gerbrand Koster Researcher RCN UiO Knut E.A. Lundin Professor UiO/OUS UiO/OUS Geir Åge Løset Researcher RCN-CIR UiO Ingrid Olsen Researcher RCN UiO Cinzia Progida Researcher NCS/NFR UiO Gustavo de Souza Researcher UiO UiO Jorunn Stamnæs Researcher UiO UiO Peter Szodoray Researcher/resident physician OUS OUS Keith Thompson Researcher UiO UiO Anders A. Tveita Researcher NCS OUS

CENTRE PERSONNEL 2015

CIR STAFF DEVELOPMENT

140

30 25

120 100

15 10

60 40

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2009

Ad m

tra

ci ni

2008

2010

2011

2012

2013

2014

2015

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ts st

D /M Sc M

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en s

st D

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Man years Head count

CENTRE FOR IMMUNE REGULATION (CIR)

* Head count includes unpaid MSc/ MD students and staff that left or joined CIR during 2015.

Inger Øynebråten Dong Wang

Researcher Researcher

S-EN RHA RCN-CIR

OUS UiO

TECHNICIANS Name Position Funding* Employer* Frode M. Skjeldal Senior engineer UiO UiO Linda Haugen Senior engineer UiO UiO Kahsai Beraki Engineer UiO UiO Sylvi Morth Staff engineer UiO UiO Merete Storflor Staff engineer UiO-CIR UiO Hilde Omholt Senior engineer NCS OUS Aaste Aursjø Senior engineer UiO UiO Kathrine Hagelsteen Biomedical Laboratory Scientist UiO UiO Linda I. Solfjell Biomedical Laboratory Scientist OUS OUS Kjersti Thorvaldsen Hagen Biomedical Laboratory Scientist OUS OUS Hege Eliassen Senior Executive Officer OUS UiO Sara Halmøy Bakke Staff engineer UiO UiO Sathiyaruby Sivaganesh Staff engineer UiO/RCN UiO/OUS Martin McAdam Research Technician RCN OUS Rahel Frick Staff engineer UiO UiO Marie K Johannesen Senior engineer UiO UiO Bjørg Simonsen Staff engineer S-EN RHA OUS Maria Ekman Stensland Staff engineer S-EN RHA OUS Stine Rosenqvist Lund Engineer S-EN RHA/RCN OUS/UiO Astrid E. V. Tutturen Staff engineer S-EN RHA OUS ADMINISTRATION Name Position Funding* Employer* Lise Kveberg Senior advisor RCN-CIR UiO POSTDOCS Name Jana Blazevski Sudhir Kumar Chauhan Xi Chen Asbjørn Christophersen Siri Dørum Dominik Michael Frei Ramakrishna Prabhu Gopalakrishnan Lisa M. Richter Kristin S. Gunnarsen Catherine Heyward Peter C. Huszthy Ole-Audun W. Haabeth GENDER BALANCE STAFF

Funding* Employer* ERC UiO UiO-CIR UiO S-EN RHA OUS RCN UiO RCN-CIR UiO RCN UiO RCN-CIR UiO RCN-CIR UiO S-EN RHA OUS UiO UiO RCN UiO S-EN RHA OUS GENDER DISTRIBUTION

20 18 16 14 12 10

39%

61%

6 4 2

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Male

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Po s

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Re se

G ro

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Female

CENTRE FOR IMMUNE REGULATION (CIR)

CIR – Centre for Immune Regulation ERC – European Research Council, Advanced grant S-EN RHA – South-Eastern Norway Regional Health Authority NCS – Norwegian Cancer Society OUS – Oslo University Hospital RCN – Research Council of Norway ImmusanT – Biotechnology company, UK UiO – University of Oslo The list of CIR staff and students include both members that left and joined the Centre during 2015. Several CIR members have changed employer, position and funding body during 2015. The listed funding body, position and employer refer to the status per December 2015.

Name Rasmus Iversen Johanne Jacobsen Ole J.B. Landsverk Peng Lei Elettra Marini Britt Nakken Ralf Stefan Neumann Fleur du Pre Bishnudeo Roy Omri Snir

Funding* Employer* ERC UiO RCN OUS S-EN RHA OUS RCN UiO NCS UiO S-EN RHA OUS RCN-CIR UiO S-EN RHA OUS ERC UiO S-EN RHA UiO

PHD STUDENTS/RESEARCH FELLOWS Name Funding* Employer* Christina Ballke UiO-CIR UiO Malin C. Bern RCN UiO Anna Bujko S-EN RHA OUS 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 Stian Foss RCN UiO Ibon Eguiluz Gracia S-EN RHA OUS Algirdas Grevys RCN UiO Kathrin Hnida RCN-CIR UiO Lene Støkken Høydahl RCN-CIR UiO Ingrid Kjos RCN UiO Shiva Dahal Koirala S-EN RHA OUS Ana Kucera UiO UiO Ida Lindeman RCN-CIR UiO Duarte Nunes De C Mateus UiO UiO Nadia Mensali UiO UiO Elisabeth Müller RCN UiO Jeannette Nilsen RCN OUS Nicolay Rustad Nilssen S-EN RHA OUS Anna Parente Ribes RCN-CIR UiO Louise Risnes S-EN RHA OUS Kine Marita K. Sand UiO UiO Vikas K. Sarna S-EN RHA OUS Fredrik Hellem Schesvold NCS OUS Øyvind Steinsbø OUS/S-EN RHA OUS Henrik Aamodt OUS OUS STUDENTS Name Ajna Avdagic Elena Daum Shuai Guo Sanjib Halder Kjartan Hennig Ina Hodnebrug Albane Joly-Battaglini Melanie Manzke Camilla Myklebust Sofie Navelsaker Hanna Noordzij Martine Schrøder Renate Skarshaug Branislava Stankovic Sowmya Subbanna Nora Valeur

ANNUAL REPORT 2015

Study MSc MSc MSc MSc Med MSc MSc MSc MSc MSc MSc MSc MSc MSc MSc MSc

Collaboration 2015 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, Univ. of Oslo and Oslo Univ. Hospital Ralph Dollner, Department of Otorhinolaryngology, Head and Neck Surgery, 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, OUH-Radiumhospitalet and UiO 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, Dept. 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, OUH-Rikshospitalet and UiO 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, OUH-Radiumhospitalet and UiO 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

CENTRE FOR IMMUNE REGULATION (CIR)

Erlend Smeland, Dept. of Cancer Immunology, OUH-Radiumhospitalet and UiO Anne Spurkland, Institute of Basic Medical Sciences, University of Oslo Harald Stenmark, Centre for Cancer Biomedicine, Univ. of Oslo and Oslo Univ. Hospital 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 Weierød, 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, Copenhagen, Denmark. Robert Anderson, ImmusanT, Cambridge US Govind Baghat, Columbia University, NY, USA 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, San Diego, CA, USA Robert Bremel, Jane Homan, IO Genetics, Madison, WI, USA Cecilia Bucci, University of Salento, IT Simone Bürgler, University Children's Hospital, Zurich, Switzerland 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 Marc Dalod, Centre d'Immunologie de Marseille-Luminy FR Mark Davis, Stanford University, US Tatiana Efimova, Washington University School of Medicine, US Peter M. Elias, University of California San Francisco, US Donald Forthal, University of California, 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 Quilmes-IMBICE, AR Peter Green, Columbia University, NY, USA Martin Hills, Zedira Gmbh, Germany Patrick Holt, Telethon Institute of Child Health Research, AU Ann Hosmalin, Cochin Institute, FR Bertrand Huard, University of Geneva, CH

ANNUAL REPORT 2015

Michael Inoyue, The University of Melbourne, Melbourne, Australia Martin Iversen,, Rigshospitalet, Copenhagen University, Copenhagen, Denmark. Bana Jabri, University of Chicago, US Leo C. James, Medical Research Council Laboratory of Molecular Biology, UK Arwyn Jones, Cardiff University, United Kingdom Franziska Jundt, Charite - Universitätsmedizin BerlinDE Thomas J.D. Jørgensen, University of Southern Denmark, DK Chaitan Khosla, Stanford University, US Chu-Young Kim, University of Texas at El Paso Frits Koning, Leiden University Medical Center, NL Ilma Korponay-Szabo, University of Debrecen Medical School, HU Daniel Kowalewski, University clinic, Tübingen, Germany Jose E. Kroll, Federal University of Rio Grande do Norte, BR Wayne Lencer, Harvard Medical School, US Ana-Maria Lennon-Dumenil, Institut Curie, Paris, FR Wiebke Ludwig-Peitsch, Klinik für Dermatologie, DE Nils Lycke, University of Gothenburg, Sweden Markku Mäki, University of Tampere, FI Bernard Malissen, Centre d'Immunologie de Marseille-Luminy, FR Kristiina Malmstrøm, Helsinki University, FI Rudolf Manz, University of Lubeck, DE Line Mathiesen: University of Copenhagen, Denmark. Bertrand Meresse, Université Paris Descartes-Sorbonne Paris Cité, FR Jeffery Miner, Washington University School of Medicine, US Jane Muir, Monash University, Melbourne, AU Jacques Neefjes, Netherlands Cancer Institute, NL Morten S. Nielsen, University of Aarhus, DK Richard Pleass: Liverpool School of Tropical Medicine, UK Andreas Pluecktum: University of Zurich, Switzerland Cornelis J.H. Pronk , Lund University, Sweden Hans-Georg Rammensee, University clinic, Tübingen, Germany 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 Hilde Schjerven, Department of Laboratory Medicine, UCSF, CA, USA Hans Henrik Lawaetz Schultz, Rigshospitalet, Copenhagen University, Copenhagen, Denmark. Juliane Stickel, University clinic, Tübingen, Germany 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)

Education and career development PHD A large number of PhD students have graduated from CIR. The ambition has been to educate 35 new PhDs during this 10 years period. A total of 38 PhD students have already successfully defended their thesis so this goal is achieved. In 2015, two female and three male students defended their thesis:

AXEL BERG-LARSEN, «Potential roles of Rab GTPases during dendritic cell maturation». Supervisors: Oddmund Bakke and Tone F. Gregers. ASBJØRN OTTO CHRISTOPHERSEN, «Studies of gluten-reactive CD4+ T cells in healthy subjects and coeliac disease patients». Supervisor: Ludvig M. Sollid

ANA KUCERA, «Characterization of novel trafficking pathways from the trans-Golgi network to the endosomal compartments». Supervisors: Oddmund Bakke, Tone F. Gregers, Jan Terje Andersen, and Cinzia Progida GURO REINHOLT MELUM, «Mucosal dendritic cells in immune homeostasis and upper airway allergy». Supervisor: Espen S. Bækkevold ØYVIND STEINSBØ, «On the IgA response to gluten in celiac disease». Supervisor: Ludvig M. Sollid

MSC In 2015, 8 graduated master students performed their scientific work at CIR. One master student graduated from the Norwegian University of Life Sciences, one from the Technical University of Denmark, and six from the University of Oslo. • Merete Storflor • Albane Joly-Battaglini • Sofie Navelsaker • Martine Schrøder • Branislava Stankovic • Nora Valeur • Rahel Frick • Stine Rosenqvist Lund

COMPLETED PHD DEGREES AT CIR PER YEAR FROM 2008 TO 2015 8 7 6

One international master student (Elena Daum) did a project at CIR for an MSc degree in Germany.

5 4 3 2 1 0

2008

2009

2010

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2011

2012

2013

2014

2015

CENTRE FOR IMMUNE REGULATION (CIR)

GENDER EQUALITY PROGRAM At CIR and generally in molecular biomedical research there is a high proportion of female PhD students and postdocs, while the majority of the senior scientists and group leaders are male. CIR and the University of Oslo value gender diversity and aim to increase the number of female researchers in senior scientist positions. Women, more so than men, leave academia during their postdoctoral engagements and transition to independent researchers. CIR acknowledges that the centre, our host institution and other academic institutions nationally and abroad are at risk of losing many talents, possessing valuable and highly specialised competency. In 2013, in line with the gender diversity strategy of the University of Oslo, CIR provided two development grants to support the career of female scientists. CIR has obtained earmarked funding from the Research Council of Norway (RCN) to launch this program. 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 has been a big success, as the two candidates either received career grants from external institutions or got a permanent academic position. The gender equality program is therefore continued in 2015 and 2016. New career development grants for female scientists were announced in the end of 2014. The applications were evaluated by our Scientific Advisory Board, and among 7 other strong applicants, Jorunn Stamnæs and Britt Nakken were selected as the top candidates and will receive the grants for 2015 and 2016. CAREER DEVELOPMENT AND OPPORTUNITIES CIR continues to support the career development of our talents. In 2014 the Medical Faculty announced through the «phasing in scheme» an associate professorship for a junior faculty member within CIR. Among strong applicants from all over the world, Shuo-Wang Qiao was recruited and offered a group leader position at CIR from August 2015. It is especially nice to welcome a female researcher among the group leaders at CIR, which currently includes 7 males and 2 females. In 2014 and 2015, 4 young CIR researchers received career development research fellowship from different funding institutions: Jan Terje Andersen, Anders Tveita, Cinzia Progida, and Denis Khnykin.

ANNUAL REPORT 2015

Ana Kucera

Camilla Myklebust

Guro Reinholt Melum

Branislava Stankovic

Asbjørn Christophersen

Britt Nakken

Kjartan Hennig

Merete Storflor

Nora Valeur

Rahel Frick

Stine Rosenqvist Lund

Øyvind Steinsbø

Sofie Navelsaker

Martine Schrøder

Anders Tveita

CENTRE FOR IMMUNE REGULATION (CIR)

ANNUAL REPORT 2015

CENTRE FOR IMMUNE REGULATION (CIR)

activities

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CENTRE FOR IMMUNE REGULATION (CIR)

The Visiting Professor program

Bana Jabri

Mark M. Davis

Bernard Malissen

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 usually give two public lectures for the whole scientific environment at the University of Oslo and the Oslo University hospital. These visits have resulted in fruitful collaborations resulting in joint publications, researcher mobility and new ideas. A total of twelve professors have been included in the Visiting Professor program, and many of them have visited us twice. In 2015, Bana Jabri (University of Chicago, USA) and Mark M. Davis (Stanford University, USA) revisited CIR for their second time in August and March respectively. Bernard Malissen from Centre d'Immunologie de Marseille-Luminy joined the Visiting Professor program in June. We are very pleased to announce that Gwendalyn J. Randolph from the Washington University School of Medicine will join the Visiting Professor faculty in 2016 and has accepted to visit CIR in June. We are very much looking forward to her visit. New Visiting Professors are nominated by CIR staff and will be invited to CIR in the future. MARK M. DAVIS Dr. Davis is the Director at Stanford Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, California, US. His focus is to understand the characteristics of a healthy humane immune system. Davis and his research group are trying to define what a normal immune response look like at the molecular and cellular level. There is no easy test to look for normal function of a patient’s immune system, and one goal of Davis’ research is to generate a simple battery of tests to be performed on a blood sample that can give information about the health status of your complex immune system.

ANNUAL REPORT 2015

The future aim is to be able to give optimal treatment to patients and customized vaccines to older people. During his visit at CIR in March, Davis gave a lecture entitled "Systems immunology and its application to human beings" as part of a minisymposium. BANA JABRI Dr. Jabri is one of the leading researchers of celiac disease in the world and has directed the research team at The University of Chicago Celiac Disease Center since 1999. Her main interest is the interplay between innate and adaptive immunity and the mechanisms underlying immune-mediated tissue destruction, with a particular emphasis on autoimmune diseases and mucosal immunity. During her visit in August she contributed with two lectures. One lecture was part of the minisymposium «Recent advances in innate immunity», and the other lecture entitled «Tissue control of effector responses» was performed as an inspiring «chalk talk» for the students and postdocs at CIR. BERNARD MALISSEN Dr. Malissen is a world leading immunologist and Director of the ISERM-CNRS Immunology Center in Marseille Luminy (CIML). He has devoted most of his working life to study antigen recognition and activation of T cells, as well as to the genetics of the T receptor. In particular, his focus is the molecular basis of T cell antigen recognition. Malissen is one of the pioneers in the field of molecular immunology in Europe, and is leading a research group at CIML together with his wife (Marie Malissen). During his visit at CIR, Malissen gave two lectures. One lecture was entitled «Integrative biology of T cell activation». The other lecture was part of a minisymposium and was entitled «Harnessing skin dendritic cells».

CENTRE FOR IMMUNE REGULATION (CIR)

Minisymposia MINI-SEMINAR, ROBINS/DAVIS MARCH 25 Professor Harlan Robins, Fred Hutchinson Cancer Research Center, Seattle, USA: Title: "Learning to read immunological memorwy with immunosequencing" Professor Mark M. Davis, Stanford University, CA, USA: Title: "Systems immunology and its application to human beings" The symposium was hosted by Centre for Immune Regulation (CIR) and K.G. Jebsen Center for Cancer Immunotherapy

DENDRITIC CELLS IN IMMUNIZATION JUNE 4 Professor Bernard Malissen, Centre d'Immunologie de Marseille-Luminy, France: Title : "Harnessing skin dendritic cells" Dr. Even Fossum, K.G. Jebsen Centre for Influenza Vaccine Research. Title: "Vaccines targeting cross-presenting dendritic cells". The symposium was hosted by Centre for Immune Regulation (CIR) and K.G. Jebsen Centre for Influenza Vaccine Research (JIV).

RECENT ADVANCES IN INNATE IMMUNITY AUGUST 27 Professor Bana Jabri, Department of Medicine, University of Chicago, USA. «Intraepithelial lymphocytes at the frontier of adaptive and innate immunity». Dr. Jenny Mjösberg, Center for Infectious Medicine (CIM), Karolinska Institutet, Stockholm. «Heterogeneity and plasticity of innate lymphoid cells in tissue homeostasis and inflammation». Dr. Lise Kveberg, Department of Immunology/Centre for Immune Regulation, University of Oslo. «Immunosensing in the gut by genetically coupled lectin-like receptors».

ANNUAL REPORT 2015

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, all the Work Package coordinators joined forces and arranged an open half-day seminar on February 24. The aim of the seminar was to increase knowledge of new scientific methods and the services offered by Core Facilities at UiO and OUS.

Core facility services and and technological expertise at OUS/UiO Speakers: • Fridtjof Lund-Johansen and Kanutte Huse (Flow cytometry Core facility (FCCF), OUS). • Greger Abrahamsen (Image Stream, IMB, UiO). • Gregor D. Gilfillan (Norwegian High Throughput Sequencing Centre, OUS). • Gustavo de Souza (Proteomics Core Facility (PCF), OUS). • Frode Miltzow Skjeldal/ Ole J.B. Landsverk (Live NorMIC-UiO imaging platform/OUS confocal CF Gaustad). • Knut Tomas Dalen (Norwegian transgenic center (NTS), UiO). • Bjørn Dalhus (Structural Biology Core Facility, OUS). • Ståle Nygård (Bioinformatics Core Facility, OUS)

CENTRE FOR IMMUNE REGULATION (CIR)

Sarah Teicmann

Ioana Visan

Guest lectures CIR organizes a series of guest lectures. Most lectures are hosted by a postdoc invitation committee. The 2015 committee consisted of Omri Snir, Lisa M. Gruber, Nadia Mensali, Kristin S. Gunnarsen and Peter C. Huszthy. In 2015, CIR organized 4 international guest lectures:

Vivianne Malmström

Jenny Mjösberg

VIVIANNE MALMSTRÖM visited CIR in March and gave a talk entitled: «Dissecting autoimmunity - T and B cell responses in Rheumatoid Arthritis». Her research is focused around understanding adaptive immune response in autoantibody-positive rheumatic disease. She primarily study rheumatoid arthritis (RA) but also myositis, SLE and vasculitis, which all have in common a strong genetic association to HLA class II that further associates with a subgroup of patients that develop a distinct set of autoantibodies. Malmström is

ANNUAL REPORT 2015

a researcher at the Center for Molecular Medicine, Karolinska University hospital, Stockholm, Sweden. JENNY MJÖSBERG visited CIR in August and gave a lecture as part of a minisymposium: "Heterogeneity and plasticity of innate lymphoid cells in tissue homeostasis and inflammation". Mjösberg is a group leader at the Center for Infectious Medicine (CIM), Karolinska University hospital, Stockholm. Her research is focused on the role of innate lymphoid cells (ILCs) in intestinal inflammation and cancer, and her research group is trying to gain insight into basic ILC biology: How these cells are differentiated, regulated and interact with other cells in the immune system in the context of gut inflammation and cancer. SARAH TEICHMANN visited CIR in November and gave a talk entitled: «Understanding cellular heterogeneity». Teichmann is a world leading young scientist in systems

CENTRE FOR IMMUNE REGULATION (CIR)

Internal activities PROJECT MEETINGS Once a month, all CIR members participates in a project meeting where research projects are presented to other colleagues within CIR. This is a great opportunity to have scientific discussions, critical review of recent data, and initiate new collaborations. It also provides a friendly venue where less experienced junior scientists can practice presentation of experimental data. The project meeting is one of the key events which gather all CIR members, and it is important for building centre identity. After the project presentation pizza and soft drinks are served and the scientific discussions continue in a more relaxed atmosphere. CLUB IMM/CIR CIR has arranged a journal club (CLUB IMM/ CIR) for all postdocs and PhD-students at CIR and the Department of Immunology where they meet to discuss recent important scientific topics and related papers. There were four Journal club meetings in 2015, all hosted by Ole Audun Haabeth, Anders Tveita and Lise Kveberg.

biology which aims to explain how individual molecules within a cell co-operate to produce the cell’s overall behaviour. Her research also offers new insights into how proteins behave. This work could help scientists to predict how proteins interact with each other and design drugs that can interfere with disease processes. Teichmann is a group leader at EMBL-EBI and senior group leader at the Wellcome Trust Sanger Institute in Cambridge, UK. She is also a Principle Research Associate in the Dept Physics/Cavendish Laboratory, and a fellow of Trinity College, Cambridge.

SUMMER PARTY For several reasons we did not arrange our annual CIR retreat in 2015. We therefore decided to have a minisymposium («Recent advances in innate immunity») in Oslo during the visit of our Visiting Professor Bana Jabri, and combine this with a summer party for all CIR members and the present international guests. The party took place at «Lille Herbern», a restaurant on a little island just outside of Bygdøy. This was an exotic venue for all our international guests, and we had a magic evening with good laughs mixed with scientific discussions.

IOANA VISAN, Senior Editor in Nature Immunology, visited NSI and CIR in June. Visan gave a talk entitled: "From bench to publishing- an editorial perspective". The lecture was hosted by the Norwegian Society for Immunology (NSI) and CIR. Visan is as a biologist with research background on T cell development, and she joined the staff of Nature Immunology in 2009.

ANNUAL REPORT 2015

CENTRE FOR IMMUNE REGULATION (CIR)

View of the Oslo-fjord from restaurant Lille-Herbern.

ANNUAL REPORT 2015

CENTRE FOR IMMUNE REGULATION (CIR)

publications 47

ANNUAL REPORT 2015

CENTRE FOR IMMUNE REGULATION (CIR)

Papers in scientific journals Aas-Hanssen K, Thompson KM, Bogen B, Munthe LA (2015). Systemic Lupus Erythematosus: Molecular Mimicry between Anti-dsDNA CDR3 Idiotype, Microbial and Self Peptides-As Antigens for Th Cells. Front Immunol, 6, 382. Bazsó A, Szodoray P, Szappanos Á, Korda J, Pálfi P, Kiss E, Poór G (2015). Systemic Autoimmune, Rheumatic Diseases and Coinciding Psoriasis: Data from a Large Single-Centre Registry and Review of the Literature. Mediators Inflamm. 2015:657907. Bern M, Sand KM, Nilsen J, Sandlie I, Andersen JT (2015). The role of albumin receptors in regulation of albumin homeostasis: Implications for drug delivery. J Control Release, 211, 144-62. Bjerkan L, Schreurs O, Engen SA, Jahnsen FL, Baekkevold ES, Blix IJ, Schenck K (2015). The short form of TSLP is constitutively translated in human keratinocytes and has characteristics of an antimicrobial peptide. Mucosal Immunol, 8 (1), 49-56.

Cover from The Journal of Biological Chemistry, August 28, 2015; 290 (35)

Volume 282 Number 11 June 2015 | ISSN 1742-464X

RING0 RING1 Catalytic site Cys431

IBR

Phospho-site Ser65

RING2 REP

State-of-the-Art Reviews Parkin structure and function High-throughput CRISPR-Cas9 screening Review Article Molecular features of the sortase enzyme family

Cover from The FEBS Journal, Volume 282(11), June 2015 FEBS_v282_i11_pod_oc.indd 1

Czajkowsky DM, Andersen JT, Fuchs A, Wilson TJ, Mekhaiel D, Colonna M, He J, Shao Z, Mitchell DA, Wu G, Dell A, Haslam S, Lloyd KA, Moore SC, Sandlie I, Blundell PA, Pleass RJ (2015). Developing the IVIG biomimetic, hexaFc, for drug and vaccine applications. Sci Rep, 5, 9526. Danilova E, Skrindo I, Gran E, Hales BJ, Smith WA, Jahnsen J, Johansen FE, Jahnsen FL, Baekkevold ES (2015). A role for CCL28-CCR3 in T-cell homing to the human upper airway mucosa. Mucosal Immunol, 8 (1), 107-14. Distefano MB, Kjos I, Bakke O, Progida C (2015). Rab7b at the intersection of intracellular trafficking and cell migration. Communicative & Integrative Biology, 8:6, e1023492, du Pré MF, Sollid LM (2015). T-cell and B-cell immunity in celiac disease. Best Pract Res Clin Gastroenterol, 29 (3), 413-23. Foss S, Watkinson R, Sandlie I, James LC, Andersen JT (2015). TRIM21: a cytosolic Fc receptor with broad antibody isotype specificity. Immunol Rev, 268 (1), 328-39.

Bürgler S, Gimeno A, Parente-Ribes A, Wang D, Os A, Devereux S, Jebsen P, Bogen B, Tjønnfjord GE, Munthe LA (2015). Chronic Lymphocytic Leukemia Cells Express CD38 in Response to Th1 Cell-Derived IFN-γ by a T-bet-Dependent Mechanism. J Immunol. 194(2):827-35.

Fossum E, Grødeland G, Terhorst D, Tveita AA, Vikse E, Mjaaland S, Henri S, Malissen B, Bogen B. Vaccine molecules targeting Xcr1 on cross-presenting DCs induce protective CD8+ T-cell responses against influenza virus. See comment in PubMed Commons belowEur J Immunol. 2015 Feb;45(2):624-35.

Cardoso I, Stamnaes J, Andersen JT, Melino G, Iversen R, Sollid LM (2015). Transglutaminase 2 interactions with extracellular matrix proteins as probed with celiac disease autoantibodies. FEBS J, 282 (11), 2063-75.

Gopinathan U, Brusletto BS, Olstad OK, Kierulf P, Berg JP, Brandtzaeg P, Øvstebø R (2015). IL-10 immunodepletion from meningococcal sepsis plasma induces extensive changes in gene expression and cytokine release in stimulated human monocytes. Innate Immun. May;21(4):429-49.

www.febsjournal.org

Parkin Restrictions

Ubl

tion by Transglutaminase 2-specific Autoantibodies in Celiac Disease. J Biol Chem, 290 (35), 21365-75.

5/18/2015 3:21:13 PM

Catassi C, Elli L, Bonaz B, Bouma G, Carroccio A, Castillejo G, Cellier C, Cristofori F, de Magistris L, Dolinsek J, Dieterich W, Francavilla R, Hadjivassiliou M, Holtmeier W, Körner U, Leffler DA, Lundin KE, Mazzarella G, Mulder CJ, Pellegrini N, Rostami K, Sanders D, Skodje GI, Schuppan D, Ullrich R et al. (2015). Diagnosis of NonCeliac Gluten Sensitivity (NCGS): The Salerno Experts’ Criteria. Nutrients, 7 (6), 4966-77. Chen X, Hnida K, Graewert MA, Andersen JT, Iversen R, Tuukkanen A, Svergun D, Sollid LM (2015). Structural Basis for Antigen Recogni-

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Grevys A, Bern M, Foss S, Bratlie DB, Moen A, Gunnarsen KS, Aase A, Michaelsen TE, Sandlie I, Andersen JT (2015). Fc Engineering of Human IgG1 for Altered Binding to the Neonatal Fc Receptor Affects Fc Effector Functions. J Immunol, 194 (11), 5497-508. Grødeland, G, Fossum, E, Bogen, B. Polarizing T and B cell responses by APC-targeted subunit vaccines (2015). Front Immunol. Jul 20;6:367. eCollection.

CENTRE FOR IMMUNE REGULATION (CIR)

Hallstensen RF, Bergseth G, Foss S, Jæger S, Gedde-Dahl T, Holt J, Christiansen D, Lau C, Brekke OL, Armstrong E, Stefanovic V, Andersen JT, Sandlie I, Mollnes TE (2015). Eculizumab treatment during pregnancy does not affect the complement system activity of the newborn. Immunobiology. 2015 Apr;220(4):452-9. Hansson KA, Døving KB, Skjeldal FM (2015). Mixed input to olfactory glomeruli from two subsets of ciliated sensory neurons does not impede relay neuron specificity in the crucian carp. J Exp Biol. Oct;218(Pt 20):3257-63. Hellerud BC, Olstad OK, Nielsen EW, Trøseid AM, Skadberg Ø, Thorgersen EB, Vege Å, Mollnes TE, Brandtzæg P (2015). Massive Organ Inflammation in Experimental and in Clinical Meningococcal Septic Shock. Shock. Nov;44(5):458-69. Huszthy PC, Sakariassen PØ, Espedal H, Brokstad KA, Bjerkvig R, Miletic H (2015). Engraftment of Human Glioblastoma Cells in Immunocompetent Rats through Acquired Immunosuppression. PLoS One, 10 (8), e0136089.

in surgical pancreatic tail resections from patients at onset of type 1 diabetes. Diabetologia. Kuczkowska K, Mathiesen G, Eijsink VG, Øynebråten I (2015). Lactobacillus plantarum displaying CCL3 chemokine in fusion with HIV-1 Gag derived antigen causes increased recruitment of T cells. Microb Cell Fact, 14 (1), 169. Løset GÅ, Berntzen G, Frigstad T, Pollmann S, Gunnarsen KS, Sandlie I (2015). Phage Display Engineered T Cell Receptors as Tools for the Study of Tumor Peptide-MHC Interactions. Front Oncol, 4, 378. Kine M. K. Sand

Lundin KE, Qiao SW, Snir O, Sollid LM (2015). Coeliac disease - from genetic and immunological studies to clinical applications. Scand J Gastroenterol, 50 (6), 708-17. Malmström K, Malmberg LP, O’Reilly R, Lindahl H, Kajosaari M, Saarinen KM, Saglani S, Jahnsen FL, Bush A, Haahtela T, Sarna S, Pelkonen AS, Mäkelä MJ (2015). Lung function, airway remodeling, and inflammation in infants: outcome at 8 years. Ann Allergy Asthma Immunol, 114 (2), 90-6.

Haabeth OA, Tveita A, Fauskanger M, Hennig K, Hofgaard PO, Bogen B (2015) Idiotype-specific CD4(+) T cells eradicate disseminated myeloma Leukemia advance online publication 10 November 2015.

Matthes T, Manfroi B, Zeller A, Dunand-Sauthier A, Bogen B, Huard B (2015). Autocrine amplification of immature myeloid cells by IL-6 in multiple myeloma-infiltrated bone marrow. Leukemia, Sep;29(9):1882-90.

Iversen R, du Pré MF, Di Niro R, Sollid LM (2015). Igs as Substrates for Transglutaminase 2: Implications for Autoantibody Production in Celiac Disease. J Immunol, 195: 5159-5168..

Nagy G, Huszthy PC, Fossum E, Konttinen Y, Nakken B, Szodoray P (2015). Selected Aspects in the Pathogenesis of Autoimmune Diseases. Mediators Inflamm, 2015:351732.

Johansen JN, Vartdal F, Desmarais C, Tutturen AE, de Souza GA, Lossius A, Holmøy T (2015). Intrathecal BCR transcriptome in multiple sclerosis versus other neuroinflammation: Equally diverse and compartmentalized, but more mutated, biased and overlapping with the proteome. Clin Immunol, 160 (2), 211-25.

Nakken B, Nagy G, Huszthy PC, Fossum E, Konttinen Y, Szodoray P (2015). Inflammatory Mediators in Autoimmunity and Systemic Autoimmune Diseases. Mediators Inflamm. 2015:878712.

Kikuchi J, Koyama D, Wada T, Izumi T, Hofgaard PO, Bogen B, Furukawa Y (2015). Phosphorylation-mediated EZH2 inactivation promotes drug resistance in multiple myeloma. J Clin Invest. 2015;125(12):4375-4390. Krogvold L, Wiberg A, Edwin B, Buanes T, Jahnsen FL, Hanssen KF, Larsson E, Korsgren O, Skog O, Dahl-Jørgensen K (2015). Insulitis and characterisation of infiltrating T cells

ANNUAL REPORT 2015

Ottesen AH, Louch WE, Carlson CR, Landsverk OJ, Kurola J, Johansen RF, Moe MK, Aronsen JM, Høiseth AD, Jarstadmarken H, Nygård S, Bjørås M, Sjaastad I, Pettilä V, Stridsberg M, Omland T, Christensen G, Røsjø H (2015). Secretoneurin is a novel prognostic cardiovascular biomarker associated with cardiomyocyte calcium handling. J Am Coll Cardiol, 65 (4), 339-51.

CENTRE FOR IMMUNE REGULATION (CIR)

49 Kristin S. Gunnarsen

Jorunn Stamnæs

Rashidian M, Keliher EJ, Bilate AM, Duarte JN, Wojtkiewicz GR, Jacobsen JT, Cragnolini J, Swee LK, Victora GD, Weissleder R, Ploegh HL (2015). Noninvasive imaging of immune responses. Proc Natl Acad Sci U S A, 112 (19), 6146-51. Rentka A, Hársfalvi J, Berta A, Köröskényi K, Szekanecz Z, Szücs G, Szodoray P, Kemény-Beke Á (2015). Vascular Endothelial Growth Factor in Tear Samples of Patients with Systemic Sclerosis. Mediators Inflamm. 2015:573681.

during Homeostasis and Inflammation: Strong Species Differences. J Invest Dermatol. Jul;135(7):1771-80. Terhorst D , Fossum E, Baranska A, Tamoutounour S, Malosse C, Garbani M, Braun R, Winteler R, Crameri R, Bogen B , Henri S , Malissen B (2015). Laser-assisted intradermal delivery of vaccines specific for cross-presenting XCR1+ dendritic cells induces anti-tumoral responses. J Immunol, 15;194:5895-902.

Sand KM, Bern M, Nilsen J, Noordzij HT, Sandlie I, Andersen JT (2015). Unraveling the Interaction between FcRn and Albumin: Opportunities for Design of Albumin-Based Therapeutics. Front Immunol, 5, 682.

Tveita AA, Schjesvold F, Haabeth OA, Fauskanger M, Bogen B (2015). Tumors Escape CD4+ T-cell-Mediated Immunosurveillance by Impairing the Ability of Infiltrating Macrophages to Indirectly Present Tumor Antigens. Cancer Res, 75 (16), 3268-78.

Skrindo I, Ballke C, Gran E, Johansen FE, Baekkevold ES, Jahnsen FL (2015). IL-5 production by resident mucosal allergen-specific T cells in an explant model of allergic rhinitis. Clin Exp Allergy, 45 (8), 1296-304.

Volta U, Caio G, De Giorgio R, Henriksen C, Skodje G, Lundin KE (2015). Non-celiac gluten sensitivity: a work-in-progress entity in the spectrum of wheat-related disorders. Best Pract Res Clin Gastroenterol, 29 (3), 477-91.

Snir O, Mesin L, Gidoni M, Lundin KE, Yaari G, Sollid LM (2015). Analysis of celiac disease autoreactive gut plasma cells and their corresponding memory compartment in peripheral blood using high-throughput sequencing. J Immunol, 194 (12), 5703-12.

Øynebråten I, Barois N, Bergeland T, Küchler AM, Bakke O, Haraldsen G (2015). Oligomerized, filamentous surface presentation of RANTES/CCL5 on vascular endothelial cells. Sci Rep, 5, 9261.

Ole-Audun W. Haabeth

Espen S. Bækkevold

Omri Snir

Sollid LM, Iversen R, Steinsbø Ø, Qiao SW, Bergseng E, Dørum S, du Pré MF, Stamnaes J, Christophersen A, Cardoso I, Hnida K, Chen X, Snir O, Lundin KE (2015). Small bowel, celiac disease and adaptive immunity. Dig Dis, 33 (2), 115-21.

Aase A, Sommerfelt H, Petersen LB, Bolstad M, Cox RJ, Langeland N, Guttormsen AB, Steinsland H, Skrede S, Brandtzaeg P (2015). Salivary IgA from the sublingual compartment as a novel noninvasive proxy for intestinal immune induction. Mucosal Immunology advance online publication 28 October 2015.

Stamnaes J, Iversen R, du Pré MF, Chen X, Sollid LM (2015). Enhanced B-Cell Receptor Recognition of the Autoantigen Transglutaminase 2 by Efficient Catalytic Self-Multimerization. PLoS One, 10 (8), e0134922.

Books and book chapters

Stamnaes J, Sollid LM (2015). Celiac disease: Autoimmunity in response to food antigen. Seminars in Immunology 27 (2015) 343–352. Steinsbø Ø, Dørum S, Lundin KE, Sollid LM (2015). Serologic Assay for Diagnosis of Celiac Disease Based on a Patient-Derived Monoclonal Antigliadin Antibody. Gastroenterology, 149 (6), 1530-1540.e3. Sundnes O, Pietka W, Loos T, Sponheim J, Rankin AL, Pflanz S, Bertelsen V, Sitek JC, Hol J, Haraldsen G, Khnykin D (2015). Epidermal Expression and Regulation of Interleukin-33

ANNUAL REPORT 2015

Brandtzaeg P. The mucosal B-cell system. Chapter 31, pp. 623-681. In: Mucosal Immunology, 4th Edition (Eds.: Mestecky J, Strober W, Russell MW, Cheroutre H, Lambrecht BN and Kelsall BL), Academic Press/Elsevier, Amsterdam, 2015. (ISBN: 978-0-12-415847-4). Brandtzæg P. Immunobiology of tonsils and adenoids. Chapter 103, pp.1985-2016. In: Mucosal Immunology, 4th Edition (Eds.: Mestecky J, Strober W, Russell MW, Cheroutre H, Lambrecht BN and Kelsall BL), Academic Press/Elsevier, Amsterdam, 2015. (ISBN: 978-012-415847-4).

CENTRE FOR IMMUNE REGULATION (CIR)

Mandecki W, Goldman E, Sandlie I, Løset GÅ. Phage Display and Selection of Protein Ligands. Chapter 9: 101-114. Practical Handbook of Microbiology, 3rd ed, 2015 (CRC Press). (ISBN: 978-14-6658-739-7) Osnes LT, Bogen B: Primære immundefekter. Klinisk Biokjemi og Fysiologi (Eds. Tor-Arne Hagve and Jens Pettter Berg), 5. edition, Oslo 2015, pp147-154. ISBN/EAN: 9788205463677 Tjønnfjord GE, Bogen B: Myeloproliferative og lymfoproliferative sykdommer. Klinisk Biokjemi og Fysiologi (Eds. Tor-Arne Hagve and Jens Pettter Berg), 5. edition, Oslo 2015, pp140146. ISBN/EAN: 9788205463677

Patents and patent applications PATENTS 2007-2015 ACCUMULATED (SORTED ALPHABETICALLY BY TITLE) • A humanized antibody against CD14, PCT/ US14/31402. Filed 21.03.2014, Tom Eirik Mollnes; Terje Espevik; Inger Sandlie; Kristin Gunnarsen; Corinne Lau • Albufuse mutations (EP11164989.3) Andersen JT and Sandlie, I (with Novozymes). • Albufuse2 Domain III extreme C-terminal (EP11164955.4) Andersen JT and Sandlie I (with Novozymes). • Albumin combination mutants (EP12177916.9 and EP12191859.9) Andersen JT and Sandlie, I. • Albumin derivatives and variants (WO2011124718 A1) Andersen JT and Sandlie I (with Novozymes). • Albumin variants (EP10159450.5) Andersen JT and Sandlie I (with Novozymes). • Albumin variants (WO2011051489 A2) Andersen JT and Sandlie I (with Novozymes). • Albumin variants (WO2012059486 A1) Andersen JT and Sandlie I (with Novozymes). • Albumin variants (WO2012150319 A1) Andersen JT and Sandlie I (with Novozymes). • Albumin variants fused to immunogens (AlbuVax) for improved transcellular delivery (61033-13082-US-P) Sandlie I, Andersen JT and Bern M.

ANNUAL REPORT 2015

• Albumin variants fused to immunogens (AlbuVax) for improved transcellular delivery, US 61/936,442, filed 06.02.2014, Jan Terje Andersen; Malin Bern; Inger Sandlie • Detection of gluten specific T cells (U.S. Provisional Patent Application Serial No. 61/823,072)¬¬¬ Sollid LM, Qiao SW, Christophersen A and Lundin KEA. Submitted to national in EP, US, AU, CA • Disulphide bond-stabilized functional soluble MHC class II heterodimers (WO2011/101681) Løset GÅ, Frigstad T, Sandlie I and Bogen B. • Homodimeric protein constructs (WO2010/61358513, EP10167291.3) Ruffini PA, Fredriksen A and Bogen B. • Identification of antibodies in mucosal cells (PCT/US2015/027315)) Di Niro R, Sollid LM and Wilson PC. • Method for screening phage display libraries against each other (WO2010/097589) Reiersen H, Løset GÅ, Hagemann UB and Owen D. • Methods of treating or preventing inflammatory disease of the intestinal tract (PCT/ GB2008/003850). Johansen F-E, Sandvik A and Engstad RE. • Modulation of albumin half-life (EP9174698.2) Andersen JT and Sandlie I. • Multivalent phage display systems and methods (WO2011/036555) Løset GÅ and Sandlie I. • New fusion proteins for the treatment of allergic diseases. (US patent no 9,005,630 B2.) Publication date Apr. 14, 2015. Inventors Maaike Dooper, Heidi Ragnhild Myrset, Bjarne Bogen. Filed by Veterinærinstituttet. • pVII phage display (WO2009/024591) Løset GÅ. • Signal sequence –independent pIX phage display (WO2010/097411) Løset GÅ. • Targeting of vaccine antigen to an intracellular compartment, Filed 22.06.2015, US62/182,737, I Øynebråten, AN Andersen, B Bogen • Vaccibodies targeted to cross-presenting dendritic cells (US serial no: 61538,186) Bogen B, Fossum E and Grødeland G.

CENTRE FOR IMMUNE REGULATION (CIR)

Malin C. Bern

ANNUAL REPORT 2015

CENTRE FOR IMMUNE REGULATION (CIR)

dissemination 53

ANNUAL REPORT 2015

CENTRE FOR IMMUNE REGULATION (CIR)

Invited lectures Andersen JT: «Inspired by nature: engineering and delivery of novel protein therapeutics». 47th Sandbjerg Meeting on Membrane Transport, May 18-20, Denmark (invited speaker) Andersen JT: «Fra molekylær grunnforskning til innovasjon og skreddersydd medisin». Inven2’s 5 years anniversary, June 4, Oslo, Norway (invited speaker). Andersen JT: «Cellular assays for evaluation of FcRn-mediated transport». Roche Diagnostics GmbH, Pentzberg, November 26, Germany (invited speaker). Andersen JT: «Inspired by nature: engineering and delivery of novel protein therapeutics». Department of Immunology Seminar, October 15, Hotell Bristol, Norway (invited speaker). Per Brandtzæg

Andersen JT: «Design of novel tailor-made proteins for therapeutic applications and studies of immunity». Department of Pharmacology, research seminar, November 18, Bygdøystuene, Oslo (invited speaker). Andersen JT: «Design of novel tailor-made proteins for therapeutic applications and studies of immunity». Section for Biochemistry and Molecular Biology (BMB), Retreat seminar, August 21, Eilert Sundts hus, Oslo (invited speaker).

Ibon Eguiluz Gracia

Andersen JT: «Fra molekylær grunnforskning til innovasjon og skreddersydd medisin Lege middel». Seminar i regi av Biotekforum og Legemiddelindustrien (LMI): Hvordan skape næringsutvikling innenfor biomedisinsk industri i Norge? February 26, Oslo (invited speaker). Andersen JT: «OUS Early Career Award 2015». Oslo University Hospital, April 24, Rikshospitalet, (prize lecture). Andersen JT: «A ladder to heaven?».Oslo University Hospital Career building grants for young researchers, November 11, Oslo (prize lecture). Bakke O: «Advanced live cell imaging». Celebration Symposium Light & Life, International Year of Light, Italian Physical Society, July 20-22, Varenna, Italy (invited speaker). Bakke O: «Imaging av levende celler». October 23, Ullevål sykehus, Oslo (invited speaker). Bogen B: «Immunosurveillance of cancer – what features should novel cancer vaccines have?» Cancer Immunotherapy conference, October 21-22, Kleivstua, Norway (invited speaker).

ANNUAL REPORT 2015

Brandtzaeg P: «IgA response in the mucosa». 2nd Hengstberger Symposium: «Microbial Sensors in the B Lymphocyte Response», January 7-8, Heidelberg, Germany (invited speaker). Brandtzaeg P: «Taking advantage of mucosal immunology: Can we use it to induce tolerance?» XIV International Small Bowel Transplant Symposium (ISBTS), June 12, Buenos Aires (invited speaker). Brandtzaeg P: «History of mucosal immuolgy: Secretory immunity and oral tolerance». Opening lecture of pre-school day, ICCMI2015 (International Congress of Mucosal Immunity), July 15, Berlin, Germany (invited speaker). Brandtzaeg P: «Impact of intestinal immune induction on compartmentalized IgA production in submandibular/sublingual salivary glands». Mucosal imunity, Symposium SC01-Innate Imunity ECI2015 (European Congress of Immunology), September 7, Vienna, Austria (invited speaker). Eguíluz-Gracia I: JM Scientific Symposium: Experimentally-induced early recruitment of CD14+monocytes in allergic rhinitis in humans. European Academy of Allergy and Clinical Immunology (EAACI) Annual Meeting, June 6-10, Barcelona, Spain (invited speaker). Haugen L: «En ny æra for lysmikroskopi». Det Norske Vitenskapsakademi, Fagsymposium Lysets år, November 11, Oslo (invited speaker). Jahnsen FL: «Immunological mechanisms in allergic rhinitis». The 10th Symposium on Specific Allergy, November, Rome (invited speaker). Jahnsen FL: «Antigen-presenting cells – Year of Immunology in Review». European Academy of Allergy and Clinical Immunology (EAACI) Annual Meeting, June 6-10, Barcelona, Spain (invited speaker). Lundin KE: «Non-celiac gluten sensitivity». Scientific Forum International Coeliac Disease Symposium, June 20, Prague, Czech republik (invited speaker). Lundin KE: «Non-celiac gluten sensitivity». Clinical Forum International Coeliac Disease Symposium, June 21, Prague, Czech republik (invited speaker). Lundin KE: «Non-celiac gluten sensitivity». Patient Forum International Coeliac Disease Symposium, June 22, Prague, Czech republik (invited speaker).

CENTRE FOR IMMUNE REGULATION (CIR)

Lundin KE: «Non-celiac gluten sensitivity is real!» Gastrodiet conference, November 3, Prato, Italy (invited speaker). Lundin KE: «Non-celiac gluten sensitivity». SAGIM meeting, November 20, Copenhagen, Denmark (invited speaker). Løset GÅ: «Engineered T Cell Receptors as Tools for the Study of Peptide-MHC Interactions», Phage Display of Therapeutic Antibodies PEGS Europe 2015, November 2-4, Lisbon, Portugal, (Invited speaker) Munthe LA: «Excellence in Recruitment», for the Deans Faculty seminar, May, Oslo (invited speaker). Munthe LA: «Core Facilities and Research Excellence», October, University of Vilnius, Lithuania (invited speaker). Munthe LA: «Immunotherapy of B cell cancers» - Strategic Initiative for Immunotherapy, November 2015 (invited speaker). Sandlie I: «How to move academic innovation to the next level? University perspective». NORIN, OCC and Oslo MedTech seminar, September 20, University of Oslo, Oslo (invited speaker). Sandlie I: «Biologiske legemidler». Biotorsdag. September 24. Universitetsbiblioteket, Universitetet i Oslo, Oslo (invited speaker). Sandlie I: «Strategies to promote innovative research and academic – industry partnerships». Seminar med UiO ledelsen, Stortingets kirkeforskning- og utdanningskomite og forskningsledere ved Brigham and Women and Harvard University, November 3, Boston, USA (invited speaker). Sandlie I: «New perspective on IgG function». Department of Immunology and Microbiology, Copenhagen University, January 30, Copenhagen, Denmark (invited speaker). Sandlie I: «Albumin as fusion partner improves drug efficacy». Seminar with Biogen and Swedish Orphan Biovitrum AB. December 2, Marlow Hotel Cambridge, Boston, USA (invited speaker). Sandlie I: «New perspective on IgG function». Harvard Digestive diseases center, December 9, Boston, USA (invited speaker). Sandlie I: «Human IgG in intracellular immunity». The Gastroenterology Division at Brigham and Women's Hospital, December 21, Boston, USA (invited speaker).

ANNUAL REPORT 2015

Skjeldal FM: «Endosomal binding kinetics of Eps15 and Hrs regulate the degradation of RTKs». NBS vintermøte Svalbard. February 13-15, Svalbard (invited speaker). Skjeldal FM: «Den dynamiske cellen», Bio Torsdag, November 26, Blindern, Oslo (invited speaker). Sollid LM: 33rd Norwegian Society for Immunology Annual Meeting. November 12, Oslo (honorary member lecture). Sollid LM: Anders Jahre’s Award Lecture: «On autoimmunity: Lessons from celiac disease», October 14, University of Oslo, Oslo (prize lecture). Sollid LM: «Understanding the initiation of chronic tissue inflammations: lessons from coeliac disease», 9th Eur Workshop on ImmuneMediated Inflammatory Diseases, September 2-4, Amsterdam, Netherland (invited keynote speaker). Sollid LM: «Genetic control of immune cell activation. Implications for pathogenesis of disease», Functional HLA genetics of Celiac Disease, August 20-23, Henningsvær, Norway (invited speaker). Sollid LM: 17th International Congress of Mucosal Immunology: Food Allergy/Celiac disease. July 14-18, Berlin, Germany (invited session chair, introductory speaker). Sollid LM: 16th International Celiac Disease Symposium, Scientific Forum: B cells and celiac disease, June 21-24, Prague, Czech Republic (invited speaker). Sollid LM: 16th International Celiac Disease Symposium, Clinical Forum: Progress in non-dietary therapies, June 21-24, Prague, Czech Republic (invited speaker). Sollid LM: Nobel Symposium. Adaptive immunity: defence and attack: «The autoantibody response of celiac disease», June 10-13, Stockholm, Sweden (invited speaker). Sollid LM: «Rationales behind novel therapies in coeliac disease» Coeliac disease: prevention and therapeutic advances, Coeliac UK meeting, March 11, London, United Kingdom (invited speaker). Sollid LM: «Celiac disease: HLA genetics and beyond». Seminar sfr Necker Hospital, Feb 9, Imagine institute, Paris, France (invited speaker).

CENTRE FOR IMMUNE REGULATION (CIR)

Stian Foss

Oral presentations

Poster presentation

Brandtzaeg P: «IgA in saliva as a surrogate for intestinal immune response against experimental enterotoxigenic Escherichia coli (ETEC) infection». The 9th Conference on Global Health and Vaccination Research, March 17-18 (oral presentation).

Qiao SW: Healthy HLA-DQ2.5+ individuals do not mount T-cell responses to gluten epitopes. 16th International Coeliac Disease Symposium, June 21–24, Prague, Czech Republic (poster presentation).

Bujko A: Blood CD14+ Monocytes Constantly Replenish Mature Macrophages in Human Small Intestine. 17th International Congress of Mucosal Immunology, July 14-18, Berlin, Germany (oral presentation). Eguíluz-Gracia I: Recipient-derived monocytes contribute to the population of alveolar macrophages in lung transplanted patients without rejection. EAACI 13th Winter School in Allergy and Basic Immunology Research, February 5-8, Les Arcs, France (oral presentation).

Duarte Nunes De C Mateus

Foss S: «Human IgG3 is a superior mediator of intracellular antiviral immunity».NSI 33rd Annual Meeting and General Assembly November 12, (oral presentation, prize for outstanding talk. Mateus D: «Sorting through SNX1 tubes regulates endosome maturation». NBS Contact Meeting, February 13-15, Svalbard, Norway (oral presentation). Noordzij HT: «iGEM competition». Realfagsdag, Norges Tekniske Vitenskapsakademi, October 21, Oslo (oral presentation).

Dahal-Koirala S: Characterization of T-cell receptor repertoire of DQ2.5-glia-α2 and DQ2.5glia-ω2 –reactive T cells. 16th International Coeliac Disease Symposium, June 21–24, Prague, Czech Republic (poster presentation). Du Pré FM: «Cooperation between gluten-specific B cells and gluten-specific T cells in celiac disease». 16th International Coeliac Disease Symposium, June 21–24, Prague (Poster presentation). Dørum S: «Gliadin-specific mAbs of gut plasma cells recognize long peptides with repeated motifs» 16th International Coeliac Disease Symposium, June 21–24, Prague (Poster presentation). Eguiluz-Gracia I: «The mononuclear phagocyte system in experimentally-induced allergic rhinitis in humans». EAACI International Symposium on Molecular Allergology, November 19-21, Lisbon, Portugal (poster presentation). Gruber L: «Human small intestinal SIRPa+CD103+CD1a+ dendritic cells display putative immunoregulatory features». 9th Word Immune Regulation Meeting, March 18-21, Davos, Switzerland (poster presentation).

Hanna Noordzij

Noordzij HT: «iGEM competition». BIO-konferansen, November 6, Oslo (oral presentation). Risnes LF: «Gluten-reactive T-cell clonotypes persist in blood and gut on a gluten-free diet and expand after gluten challenge». NSI annual meeting, November, Oslo (oral presentation).

Louise Fremgaard Risnes

Qiao SW: Direct ex vivo characterisation of antigen-specific T cells in coeliac disease. Workshop: Genetic control of immune cell activation, August 21-24, Lofoten, Norway (oral presentation). Sarna V: «Ny blodprøvebasert cøliakitest som er uavhengig av inntak av glutenholdig kost», Norsk Gastroenterologisk forenings årsmøte, February 6, Lillehammer (oral presentation)

Gunnarsen KS: «Characterization of the T cell response against immunodominant DQ2.5 epitopes in coeliac disease». 16th International Coeliac Disease Symposium, June 21–24, Prague, Czech Republic (poster presentation). Høydahl LS: DuPre F, Bergseng E, Gunnarsen KS, Qiao SW, Sollid LM, Sandlie I, and Løset GÅ. Isolation and characterization of DQ2.5-glia-α1aspecific antibodies. 16th International Coeliac Disease Symposium, June 21–24, Prague, Czech Republic (poster presentation). Iversen R: «Proteomic analysis of anti-transglutaminase 2 autoantibodies in celiac disease». Workshop on: Genetic control of immune cell activation. Implications for autoimmune disease. August 20-24, Henningsvær, Lofoten (poster presentation). Kjos I: «The small GTPase Rab7b negatively regulates autophagy». EMBO Conference «Autophagy signaling and progression in health and disease», September 9-12, Chia, Italy (poster presentation).

Vikas K. Sarna

ANNUAL REPORT 2015

CENTRE FOR IMMUNE REGULATION (CIR)

Koirala SD: «Characterization of T-cell receptor repertoire of DQ2.5-glia-α2 and DQ2.5-glia-ω2– reactive T cells». 16th International Coeliac Disease Symposium, June 21–24, Prague, Czech Republic (Poster presentation). Landsverk OJB: «Plasma cells are long-lived in human small intestine». Word Immune Regulation Meeting, March 18-21, Davos, Switzerland (poster presentation). Mensali N: «Invariant chain as a vaccination vehicle for colorectal cancer». 13th CIMT Annual meeting, May 11-13 2015, Mainz, Germany (poster presentation). Noordzij HT: «Transport of albumin and immunoglobulin G in the human placenta». Department of Immunology seminar, Hotell Bristol, October 15, Oslo (iPAD presentation). Richter L: Monocytes give rise to SIRPa+ Dendritic cells in the human small intestine. CFCD (Club Francophone des Cellules Dendritiques) Annual Meeting, December 7-8, Paris, France (poster presentation). Risnes LF: «Comprehensive TCR repertoire analysis of CD4+T cells in gut and blood after 14day gluten challenge» 16th International Coeliac Disease Symposium, 21–24 June 2015, Prague, Czech Republic (poster presentation). Stamnæs J: «Enhanced B-cell receptor recognition of the autoantigen TG2 by enzymatic catalytic self-multimerization» 16th International Coeliac Disease Symposium, June 21–24, Prague, Czech Republic (poster presentation). Szodoray P: «Incomplete Tolerance in Anergic B Cells in SLE: T Helper Signals Restore B Cell Receptor Signaling in Autoreactive Anergic B Cells by Upregulating CD45 Phosphatase Activity». American College of Rheumatology Annual Meeting, November 6-11, San Francisco, USA (poster presentation).

Presentation to a targeted audience and the public Brandtzaeg P: «Morsmelkens immunologi». Kurs om amming, Nasjonal kompetansetjeneste for amming, Kvinne- og barneklinikken, Oslo Universitetssykehus Rikshospitalet, November 4, Oslo (invited speaker).

ANNUAL REPORT 2015

Brandtzaeg P: «Minnetale over professor dr. med. Torstein Hovig». Det Norske VidenskapsAkademi (DNVA), November 19, Oslo (invited speaker). Lundin KE: «Gluten sensitivitet». UiO Med Fak 200 års jubileum, Universitetets aula, March 18, Oslo (invited speaker). Lundin KE: «Nytt om cøliaki og glutensensitivitet». Norsk cøliakiforening, September 21, Trondheim (invited speaker). Lundin KE: «Nytt om cøliaki og glutensensitivitet». Norsk cøliakiforening, September 28, Bergen (invited speaker). Munthe LA: «Dermatology in next centennial», for the 100 year anniversary of The Dermatology and Venerology Assoc., November, Oslo (invited speaker).

Lisa M. Richter

Richter L: «Pathology behind the scenes», blog by Lisa Richter http://lisa-richter.de/?m=201510 Sandlie I: «Biologiske legemidler». Legemiddel– verket, February 26, Oslo (invited speaker).

Sandlie I: «Forsknings- og teknologisentre for framtiden ved Universitetet i Oslo». NHO seminar, April 10, Middelthunsgt. Oslo (invited speaker). Sandlie I: «Nye biologiske legemidler». Viten på lørdag, Realfag og teknologi, June 2015, Gamle festsal, Universitetet i Oslo, Oslo (invited speaker).

Christina Ballke

Media coverage Ludvig Sollid, interview in Genomeweb, New York: «Oslo Team Uses Mass Spec to Characterize Gluten Peptide Binding in HLAs Linked to Celiac Disease». January 7, 2015. https://www. genomeweb.com/proteomics-protein-research/ oslo-team-uses-mass-spec-characterize-glutenpeptide-binding-hlas-linked Christina Hoffmann, Espen Bækkevold, and Frode Jahnsen: «Treatment against seasonal hay fever should be initiated prior to season, Norwegian study shows why». May 4-6, 2015. Medical news today (MNT) http://www.medicalnewstoday.com/releases/293469.php and Science Daily http://www.sciencedaily.com/ releases/2015/05/150504103421.htm.

CENTRE FOR IMMUNE REGULATION (CIR)

Knut E.A. Lundin

Knut Lundin as expert commentary in Washington post: «For many, gluten isn’t the villain it gets cracked up to be», June 29, 2015. http://www. washingtonpost.com/national/health-science/ for-many-gluten-isnt-the-villain-it-gets-crackedup-to-be/2015/06/29/9a0f3396-e9fd-11e4-9a6ac1ab95a0600b_story.html? postshare=3961435660855014 Knut Lundin as expert commentary in VG: «Synd at en så ung jente som deg kan være så syk», July 1, 2015. http://www.vg.no/forbruker/ matintoleranse-og-allergier/synd-at-en-saa-ungjente-som-deg-kan-vaere-saa-syk/a/23456914/. Interview with CIR members: Livets harde universitet. Universitas, August 22, 2015. http://universitas.no/kultur/60727/livets-harde-universitet Hanna Theodora Noordzij: Vitenskap & Historie, Nr 3 2015 (July/August), Norway "Fremtidens medisinske og biologiske revolusjon. Programmerbare bakterier» http://2015.igem. org/wiki/images/1/12/UiOslo_Vitenskap_Historie_iGEM.pdf

Hanna Theodora Noordzij: «På laboratoriet kan forskere i dag lage selvlysende trær. Men vil det straffe seg å leke gud? Skaperverkstedet» Klassekampen, August 29-30 2015, Norway. http://2015.igem.org/wiki/images/d/d4/UiOslo_ klassenkampen.pdf Asbjørn Christophersen and Knut Lundin: Story in NRK, Dagsrevyen, regarding new test of celiac disease. September 20, 2015. http://www.nrk.no/ norge/ny-coliaki-test-sparer-deg-for-gastroskopi-1.12554365. Asbjørn Christophersen: «Ny blodprøve kan gi enkel test for cøliaki». Forskning.no, September 20, 2015. http://forskning.no/helse-mat-allergi/2015/09/ny-blodprove-kan-gjore-det-enkeltteste-coliaki Nextera AS in collaboration with Janssen Biotech Inc. Press release and commentary on the Oslo Cancer Cluster homepage, September 21, 2015. http://www.businesswire.com/news/ home/20150921005528/en/Nextera-AnnouncesResearch-Collaboration-Johnson-Johnson-Innovation%20-%20.Vf_VCnY4XvU http://oslocancercluster.no/2015/09/21/nextera-as-announcesresearch-collaboration-with-johnson-johnsoninnovation/.

Hanna Theodora Noordzij: «iGEM UiO 2015-verdensmesterskap i syntetisk biologi» NRK EKKO, September 23-24, 2015, Norway. Podcast: http:// nl.nrk.no/podkast/aps/20062/NRKLT66020_9B17 68E8B40D43A0A5F688BE43271CAF.MP3 Jan Terje Andersen: «Ung forsker vant pris», Dagens Medisin, September 24, 2015. http:// www.dagensmedisin.no/artikler/2015/09/24/ ung-forsker/ Jan Terje Andersen: Promoting the new Life Science building in Gaustadbekkdalen to the Director of Innovation Norway October 15, 2015. Blog: http://morten.ifi.uio.no/?p=18096 Asbjørn Christophersen: «Q&A with researcher: Simplified diagnosis of celiac disease». Beyond celiac, Research News, October 26, 2015. http:// www.beyondceliac.org/research-news/ViewResearch-News/1394/postid--16332/ Asbjørn Christophersen: «Ny blodprøve kan lette diagnostisering av cøliakere». Norsk cøliakiforening, glutenFRI no. 4-2015, p6-7. http:// digital.findexaforlag.no/i/605886-glutenfriutgave-4-2015 Ludvig M. Sollid: Månedens innovatør i Helse Sørøst. November 2015. http://www.helsesorost.no/aktuelt_/nyheter_/Sider/Innovatørennovember-2015.aspx Jan Terje Andersen: «Fremragende forskere hedret med pris». http://www.oslo-universitetssykehus.no/aktuelt_/nyheter_/Sider/ Fremragende-forskere-hedret-med-pris.aspx Jan Terje Andersen: Promoting «Hjernekraft»kampanjen at Forskerforbundet. https://www. forskerforbundet.no/Global/hjernekraftverk/ Forskerportrett2.pdf Jan Terje Andersen: «Fridtjof Nansens belønning for fremragende forskning». http://www.dnva. no/nyheter/vis.html?tid=63603

Knut Lundin and Ludvig Sollid in NRK Radio, nyhetsmorgen: «Cøliakipille i anmarsj». September 23, 2015. https://radio.nrk.no/ serie/nyhetsmorgen/NPUB50018915/23-092015#t=35m28s

ANNUAL REPORT 2015

CENTRE FOR IMMUNE REGULATION (CIR)

8 Trykksak 6

Ø M E R KE T ILJ

Redaktør: Lise Kveberg, UiO Foto©UiO: Øystein Horgmo, Yngve Vogt, Kristin Ellefsen, Lise Kveberg Design: Millimeterpress/Lise Myhre. Trykk: Rolf Ottesen

Annual Report

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

2010

Centre for Immune Regulation (CIR) Phone (+47) 23 07 35 00 Fax (+47) 23 07 35 10 Email post@cir.uio.no www.cir.uio.no