JIRC: Two years of operation by Millimeterpress as

Jebsen Inflammation Research Centre

Two years of operation

TWO YEARS OF OPERATION

JEBSEN INFLAMMATION RESEARCH CENTER (JIRC)

contents Vision statement 4 Main accomplishments 2013–2015 5 Director’s comments 6 Scientific currency 8 Innovation 10 Norwegian Inflammation Network 12 research groups Aukrust/Yndestad group Haraldsen group Karlsen group Kvale group Lie group Mollnes group Olweus group Taskén/Aandahl group

10 20 22 24 28 30 32 36

activities NORIN seminars National Microbiota Conference Internal activities

42 43 43

young investigator profiles Young Investigator Profiles

about JIRC Facts and figures – overview of JIRC 52 Scientific Advisory Board 53 Staff 54 Collaboration – national and international 56 Funding 60 publications Publications

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JEBSEN INFLAMMATION RESEARCH CENTER (JIRC)

Vision statement CHRONIC INFLAMMATION AFFECTS A LARGE FRACTION OF THE POPULATION AND FREQUENTLY LEADS TO SEVERE DYSFUNCTION, FIBROSIS AND ORGAN FAILURE. WITH THE GOAL OF IMPROVING TREATMENT, THE VISION OF THE K.G. JEBSEN INFLAMMATION RESEARCH CENTRE IS TO ADDRESS SOME SIMPLE, BUT BIG AND YET UNRESOLVED QUESTIONS ESSENTIAL FOR UNDERSTANDING MECHANISMS OF CHRONIC INFLAMMATORY DISEASES:

n Why does inflammation not

n How does inflammation progress

resolve? – what determines whether inflammation is transient or becomes chronic?

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to fibrosis? – to what extent do disease-specific factors and individual patient susceptibility drive chronic inflammatory processes to tissue destruction and scarring rather than to repair?

JEBSEN INFLAMMATION RESEARCH CENTER (JIRC)

MAIN ACCOMPLISHMENTS 2013â&#x20AC;&#x201C;2015 n Developed HLA sequencingn Identified role of NLRP3

methods based on highthroughput technology and delineation of the HLA association in PSC and IBD n Development of a complete

in-house platform for gut microbiota profiling and demonstration of a unique microbial profile in multiple patient groups

inflammasome in myocardial ischemia-reperfusion. n Identified role of Notch

signalling in proinflammatory responsiveness of endothelial cells n Demonstration that combined

inhibition of complement and CD14 improves survival in experimental sepsis

n Proof-of-concept that

microsphere affinity proteomics can efficiently screen and identify proteome-wide targets for auto-antibodies found in autoimmune disease.

n First intervention study targeting

gut microbiota in HIV and showing favourable modulation of proinflammatory markers n Secondary preventive effect

n Novel technology for high-

throughput detection of T-cell epitopes and the T-cell receptors recognizing them

of ASA in colorectal cancer examined in a registry-based study with 23,000 patients and showing reduced cancerspecific and overall mortality

n Discovery of lipid antigen

presentation by biliary epithelium to NKT cells

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n Establishment of the Norwegian

Inflammation Network (NORIN)

JEBSEN INFLAMMATION RESEARCH CENTER (JIRC)

Directorâ&#x20AC;&#x2122;s comments It is a great pleasure to write these comments with respect to the first two years of our operation as a K.G. Jebsen Centre. From a position of combining the very broad expertise of established investigators in the field and developing a wide range of projects of exceptionally high scientific quality, JIRC is now extracting work packages that consolidate the translational value of the investment and serve to demonstrate the added value of Jebsen-funding.

JIRC is in the midst of identifying and validating putative biomarkers and therapies. We are currently identifying exciting, putative anti-inflammatory targets of semaphorinand Notch signalling, and we are assessing how Toll-like receptor targeting can be combined with inhibition of the complement system. At more advanced stages, we are pursuing a small molecular compound that affects ischemia-reperfusion injury, we are in the midst of assessing the adjuvant effect of COX-2 inhibition in a TB vaccine setting, and we have shown the beneficial effect of aspirin with respect to relapse of colorectal cancer. Another asset of JIRCs success is that our centre proves to provide an optimal setting to train new talents and to develop scientific careers. This is reflected in the fact that several of our young scientists have received career development grants from various sources.

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JIRC returned to ThorbjĂ¸rnrud for the third annual retreat in January, gathering more than 100 participants, including Board Members of the K.G. Jebsen foundation. This retreat is organized by our postdocs who select and invite speakers, organize poster presentations and provide the setting for fruitful scientific discussions and social gatherings. This is another opportunity to thank our invited guests for their contributions, as well as our organizing committees and our

JEBSEN INFLAMMATION RESEARCH CENTER (JIRC)

administrative coordinator, Tara Sarin, for all their efforts. Taken together, it is satisfying to state that JIRC is at the centre of a developing ecosystem that provides the tools to grow, nurture and sustain scientific development, innovation and the careers of a future generation of scientists in the field of inflammation.

DIRECTOR GUTTORM HARALDSEN

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Scientific currency PAPERS JIRC scientists have been highly prolific in the first two years and report some 260 publications, 110 of which are credited the K.G. Jebsen Foundation, testifying that the main body of the work reported has been done since the inception of the centre. Furthermore, 60 of these papers are collaborative papers with two or more PIs, demonstrating the effect of the JIRC scientific leadership strategy for cohesion and collaboration, generating true synergy and added value. PRIZES AND AWARDS JIRC Deputy Director Kjetil Taskén is being awarded the King Olav V’s Prize for Cancer Research for 2016 by the Norwegian Cancer Society for his work on immunotherapy. In 2016, Professor Kreyberg’s prize in pathology was awarded to JIRC postdoctoral fellow, Eirik Sundlisæter. Kreyberg’s prize is awarded for the best doctoral degree dissertation in pathology the last four years. Sundlisæter defended his doctoral thesis “Involvement of Notch signalling in quiescence and inflammatory activation of endothelial cells” in 2013. Professor Pål Aukrust received the prestigious Research Prize from the University of Oslo in 2013 for his ground breaking efforts within the research field of infectious and inflammatory diseases, also in connection with HIV and coronary diseases. Pål Aukrust was also elected to the Norwegian Academy of Science and Letters in 2015, as one of two new members of the group for Physiology and Medicine. The Oslo University Hospital's Excellent Researcher Award 2016 and Early Career Award 2016 were recently awarded to JIRC group leader Pål Aukrust and JIRC researcher Espen Melum, respectively.

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CONTRIBUTION TO THE LOCAL RESEARCH ENVIRONMENT In addition to the productive scientific interactions of new and future collaborations and opportunities, there are several indirect effects of establishing the centre. First, it is worth noting that JIRC scientists are exceptionally successful in their competition for external grants. Second, our incentive to establish NORIN (Norwegian Inflammation Network, see page 12–13) brings inflammation research to the public agenda by inviting decision makers to a forum of interaction, by creating a meeting point for scientists, clinicians, industry and patient organizations suited to develop innovative ideas and increasing translational awareness, as well as nurturing a creative environment. NORIN seminars are open to anyone interested and we actively invite the broader community to attend these events. Patient organizations are strongly involved in inflammation research by being members of NORIN, by being represented in the board of NORIN and by co-hosting an annual NORIN seminar that was arranged for the first time in March 2015. The public profile of NORIN also gives significant visibility to JIRC. Third, we are successfully developing the careers of future group leaders. Several young co-PIs were included in the original application (Yndestad, Aandahl) and additional scientists with a strong potential to become independent scientists have been identified after the establishment of JIRC (Hol, Hov, Melum, Reikvam, Skånland, Trøseid, all presented on pages 46–49). Furthermore, senior postdocs are given the opportunity to supervise students and publish as senior authors and they are enrolled in the mentoring program at the university.

JEBSEN INFLAMMATION RESEARCH CENTER (JIRC)

Photo: Terje Heiestad

JIRC Deputy Director Kjetil Taskén is being awarded the King Olav V’s Prize for Cancer Research for 2016 by the Norwegian Cancer Society for his work on immunotherapy.

Pål Aukrust was elected to the Norwegian Academy of Science and Letters in 2015, as one of two new members of the group for Physiology and Medicine.

Photo: Terje Heiestad

In 2016, Professor Kreyberg’s prize in pathology was awarded to JIRC postdoctoral fellow, Eirik Sundlisæter

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Researcher Award 2016 and Early Career Award 2016 were recently awarded to JIRC group leader Pål Aukrust and JIRC researcher Espen Melum, respectively.

JEBSEN INFLAMMATION RESEARCH CENTER (JIRC)

Innovation Translational research as defined by the NIH is at the core of JIRCs activities: ‘moving laboratory discoveries to preclinical validation and towards clinical trials’. The first years of JIRC operation have proven our ability to perform at each of these levels and it is a pleasure to report that we are in translational progress in several of our current activities. Indeed, this statement has support at several levels: First, JIRC-scientists receive Innovation Support from the Norwegian Research Council to develop several projects: • A novel treatment regimen for inflammatory diseases: Targeting the interaction between the complement system and CD14 (Mollnes group) • Novel technology for identification of T cell targets and therapeutic T cell receptors for use in cancer immunotherapy (Olweus group)

Olweus group

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• Compounds that regulate phospholamban phosphorylation with possible cardioprotective effect in the post-infarction heart (Taskén group) • Compounds to inhibit Notch signalling in inflammation (Haraldsen group) Second, JIRC has a strong translational focus and great capability of pursuing clinical exploratory and clinical intervention trials in the inflammation area. With respect to clinical intervention trials, the phase II clinical intervention trial with COX-2 inhibitor in HIV has been completed and closed with 80 patients in 4 different arms. The material is now being analysed to assess efficacy on primary (vaccine boosting) and secondary (immune stimulation) end points. Furthermore, the first intervention study targeting gut microbiota in HIV (with Biola) has been completed. In addition, four new clinical intervention trials have been planned, approved and financed since the start of JIRC: two targeting gut microbiota in CVID and HIV and one examining possibilities for reversing local immune suppression as a consequence of inflammation and immune exhaustion in tuberculosis with COX-2 inhibitor. This latter study will also examine the effect of new therapeutic vaccine candidates and the vaccine boosting effect of COX-2 inhibitor. The most is the assessment of secondary preventive effects in response to aspirin in metastatic colorectal cancer following demonstration of benefit in primary cancer in a registry coupling study. Moreover, since the start of JIRC a number of new exploratory clinical trials and/or investigation of disease mutations in families have also been started. In total, 6 clinical intervention trials (4 new) are either being

JEBSEN INFLAMMATION RESEARCH CENTER (JIRC)

reported, ongoing or starting, and some 13 exploratory clinical trials and clinical descriptive studies are ongoing. Third, JIRC has founded the Norwegian Inflammation Network (NORIN) as a member association that represents an innovation cluster in inflammation research and development (described in more detail in the following section). Fourth, JIRC PIs have generated several projects with companies such as the benchmarking of recombinant antibodies generated by Genentech to target the Notch signalling system, and a GlaxoSmithKline collaboration to assess PI3K inhibitors in KOLS. JIRC investigators are also involved in designing “Digital Life Norway”, a virtual centre and project portfolio integrating bioinformatics and systems biology and harnessing algorithms to exploit available information and individualize therapy.

Mollnes group

Finally, we have taken the initiative to establish an Innovation Program at the UiO similar to the SPARK program at Stanford University. This was established by hosting Prof. Daria Mochly-Rosen, founder of SPARK at a seminar arranged 2 September 2015, by NORIN, Oslo Cancer Cluster, Nansen Neuroscience Network and Oslo Medtech. The aim is to implement a similar translational program at the University of Oslo that can operate beyond the usual technology transfer track and teach faculty how to advance scientific discoveries.

Fifth, JIRC scientists submit DOFIs (disclosure of inventions) on a regular basis, several of which have resulted in new patent applications being filed in the first two years of JIRC. JIRC also plans to make the scFv library of human immunoglobulins (Biotek2021 funded) available to the scientific community by involving Inven2, the UiO/OUH technology transfer office. Furthermore, another Biotek2021-funded project examining compounds that interfere with phospholamban phosphorylation are now shown to have a clean pharmacological effect of negative cardiac inotropy in animals and prevent reperfusion damage in a model of ischemia-reperfusion reducing the size of infarctions by 30–40%. Taskén group

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Norwegian Inflammation Network (NORIN)

Ă&#x2026;KE ELDEN General Manager

The Norwegian Inflammation Network (NORIN) is an innovation cluster that we initiated in 2014 to gather companies, organizations, research and educational institutions that contribute to research, innovation and knowledge dissemination in inflammation and immunology. The purpose is to encourage innovation of new medical products and services through long lasting interaction between academic and industrial environments, providing a platform for research and development to generate new solutions in prevention, diagnosis, treatment and rehabilitation. NORIN serves as a forum for stakeholders in research, innovation and knowledge transfer in inflammatory diseases and immunology. The cluster was established as a membership association in March 2014 with 29 founding members from industry, patient organizations, the University of Oslo and five research centres and has now grown to more than 50 members. The purpose is to stimulate innovation of new medical products and services through collaboration between academic and industrial environments. Strong efforts have been put into the creation of this network and a solid foundation has been established through the in-kind contribution of the JIRC Director

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and Administrative Coordinator. NORIN has high ambitions to continue to strengthen its position as a global knowledge and innovation center. The cluster has up until recently been financed by membership fees but has now also secured start-up funding from Innovation Norway and the Norwegian Research Council through the BIA program as a research and innovation network. This foundation of funding has allowed NORIN to hire a General Manager, Ă&#x2026;ke Elden, who comes from the pharmaceutical industry. He has been vital in moving the initiative forward by generating ideas, promoting the cluster and planning the networking meetings. The board of NORIN is currently composed of nine highly experienced member representatives ranging from academia/ research, clinicians, entrepreneurs, SMB and large international businesses and patient organizations. The board includes:

JEBSEN INFLAMMATION RESEARCH CENTER (JIRC)

ARNE RØSETH Lovisenberg Hospital: Representative for the clinical research environment TOBIAS HEATTA-SPEICHER Abbvie Norway: Representative for established pharmaceutical companies MERETE EKMARK Takeda: Co-opted board member

ARNE SCHATTEN Landsforeningen mot fordøyelsessykdommer: Representative for the patient organizations

KAROLINE SCHETNE Janssen: Representative for established pharmaceutical companies

ØYVIND MOLBERG Oslo University Hospital: Representative for the clinical research environment GURO LØVIK GOLL Diakonhjemmet Hospital: Representative for the clinical research environment

GEIR ÅGE LØSET Nextera: Representative for start-up organizations

GUTTORM HARALDSEN JIRC, University of Oslo and Oslo University Hospital: Board President and academic representative

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JEBSEN INFLAMMATION RESEARCH CENTER (JIRC)

research groups

ANNUAL REPORT 2015

JEBSEN INFLAMMATION RESEARCH CENTER (JIRC)

Aukrust & Yndestad group The focus of our group is to understand the role of inflammatory mechanisms in cardiovascular disease (CVD), in particular atherosclerosis and chronic heart failure. Our ambition is to delineate novel therapeutic targets and biomarkers, possibly leading to new prevention or treatment modalities for these disorders. We use a translational approach to research that involves the characterization of inflammatory processes in patients with atherosclerosis, stroke, myocardial infarction and heart failure, mechanistic studies in in vitro models and mouse models, and finally clinical intervention trials in patients with CVD. Results from each approach feedback to a very productive circuit of translational medicine.

PĂĽl Aukrust

KEY PROJECT SUMMARIES INNATE IMMUNE RESPONSES The innate immune system is the first line of defense against pathogens. Several endogenous damage-associated molecular patterns with relevance to CVD such as oxLDL, heat shock proteins, hypoxia, reactive oxygen species, and extracellular ATP are also potent inducers of innate immune responses. While this response serves protection, innate immune activation can have severe pathophysiological consequences. Our hypothesis is that innate immune mechanisms are central in initiation of inflammation in CVD and that this contributes to development of atherosclerosis and heart failure. We focus on characterizing pathogenic effects in CVD of (i) the NLRP3 inflammasome, (ii) the DNA sensor TLR9, and (iii) the complement system by means of transgenic models and highly specific inhibitory compounds.

Arne Yndestad

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DNA BASE DAMAGE REPAIR Aging, ROS and chronic stress may cause damage to both nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) that are counteracted by DNA repair mechanisms. It is thought that failure to repair contributes to the development of non-communicable disease. We have focused on the base excision repair pathway and, in particular, the first step in this process, DNA glycosylase activity (e.g., Neil3, Neil1, Neil2, OGG1, Mutyh). The aim is on characterizing their pathogenic effect in (i) atherosclerosis, (ii) lipid metabolism, (iii) mitochondrial function and inflammation. METABOLICALLY INDUCED INFLAMMATION: METAFLAMMATION Metabolic stress appears also to trigger inflammation. This metabolically triggered inflammation has been established in obesity-related disorders, but its role in atherosclerosis and myocardial disorders remains unclear. How metabolic stress activates inflammation and how these processes can be attenuated is also incompletely understood. We will study: (i) NLRP3 inflammasome as a sensor of metabolic stress; (ii) nicotinamide phosphoribosyl transferase (NAMPT) and its interaction with the NLRP3 inflammasome in response to metabolic stress and (iii) therapeutic approaches for resolving metaflammation. INFLAMMATORY MEDIATORS AS BIOMARKERS OF CVD There is clearly a need for better biomarkers in CVD, not only for better risk stratification, but also for better evaluation of therapeutic responses. Based on the important role of inflammation in various forms of CVD, markers that reflect different aspects of the

JEBSEN INFLAMMATION RESEARCH CENTER (JIRC)

inflammatory pathways that are activated in these patients could be promising biomarkers. Our emphasis is on (i) large population studies of apparently healthy individuals with long term follow up in relation to CV events, (ii) predictive values of inflammatory biomarkers in a large population of patients with acute coronary syndrome, (iii) identification of non-responders to anti-inflammatory therapy and identification of inflammatory signatures in approach to personalized medicine in CVD. CENTRAL PUBLICATIONS • Sandanger Ø, Ranheim T, Vinge LE, Bliksøen M, Alfsnes K, Finsen AV, Dahl CP, Askevold ET, Florholmen G, Christensen G, Fitzgerald KA, Lien E, Valen G, Espevik T, Aukrust P, Yndestad A (2013). The NLRP3 inflammasome is up-regulated in cardiac fibroblasts and mediates myocardial ischaemia-reperfusion injury. Cardiovasc Res, 99(1):164-74. • Ueland T, Nymo SH, Latini R, McMurray JJ, Kjekshus J, Yndestad A, Fucili A, Grosu A, Masson S, Maggioni AP, Gullestad L, Aukrust P (2013). Investigators of the Controlled Rosuvastatin Multinational Study in Heart Failure (CORONA) trial; Investigators of the GISSI-Heart Failure (GISSI-HF) trial. CCL21 is associated with fatal outcomes in chronic heart failure: data from CORONA and GISSIHF trials. Eur J Heart Fail., 15(7):747-55.

• Nymo SH, Hulthe J, Ueland T, McMurray J, Wikstrand J, Askevold ET, Yndestad A, Gullestad L, Aukrust P (2014). Inflammatory cytokines in chronic heart failure: interleukin-8 is associated with adverse outcome. Results from CORONA. Eur J Heart Fail., 16(1):68-75. • Halvorsen B, Dahl TB, Smedbakken LM, Singh A, Michelsen AE, Skjelland M, Krohg-Sørensen K, Russell D, Höpken UE, Lipp M, Damås JK, Holm S, Yndestad A, Biessen EA, Aukrust P (2014). Increased levels of CCR7 ligands in carotid atherosclerosis: different effects in macrophages and smooth muscle cells. Cardiovasc Res., 102(1):148-56. • Skarpengland T, Laugsand LE, Janszky I, Luna L, Halvorsen B, Platou CG, Wang W, Vatten LJ, Damås JK, Aukrust P, Bjørås M, Åsvold BO (2015). Genetic variants in the DNA repair gene NEIL3 and the risk of myocardial infarction in a nested case-control study. The HUNT Study. DNA Repair (Amst), 28:21-7. • Trøseid M, Ueland T, Hov JR, Svardal A, Gregersen I, Dahl CP, Aakhus S, Gude E, Bjørndal B,Halvorsen B, Karlsen TH, Aukrust P, Gullestad L, Berge RK, Yndestad A (2015). Microbiota-dependent metabolite trimethylamine-N-oxide is associated with disease severity and survival of patients with chronic heart failure. J Intern Med., 277(6):717-26. • Sandanger Ø, Gao E, Ranheim T, Bliksøen M, Kaasbøll OJ, Alfsnes K, Nymo SH, Rashidi

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A, Ohm IK, Attramadal H, Aukrust P, Vinge LE, Yndestad A (2016). NLRP3 inflammasome activation during myocardial ischemia reperfusion is cardioprotective. Biochem Biophys Res Commun., 469(4):1012-20. • Kleveland O, Kunszt G, Bratlie M, Ueland T, Broch K, Holte E, Michelsen AE, Hopp E, Bendz B, Amundsen B, Espevik T, Aakhus S, Damås JK,# Aukrust P,# Wiseth R,# Gullestad L.# The interleukin-6 receptor antagonist Tocilizumab reduces inflammation and myocardial damage in non-ST elevation myocardial infarction – results from a randomized, double-blind, placebo controlled study.#Shared last authorship. Eur Heart J. In press.

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KEY ACHIEVEMENTS • Identified role of NLRP3 inflammasome in myocardial ischemia-reperfusion. • Demonstrated that DNA base repair damage pathway is involved in the development of experimental atherosclerosis. • Performed “proof-of-concept” study and demonstrated beneficial effect of IL-6 inhibition in patients with nonST elevation myocardial infarction.

JEBSEN INFLAMMATION RESEARCH CENTER (JIRC)

AMBITIONS FOR 2016–2017 • Elucidate role of NLRP3 in cardiac repair processes and remodeling. • Determine potential of dual inhibition of complement and toll-like receptor signalling in experimental CVD. • Study interaction between DNA damage and repair, mitochondrial dysfunction and inflammation.

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Haraldsen group Our group aims to dissect inflammatory responses with an emphasis on the reactive mechanisms of tissue resident cells and development of fibrosis. One focus is to understand the function of alarmins that amplify the immune response and another focus is the Notch signalling system that strongly regulates that inflammatory response and represents a target of potential drug development. Based on our discovery of interleukin-33 as a nuclear protein in quiescent vascular endothelial cells (Am J Pathol 2008) and proposal that nuclear IL-33 may act as an alarmin when released from damaged or necrotic cells (Trends Immunol 2009), we demonstrated that IL-33 is a direct target of Notch signaling (Am J Pathol 2012). This finding was also the opening to understand that Notch signalling strongly affects the responsiveness of vascular endothelial cells to proinflammatory activation. This was demonstrated in endothelial cell-specific cre/lox mutants and with the example of the adhesion molecule VCAM-1 shown to be affected by Notch1 interaction with VCAM-1 superenhancers.

Guttorm Haraldsen

KEY PROJECT SUMMARIES To expand our understanding of IL-33 function we have: • Analysed IL-33-deficient mice in a model of kidney fibrosis (UUO) and revealed that collagen transcription is enhanced when IL-33 is absent. Predictive analysis of putative upstream transcription regulators performed by assessing known targets among differentially expressed genes indicated a stronger response to TGF-β in the absence of IL-33. IL-33 is predominantly found in activated myofibroblasts upon urinary

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obstruction and we therefore suppressed IL-33 expression (siRNA) in TGF-β-activated fibroblasts, verifying that a panel of target genes are more responsive to TGF when IL33 is suppressed. Ongoing efforts are designed to assess mechanisms of interference with the main transducers of the TGF-signalling cascade such as SMAD2/3 and Erk1/2. • generated IL-33-deficient Sprague Dawley rats by means of CRISPR/cas9 technology because the mouse is not well suited to understand the function of IL-33 in endothelial cells. • characterized the regulation of IL-33 in human, porcine and murine keratinocytes and revealed strong, species-specific differences. Discovered that hypo-osmotic stress is a powerful inducer of IL-33 expression in human keratinocytes. • analysed plasma levels of IL-33 in a cohort of multitrauma patients (collaboration with Torsten Eken, Ullevål OUH) and shown association with increased mortality. To expand our understanding of endothelial Notch function in inflammation, we have: • pursued the observation that inhibition of Notch signalling in vascular endothelial cells attenuates inflammation (collaboration with Ralf Adams, MPI Münster) by assessing the inhibitory effect of human recombinant antibodies to Notch ligands (collaboration with Chris Siebel, Genentech) and receptors in DNFB-induced contact hypersensitivity and two models of arthritis (CIA and CAIA) • initiated the generation of single chain Fv immunoglobulin library expressed in bacteriophage to generate human recombinant antibodies

JEBSEN INFLAMMATION RESEARCH CENTER (JIRC)

CENTRAL PUBLICATIONS • Pollheimer J, Balogh J, Jetne R, Skånland SS, Sponheim J, Brox MJ, Sundlisæter E, Loos T, Vatn M, Kasprzycka M, Wang J, Küchler AM, Taskén K, Haraldsen G*, Hol J (2013). Interleukin-33 drives a proinflammatory endothelial activation that selectively targets non-quiescent cells. Arterioscler Thromb Vasc Biol, 33:e47-55. • Tveita AA, Schjesvold FH, Sundnes O, Haabeth OA, Haraldsen G, Bogen B (2014). Indirect CD4+ T cell-mediated elimination of MHC IINEG tumor cells is spatially restricted and fails to prevent escape of antigen-negative cells. Eur J Immunol, 44:2625-37. • Skårn M, Noordhuis P, Wang MY, Veuger M, Henrichson Kresse S, Egeland EV, Micci F, Namløs HM, Håkelien AM, Olafsrud SM, Lorenz S, Haraldsen G, Kvalheim G, Meza-Zepeda LA, Myklebost O (2014). Generation and Characterization of an Immortalized Human Mesenchymal Stromal Cell Line. Stem Cells Dev., 23:2377-89. • Pandya AD, Leergaard TB, Dissen E, Haraldsen G, Spurkland A (2014). Expression of the T-cell specific adapter protein in human tissues. Scand J Immunol., 80:169-79. • Øynebråten I, Barois N, Bergeland T, Kücler AM, Bakke O, Haraldsen G (2015). Oligomerized, filamentous surface presentation of RANTES/CCL5 on vascular endothelial cells. Scientific Reports, 5:9261. • 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 During Homeostasis and Inflammation: Strong Species Differences. J Invest Dermatol., 135:1771-80. • Schrumpf E, Tan C, Karlsen TH, Sponheim J, Björkström NK, Sundnes O, Alfsnes K, Kaser A, Jefferson DM, Ueno Y, Eide TJ, Haraldsen G, Zeissig S, Exley MA, Blumberg RS, Melum E (2015). The biliary epithelium presents antigens to and activates natural killer T cells. J Hepatology,62:1249-1259 KEY ACHIEVEMENTS • Identified role of Notch signalling in proinflammatory responsiveness of endothelial cells • Discovered hypoosmosis as strong inductor of epithelial IL-33 • Generated IL-33-deficient rat AMBITIONS FOR 2016-2017 • Publish vascular Notch1-regulation of inflammation • Develop recombinant human antibodies to ligands and receptors of the Notch signalling system. • Explore anti-inflammatory effect of antibodies in model of primary sclerosing cholangitis and inflammatory bowel disease. • Characterize proinflammatory responsiveness and vascular function in IL-33-deficient rats. Depending on phenotype, further characterization in JIRC models.

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JEBSEN INFLAMMATION RESEARCH CENTER (JIRC)

Karlsen group The research focus of the Karlsen group relates to clinical and basic aspects of the chronic liver disease primary sclerosing cholangitis (PSC). Projects are developed within three thematic areas: (i) genetic studies with a focus on the HLA, (ii) microbiome studies in health and disease and (iii) experimental studies on bile duct inflammation in mice. KEY PROJECT SUMMARIES In genetics, the major studies have been related to new methodology for HLA typing using next-generation sequencing, as well as exploiting genetic data and advanced statistics to understand in more detail the disease risk genes located in the HLA complex as a starting point for understanding antigen-specific, disease-relevant immune responses. A major focus of the genomics and metagenomics groups has been to establish materials and methods to study the gut microbiota in inflammatory diseases. Using sequencingbased methodology (i.e. culture independent, which was not possible previously), a full overview of the gut microbial content can be achieved from extracted bacterial DNA. The gut microbiota is important for the immune system and metabolism, and we believe that an altered gut microbial profile may influence the host via gut leakage, direct effects on the mucosal immune system or bacterial metabolites. Measures of systemic metabolites reflecting activity in the gut is therefore also important. Major study designs are crosssectional studies to detect disease specific gut microbiota profiles, but longitudinal and microbiota-targeted interventional studies are important to develop clinically relevant microbiota medicine. Our experimental studies are focusing

Tom Hemming Karlsen

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on regulatory mechanisms involved in bile duct inflammation. These mechanisms are believed to be among the key effector mechanisms in PSC. We specifically aim to understand the role of certain subsets with regulatory properties within the immune system. We have had a particular focus on Natural Killer T (NKT) cells that are abundant in the liver and exhibit regulatory properties. In addition, we perform detailed follow-up studies of genetic findings. During the last two years we have closely investigated a family affected by PSC with a clearly defined mutation. Genetically modified mouse models constitute a key tool to study both the regulatory properties of immune subsets in the bile ducts and the function of disease associated genetic variants. We have therefore established models with spontaneous as well as induced bile duct inflammation. SELECTED PUBLICATIONS â&#x20AC;˘ Berntsen NL, Klingenberg O, Juran BD, Benito de Valle M, Lindkvist B, Lazaridis KN, Boberg KM, Karlsen TH, Hov JR (2015). Association Between HLA Haplotypes and Increased Serum Levels of IgG4 in Patients With Primary Sclerosing Cholangitis. Gastroenterology, 148 (5), 924-927. â&#x20AC;˘ Goyette P, Boucher G, Mallon D, Ellinghaus E, Jostins L, Huang H, Ripke S, Gusareva ES, Annese V, Hauser SL, Oksenberg JR, Thomsen I, Leslie S; International Inflammatory Bowel Disease Genetics Consortium; Australia and New Zealand IBDGC; Belgium IBD Genetics Consortium; Italian Group for IBD Genetic Consortium; NIDDK Inflammatory Bowel Disease Genetics Consortium; United Kingdom IBDGC; Wellcome Trust Case Control Consortium; Quebec IBD Genetics Consortium, Daly MJ, Van Steen K, Duerr RH, Barrett JC, McGov-

JEBSEN INFLAMMATION RESEARCH CENTER (JIRC)

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ern DP, Schumm LP, Traherne JA, Carrington MN, Kosmoliaptsis V, Karlsen TH*, Franke A, Rioux JD. (2015) (*Shared senior author). High-density mapping of the MHC identifies a shared role for HLA-DRB1*01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis. Nat Genet, 47 (2), 172-9. Hov JR, Zhong H, Qin B, Anmarkrud JA, Holm K, Franke A, Lie BA, Karlsen TH (2015). The Influence of the Autoimmunity-Associated Ancestral HLA Haplotype AH8.1 on the Human Gut Microbiota: A Cross-Sectional Study. PLoS One, 10 (7), e0133804. Kummen M, Holm K, Anmarkrud JA, Nygård S, Vesterhus M, Høivik ML, Trøseid M, Marschall HU, Schrumpf E, Moum B, Røsjø H, Aukrust P, Karlsen TH, Hov JR (2016).The gut microbial profile in patients with primary sclerosing cholangitis is distinct from patients with ulcerative colitis without biliary disease and healthy controls. Gut (in press). Liaskou E, Henriksen EK, Holm K, Kaveh F, Hamm D, Fear J, Viken MK, Hov JR, Melum E, Robins H, Olweus J, Karlsen TH*, Hirschfield GM* (2015). *Shared senior author. Highthroughput T-cell receptor sequencing across chronic liver diseases reveals distinct diseaseassociated repertoires. Hepatology (in press). Næss S, Lie BA, Melum E, Olsson M, Hov JR, Croucher PJ, Hampe J, Thorsby E, Bergquist A, Traherne JA, Schrumpf E, Boberg KM, Schreiber S, Franke A, Karlsen TH (2014).

Refinement of the MHC risk map in a scandinavian primary sclerosing cholangitis population. PLoS One, 9 (12), e114486. • Schrumpf E, Tan C, Karlsen TH, Sponheim J, Björkström NK, Sundnes O, Alfsnes K, Kaser A, Jefferson DM, Ueno Y, Eide TJ, Haraldsen G, Zeissig S, Exley MA, Blumberg RS, Melum E (2015). The biliary epithelium presents antigens to and activates natural killer T cells. Hepatology, 62 (4), 1249-59. KEY ACHIEVEMENTS • Developed HLA sequencing-methods based on high-throughput technology and delineation of the HLA association in PSC and IBD • Discovery that the biliary epithelium presents lipid antigens • Development of a complete in-house platform for gut microbiota profiling and demonstration of a unique microbial profile in multiple patient groups AMBITIONS FOR 2016-2017 • Improve our understanding of bile duct inflammation as a platform to establish treatment options for patients with PSC • Translate our current understanding of the gut microbiota into clinical practice by defining microbial biomarkers and performing microbiota-targeted treatment trials

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JEBSEN INFLAMMATION RESEARCH CENTER (JIRC)

Kvale group Chronic infections such as HIV, tuberculosis and viral hepatitis have common challenges with costly or limited treatment options, as well as microbial resistance. Development of novel therapeutic modalities is therefore necessary but requires a better biological understanding of disease mechanisms. The immune response to chronic infections is a balance between activating and inhibitory mechanisms that serves to fight infection, yet it must also protect the host against an excessive and harmful reaction from the immune system. The dynamics of this balance varies between patients and is still not understood. The research group works with a translational approach and cooperates with basic biomedical research groups and in various consortiums to increase the insight into the immunopathogenesis of chronic infections, to study new parameters for prognostic classification and treatment effects, and to test new therapy regimens.

Dag Kvale

KEY PROJECT SUMMARIES HIV Regulatory T cells (Tregs) inhibit effective immune responses in chronic HIV infection. Detailed functional characterization of Tregs in various stages of HIV infection is carried out on biobank samples. We also explore dysfunctional general and HIV-specific immune responses during HIV infection, including explorative assays designed to quantify inhibitory signalling pathways that inhibit HIV antigen-specific proliferative T cell activation. In a controlled clinical study with 60 patients we are comparing T cell dependent vaccine responses and HIV-associated immune activation in patients receiving a cyclooxygenase-2 inhibitor (COX-2i)

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for 24 weeks. We are also assessing GM-CSF or Alhydrogel as adjuvant in HIV-1-infected subjects on antiretroviral therapy (ART) in a clinical interventional study with an HIV Env C5 (conserved domain 5) fusion protein vaccine. Immunological non-responders, a patient subgroup with insufficient immune recovery of T cells despite effective ART, are at higher risk to develop non-AIDS morbidity including cardiovascular events and metabolic syndrome. This patient group needs to be better characterized to test out new therapeutic targets, including probiotics. To this end, enhanced intestinal leakage of inflammatory triggers may be a major contributor to HIV-associated chronic inflammation and immune activation. A controlled clinical trial has been carried out using probiotic milk and allowed us to demonstrate reduced biomarkers for coagulation and inflammation in the intervention group. We are currently conducting an exploratory study on probiotic intervention designed to observe changes in systemic and mucosal immunity with in depth analyses on gut biopsies and functional studies of mucosal T cells. TUBERCULOSIS (TB) We focus on therapeutic vaccination and immune modulation in TB with the aim to develop new treatment strategies for the multidrug-resistant TB pandemic. We have explored the COX-prostaglandin E2 pathway and immune dysfunction in TB by assessing modulation of T cell signalling, in depth studies of T effector and regulatory T cell function in TB as well as the effects of antiinflammatory modulators. We have started a phase I clinical trial of an inflammation

JEBSEN INFLAMMATION RESEARCH CENTER (JIRC)

modulating COX-2i without or in combination with a therapeutic TB vaccine (H56:IC) provided by our partners at Statens Serum Institute in Denmark to assess the role of hyper-activated macrophages and T cells subsets in the pathogenesis of active TB disease. We have also performed functional immune characterizations on biobank samples from TB patients where we find that several subsets of cytokine producing cells and T regulatory cells are associated with effects of therapy. Thus our main aims are to develop new diagnostic and prognostic biomarkers, and define candidate biomarkers for diagnosis, prognosis, and therapeutic effects in patients with active TB, including those infected with drug-resistant strains. CENTRAL PUBLICATIONS • Feruglio SL, Tonby K, Kvale D, Dyrhol-Riise AM (2015). Early dynamics of T helper cell cytokines and T regulatory cells in response to treatment of active Mycobacterium tuberculosis infection. Clin Exp Immunol., 179 (3), 454-65. • Gaardbo JC, Trøseid M, Stiksrud B, Midttun Ø, Ueland PM, Ullum H, Nielsen SD (2015). Increased Tryptophan Catabolism Is Associated With Increased Frequency of CD161+Tc17/ MAIT Cells and Lower CD4+ T-Cell Count in

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HIV-1 Infected Patients on cART After 2 Years of Follow-Up. J Acquir Immune Defic Syndr., 70 (3), 228-35. Hartling HJ, Birch C, Gaardbo JC, Hove M, Trøseid M, Clausen MR, Gerstoft J, Ullum H, Nielsen SD (2015). T-cell homeostasis in chronic HCV-infected patients treated with interferon and ribavirin or an interferon-free regimen. APMIS, 123 (10), 903-11. Lieske NV, Tonby K, Kvale D, Dyrhol-Riise AM, Tasken K (2015). Targeting Tuberculosis and HIV Infection-Specific Regulatory T Cells with MEK/ERK Signaling Pathway Inhibitors. PLoS One, 10 (11), e0141903. Pedersen KK, Eiersted MR, Gaardbo JC, Pedersen M, Gerstoft J, Troseid M, Nielsen SD (2015). Lower Self-Reported Quality of Life in HIV-Infected Patients on cART and With Low Comorbidity Compared With Healthy Controls. J Acquir Immune Defic Syndr, 70 (1), 16-22. Prebensen C, Ueland T, Michelsen AE, Lind A, Pettersen FO, Mollnes TE, Aukrust P, DyrholRiise AM, Kvale D (2015). High MIP-1β Levels in Plasma Predict Long-Term Immunological Nonresponse to Suppressive Antiretroviral Therapy in HIV Infection. J Acquir Immune Defic Syndr., 69 (4), 395-402. Stiksrud B, Nowak P, Nwosu FC, Kvale D, Thalme A, Sonnerborg A, Ueland PM, Holm K, Birkeland SE, Dahm AE, Sandset PM, Rudi

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JEBSEN INFLAMMATION RESEARCH CENTER (JIRC)

K, Hov JR, Dyrhol-Riise AM, Trøseid M (2015). Reduced Levels of D-dimer and Changes in Gut Microbiota Composition After Probiotic Intervention in HIV-Infected Individuals on Stable ART. J Acquir Immune Defic Syndr., 70 (4), 329-37. • Tonby K, Ruhwald M, Kvale D, Dyrhol-Riise AM (2015). IP-10 measured by Dry Plasma Spots as biomarker for therapy responses in Mycobacterium Tuberculosis infection. Sci Rep., 5, 9223. • Trøseid M, Nestvold TK, Nielsen EW, Thoresen H, Seljeflot I, Lappegård KT (2015). Soluble CD14 is associated with markers of vascular dysfunction in bariatric surgery patients. Metab Syndr Relat Disord., 13 (3), 119-24. • Wergeland I, Pullar N, Assmus J, Ueland T, Tonby K, Feruglio S, Kvale D, Damås JK, Aukrust P, Mollnes TE, Dyrhol-Riise AM (2015). IP-10 differentiates between active and latent tuberculosis irrespective of HIV status and declines during therapy. J Infect., 70 (4), 381-91.

AMBITIONS FOR 2016–2017 • Finalize the data from a clinical intervention trial testing the effects of COX-2 inhibitors on vaccine responses and HIVassociated chronic immune activation. • Pursue data from an animal model and clinical intervention testing the effects of COX-2 inhibitors on active TB and on the immunogenicity of therapeutic TB vaccine. • Finalize data from a clinical intervention study assessing the in situ effect of probiotics on mucosal barrier function in immunological non-responder HIV-infected patients.

KEY ACHIEVEMENTS • First clinical intervention study showing that probiotic supplementation favourably modulates pro-inflammatory markers associated with increased cardiovascular risk in HIV-infected patients. • In treatment naïve HIV-infected patients, high levels of the chemokine MIP-1β, was the only parameter among 37 candidate biomarkers that predicted inadequate increase of CD4 counts after initiation of effective antiretroviral therapy. • HIV patients with inadequate CD4 responses to antiretroviral therapy have high levels of IP-10, more activated and differentiated T cells as well as activated T regulatory cells. • The chemokine IP-10 extracted from dried blood spots reflects effective therapy in patients with active TB infection and may have potential as point-of-care test. • Nasal vaccination with HIV p24 peptides modulates local and systemic cellular and humoral vaccine responses in a dosedependent manner.

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JEBSEN INFLAMMATION RESEARCH CENTER (JIRC)

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JEBSEN INFLAMMATION RESEARCH CENTER (JIRC)

Lie group Our research group focuses on genomic and transcriptomic profiling of autoimmune diseases, primarily rheumatoid arthritis. We have three main project areas: (i) Qualitative and quantitative HLA genetics of autoimmune disease; (ii) Transcriptomics of T cells and antigen-presenting cells from thymus and relation to autoimmune risk loci; (iii) Genetics and epigenomics of rheumatoid arthritis and treatment response. Our goal is to understand the influence of genetic factors underlying autoimmune diseases.

Benedicte Lie

KEY PROJECT SUMMARIES Quantitative measures of HLA expression: Quantitative measurement of HLA alleles at RNA level is challenging both using microarray and RNA sequencing due to the fact that HLA alleles have extensive exon polymorphisms leading to technical artefacts (e.g. the reference genome containing only one allele at each HLA locus which disturbs the mapping of reads). To overcome this, we have generated a pipeline to assess HLA allelic expression levels from RNA sequencing. We have performed a cis expression quantitative trait locus (eQTL) screen of autoimmune risk variants to investigate their influence on gene expression in thymus. We identified several risk loci that both serve as thymic eQTLs and that were predicted to interfere with transcription factors important in T cell development. Furthermore, we have described the transcriptome of a panel of twelve immune cells isolated from thymus, including both T cell subsets and different antigen-presenting cells, by RNA sequencing. In a cohort of rheumatoid arthritis patients, we have isolated various T and B

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cells from patients at the time of diagnosis and three months after starting on methotrexate. High-throughput sequencing of these cells are preformed to obtain methylation, microRNA and gene expression profiles that will be correlated with treatment response. CENTRAL PUBLICATIONS • Maehlen MT, Provan S, Semb AG, Uhlig T, Haavardsholm E, Olsen I, Kvien TK, Lie BA (2013). Associations between APOE genotypes and disease susceptibility, joint damage and lipid levels in patients with rheumatoid arthritis. PLoS One 8(4):e60970. • Nordang G, Flåm SF, Mæhlen M, Kvien TK, Viken MK, Lie BA (2013). HLA-C alleles confer risk for anti-citrullinated peptide antibody positive rheumatoid arthritis independent of DRB1 alleles. Rheum 52: 1973-82. • Maehlen MT, Olsen IC, Andreassen BK, Viken MK, Jiang X, Alfredsson L, Källberg H, Brynedal B, Kurreeman F, Daha N, Toes R, Zhernakova A, Gutierrez-Achury J, de Bakker P, Martin J, Teruel M, Gonzalez-Gay MA, Rodriguez-Rodriguez L, Balsa A, Uhlig T, Kvien TK, Lie BA (2015). Genetic risk and number of autoantibodies in patients with rheumatoid arthritis: Assessing the effect of genetic risk scores. Ann Rheum Dis 74:762-8. • Amundsen SS, Viken MK, Sollid LM, Lie BA (2014) Coeliac disease associated polymorphisms influence thymic gene expression. Genes Immun 15: 355-360. • Li YR, Li J, Bradfield J, Mentch F, Abrams D, Hou C, Guo Y, Thomas K, Qui H, Chiavacci R, Kim C, Wang F, Snyder J, Wei Z, Cardinale C, Connolly J, Glessner J, Li D, Richie MD, Flatø B, Førre Ø, Denson L, Thompson SD, Becker ML, Guthery SL, Latiano A, Perez E, Resnick E, Annese V, Wilson DC, Silverberg MS, Lie BA,

JEBSEN INFLAMMATION RESEARCH CENTER (JIRC)

Punaro M, Dubinsky M, Kugathasan S, Monos D, Maier L, Strisciuglio C, Staiano A, Miele E, Ellis JA, Munro JE, Sullivan K, Grant SFA, Wise C, Chapel H, Cunningham-Rundles C, Orange JS, Sleiman P, Behrens EM, Griffiths A, Li H, Satsangi J, Finkel T, Polychronakos C, Baldassano RN, Keating B, Hakonarson H (2015) Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases. Nat Med 1018-27.

AMBITIONS FOR 2016–2017 • Study the role of methylation and microRNA in rheumatoid arthritis patients with relation to methotrexate response. • Describe the transcriptome of antigenpresenting cells and T cells from thymus • Quantify the expression levels of HLA alleles in a panel of antigen-presenting cells from thymus

KEY ACHIEVEMENTS • Dissected the HLA association in rheumatoid arthritis and revealed independent risk contribution from HLA-C alleles. • Shown that the genetic risk load for rheumatoid arthritis increases with number of autoantibodies. • Detected several autoimmune genetic variants that is associated with the level of gene expression in thymus. • Established a pipeline for quantification of HLA allele expression from RNA sequencing data.

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JEBSEN INFLAMMATION RESEARCH CENTER (JIRC)

Mollnes group The Mollnes group is focused on understanding the complement system, which is an important part of innate immunity, serving first-line defense against invading microorganisms. However, it is becoming clear that the complement system also affects general host homeostasis, being involved in a number of inflammatory and metabolic systems. Regulatory control mechanisms normally prevent the complement system from extensive and systemic activation, thereby protecting the host from self-damage. Under various disease conditions, complement is improperly activated, either locally, leading to tissue damage, or systemically, at the risk of serious homeostatic disturbances. The main scientific objective of the group the last years has been to explore the importance of complement in human disease and in particular to elucidate the cross-talk between complement and the Toll-like-receptors of the innate immune response. The main aim of the group is to develop a platform for a combined inhibitory therapeutic approach of these two innate immune systems to attenuate inflammatory damage.

Tom Eirik Mollnes

KEY PROJECT SUMMARIES A primary research goal for the Mollnes group is to elucidate the role of complement as a primary inducer of the inflammatory reaction and thereby form a basis for a future therapeutic approach in complementmediated disease processes. For this purpose we have developed novel assays for detection and quantification of complement activation products based on monoclonal antibodies to activation-dependent epitopes on a number of complement components; the most important one being the assay for TCC (the terminal sC5b-9 com-

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plement complex). These assays are used to detect complement activation experimentally and clinically, and to evaluate the effect of various complement inhibitors in experimental models. In a human whole blood model, developed in our laboratory, in which all potential inflammatory mediators interact mutually, we are currently studying the effect of complement inhibition on a number of arms of the inflammatory network. Current experimental in vitro and in vivo protocols, as well as clinical studies, focus on inflammatory diseases with emphasis on infection, sepsis and inflammatory response syndrome, ischemia-reperfusion injury, transplant rejection and biocompatibility of medical devices. Based on the cross-talk between complement and the Toll-like receptor system, the group has put forward a hypothesis of combined inhibition of complement and CD14 as a therapeutic approach to attenuate the inflammatory reaction induced by danger signalling both from external (PAMPs) and internal (DAMPs) ligands. CENTRAL PUBLICATIONS • Huber-Lang M, Barratt-Due A, Pischke SE, Sandanger Ø, Nilsson PH, Nunn MA, Denk S, Gaus W, Espevik T, Mollnes TE (2014). Double-blockade of CD14 and complement C5 abolishes the cytokine storm and improves morbidity and survival in polymicrobial sepsis in mice. J Immunol., 192:5324-5331. • Volokhina E, Bergseth G, van de Kar N, van den Heuvel L, Mollnes TE (2015). Eculizumab treatment efficiently prevents C5 cleavage without C5a generation in vivo. Blood, 126:278-279. • Skjeflo EW, Sagatun C, Dybwik K, Aam S, Urving SH, Nunn MA, Fure H, Lau C, Brekke

JEBSEN INFLAMMATION RESEARCH CENTER (JIRC)

OL, Huber-Lang M, Espevik T, Barratt-Due A, Nielsen EW, Mollnes TE (2015). Combined inhibition of complement and CD14 improved outcome in porcine polymicrobial sepsis. Crit Care, 19:415 (1-8). • Nymo S, Gustavsen A, Nilsson PH, Lau C, Espevik T, Mollnes TE (2015). Human endothelial cell activation by Escherichia coli and Staphylococcus aureus is mediated by TNF and IL-1β secondarily to activation of C5 and CD14 in whole blood. J Immunol., 196:22932299. • Gustavsen A, Nymo S, Landsem A, Christiansen D, Ryan L, Husebye H, Lau C, Pischke SE, Lambris JD, Espevik T, Mollnes TE (2016). Combined inhibition of complement and CD14 attenuates bacteria-induced inflammation in human whole blood more efficiently than antagonizing TLR4-MD2. J Infect Dis. (E-Published ahead of print March 1). KEY ACHIEVEMENTS • Identified complement (C3 and C5) and CD14 as the key molecules responsible for the inflammatory reaction induced both by Gram-negative and Gram-positive bacteria, both in vitro and in vivo. • Extended these studies to show that combined inhibition of complement and CD14 abolish the inflammatory reaction and improve survival induced by experimen-

tal polymicrobial sepsis both in mice and pigs, leading to a hypothesis of combined complement- and CD14 inhibition as a general treatment approach for inflammatory reactions in human diseases. AMBITIONS FOR 2016–2017 • Develop novel complement activation assays for application in basic and clinical research. • Study complement activation in patients with diseases being tentative candidates for future complement intervention. • Link complement research to TLRs and in particular the TLR co-receptor CD14. • Investigate the effect on inflammation by modulating complement activation and CD14. • Based on the above, to develop a therapeutic regimen to treat human diseases based on a combined inhibition of complement and CD14.

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JEBSEN INFLAMMATION RESEARCH CENTER (JIRC)

Olweus group The Olweus group is focused on studies of immune receptor specificities and target discovery within inflammation (K.G. Jebsen Center for Inflammation Research - JIRC) and cancer immunotherapy (K.G. Jebsen Center for Cancer Immunotherapy - JCIT). The group develops, in close collaboration with JCIT and JIRC partners, new highthroughput technologies that (i) allow discovery of targets for autoantibodies, (ii) link T cell receptor (TCR) sequence to TCR specificities, and (iii) allows discovery of T-cell epitopes and the T-cell receptors that recognize them. In addition, the group has used frontline technologies to study the cytokine responsiveness in Common Variable Immunodeficiency (CVID) to better characterizes the dysfunctional immune response in this disease and allow subclassification of patients for improved therapy.

Johanna Olweus

KEY PROJECT SUMMARIES Novel technology for high-throughput detection of auto-antibody reactivities: Antibodies to self-proteins are commonly found in serum from patients with inflammatory diseases. In certain auto-immune disorders, these reactivity patterns have diagnostic implications. Current knowledge about auto-antibodies is limited because identification of the self-proteins is challenging. To overcome this problem JIRC has collaborated with the JCIT to develop new high-throughput screening technology. Post-docs Adi Mehta (JIRC) and Krzysztof Sikorski (JCIT) work in close collaboration in the laboratory of Fridtjof Lund-Johansen (JCIT partner) to produce bead-based arrays with thousands of full-length human proteins. With this technology it is feasible to test more than a hundred patient sera for reactivity against

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thousands of proteins in a one-day experiment, an efficacy that opens entirely new possibilities to detect auto-antibodies and determine their role in pathogenesis and diagnostics. Novel technology for high-throughput detection of T-cell epitopes and the T-cell receptors recognizing them. This novel technology platform has allowed discovery of a large number of novel T-cell epitopes and their cognate TCRs. Cytokine responsiveness in Common Variable Immunodeficiency (CVID). CVID is defined by hypogammaglobulinemia and B-cell dysfunction, in the majority of cases for unknown reasons. It is still unknown whether CVID is a primary B-cell defect or a secondary response to defects in T-cells, as T-cell help is instrumental for B-cell differentiation and activation, immunoglobulin (Ig) production, and Ig class switching. In a collaboration between the groups of Olweus and Pål Aukrust and Kjetil Taskén, our aim has been to characterize the cytokine responsiveness in CVID, using phospho-specific flow cytometry to study (i) the intrinsic responsiveness in B cells to cytokines, and (ii) the T-cell responsiveness and polarization. T-cell receptor (TCR) repertoires in autoimmune disease. The Olweus group initiated a conceptually novel approach to link TCR sequence information to antigen-specificities in multiple sclerosis. Olweus has collaborated with Tom Hemming Karlsen on projects that were aimed at characterizing diseaseassociated T-cell receptor repertoires by next generation sequencing in the nonviral chronic liver diseases primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC), using alcoholic liver disease (ALD) as a control group. Moreover, recruitment of

JEBSEN INFLAMMATION RESEARCH CENTER (JIRC)

long-lived gut-derived memory T cells to the liver is believed to drive hepatic inflammation in primary sclerosing cholangitis (PSC). Paired liver and gut samples of PSC patients with concurrent inflammatory bowel disease (IBD) were analysed to assess the potential overlap in T-cell clonotypes between the two compartments. CENTRAL PUBLICATIONS • Erlend Strønen, Mireille Toebes, Sander Kelderman, Marit M. van Buuren, Weiwen Yang, Nienke van Rooij, Marco Donia, MaxiLu Böschen, Fridtjof Lund-Johansen, Johanna Olweus, Ton N. Schumacher (2016). Targeting of cancer neoantigens with donor-derived T cell receptor repertoires. Science. DOI: 10.1126/ science.aaf2288. • Mensali N, Ying F, Yang W, Walseng E, Kumari S, Fallang LE, Oei Yi Sheng V, Kolstad A, Uckert W, Malmberg K, Wälchli S, Olweus J. Targeting B-cell neoplasia with T-cell receptors recognizing a CD20-derived peptide on patient-specific HLA. OncoImmunology, in press. • Liaskou E, Henriksen EK, Holm K, Kaveh F, Hamm D, Fear J, Viken MK, Hov JR, Melum E, Robins H, Olweus J*, Karlsen TH*, Hirschfield GM*(2015). High-throughput T-cell recep-

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tor sequencing across chronic liver diseases reveals distinct disease-associated repertoires. Hepatology. Kolstad A, Kumari S, Walczak M, Madsbu U, Hagtvedt T, Bogsrud TV, Kvalheim G, Holte H, Aurlien E, Delabie J, Tierens A, Olweus J (2015). Sequential intranodal immunotherapy induces antitumor immunity and correlated regression of disseminated follicular lymphoma. Blood, 125:82-89. Walseng E, Walchli S, Fallang LE, Yang W, Vefferstad A, Areffard A, Olweus J. Soluble T-cell receptors produced in human cells for targeted delivery (2015). PLoS One, 10:e0119559. Walchli S, Kumari S, Fallang LE, Sand KM, Yang W, Landsverk OJ, Bakke O, Olweus J*, Gregers TF* (2014). Invariant chain as a vehicle to load antigenic peptides on human MHC class I for cytotoxic T-cell activation. Eur J Immunol., 44:774-784. Taraldsrud E, Fevang B, Aukrust P, Beiske KH, Floisand Y, Froland S, Rollag H, Olweus J (2014). Common variable immunodeficiency revisited: normal generation of naturally occurring dendritic cells that respond to Toll-like receptors 7 and 9. Clin Exp Immunol., 175:439-448. Kumari S, Walchli S, Fallang LE, Yang W,

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Lund-Johansen F, Schumacher TN, Olweus J (2014). Alloreactive cytotoxic T cells provide means to decipher the immunopeptidome and reveal a plethora of tumor-associated selfepitopes. Proc Natl Acad Sci U S A, 111:403408. • Lossius A, Johansen JN, Vartdal F, Robins H, Benth JS, Holmoy T, Olweus J (2014). Highthroughput sequencing of TCR repertoires in multiple sclerosis reveals intrathecal enrichment of EBV-reactive CD8 T cells. Eur J Immunol. • Vesterhus M, Hov JR, Holm A, Schrumpf E, Nygård S, Godang K, Andersen IM, Naess S, Thorburn D, Saffioti F, Vatn M, Gilja OH, Lund-Johansen F, Syversveen T, Brabrand K, Parés A, Ponsioen CY, Pinzani M, Färkkilä M, Moum B, Ueland T, Røsjø H, Rosenberg W, Boberg KM, Karlsen TH. Enhanced liver fibrosis score predicts transplant-free survival in primary sclerosing cholangitis (2015). Hepatology, 62:188-97.

clonotypes in primary biliary cirrhosis, primary sclerosing cholangitis and alcoholic liver disease, and found evidence for antigen-driven clonal expansions. These findings indicate that differential TCR signatures, as determined by highthroughput sequencing, may represent an imprint of distinctive antigenic repertoires present in the different chronic liver diseases (Hepatology 2015). • Identified memory T cells of common clonal origin were in paired gut and liver samples of PSC-IBD patients, supporting the hypothesis of memory T-cell migration between the gut and liver of PSC patients. (Submitted, in revision).

KEY ACHIEVEMENTS • Screened 374 sera from healthy controls and patients with primary sclerosing cholangitis, auto-immune hepatitis and primary biliary cirrhosis (PBC) to show highly consistent reactivity to more than 50 proteins in patients with PBC, including the known auto-antigen DLAT. The results yield new insight into recognition of self-proteins in PBC. • Novel technology for high-throughput detection of T-cell epitopes and the T-cell receptors recognizing them, discovering 36 out of 50 predicted T-cell epitopes using the novel technology (PNAS 2014, and one patent application filed). • Identified unique signaling patterns in B cells from CVID patients that predict disease severity. • Discovered a defective signaling pathway in T cells that defines a subgroup of CVID patients with adverse disease. • Demonstrated that the cerebrospinal fluid of patients with multiple sclerosis (MS) is enriched for CD8+T cells reactive with Epstein Barr Virus, a candidate diseasedriving pathogen in MS (Eur J Immunol 2014). • Demonstrated the presence of liverinfiltrating disease-associated T cell

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JEBSEN INFLAMMATION RESEARCH CENTER (JIRC)

AMBITIONS FOR 2016–2017 • The identification of novel, putative auto-antigens in PBC provide rationale for a large-scale screening study with serum from patients with a wide range of inflammatory and auto-immune disorders. • Researchers at JCIT have recently obtained proof-of-principle for production of an array with MHC peptide complexes will be used to screen for high affinitybinders to various MHC class I alleles. The results will be useful to predict epitopes recognized by CD8+ T cells. The first 600-plex is expected to be ready early Q3 2016.

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JEBSEN INFLAMMATION RESEARCH CENTER (JIRC)

Taskén & Aandahl group We investigate immune-modulation in response to prostaglandins- and regulatory T cell (Treg) function with applications in immune disease, inflammation, transplantation and tumor immunology. We aim to understand complex intracellular signaling networks, the spatial and temporal resolution of signaling and how such signal networks require subcellular anchoring and localization in immune cells and other cell types with applications to pathophysiology. The group maps signaling pathways to identify targets, develops tools to interfere with their function (peptidomimetics, small molecular compounds) and validates them in preclinical disease- specific models, aiming to take things forward in a translational context.

Kjetil Taskén

KEY PROJECT SUMMARIES Regulatory and effector T cell signaling and function We have extensively studied T cell signaling, more recently using methods such as phosphoflowcytometry and phosphoproteomics, allowing for a systemic overview of signal networks. Recent work includes analysis of CD28 and CD2 co-receptor signaling in effector T cells (Teffs) (Skånland et al., Biochem. J. 2014), a very interesting analysis of how Treg suppression affects Teff signaling and how partial or full activation of Treg affects Teff memory and sensitivity to re-suppression (Chellappa et al, J. Leukocyte Biol., 2016), studies of how a set of agonists and antagonists that specifically targets each of the four prostaglandin E2 (PGE2) receptors (EP1, EP2, EP3 and EP4) affects Teff and Treg signal networks and phosphoproteomes (collab. A. Heck, ongoing) and how CXCR4 and CCR5 chemokine receptor

Einar Martin Aandahl

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signaling integrates with T cell receptor signaling (ongoing). In clinical materials we have looked at Treg function and effects on Teff immune responses in HIV and tuberculosis (Lieske et al, PLoS One 2015, Stiksrud, Lorvik et al, J AIDS in press), in malignant ascites (Landskron et al, Cancer Immunol. Immunother. 2015), pancreatic cancer (Chellappa et al, OncoImmunol., 2016) and cholangiocarcinoma (Chellappa et al., resubmitted). In pancreatic cancer, FoxP3+ Tregs that co-express RORγt and are both pro-inflammatory and immunosuppressive, were found to be expanded. Blocking prostaglandin-mediated immune suppression in the gut: We earlier demonstrated that regulatory T cells and prostaglandin E2 (PGE2) suppresses anti-tumor immune responses in colorectal cancer (Yaqub et al, Cancer Immunol. Immunother. 2008; Brudvik et al, Cancer Immunol. Immunother. 2012). These observations add to reports that PGE2 stimulates tumor growth and angiogenesis in colorectal cancer. While COX inhibitors and acetylsalicylic acid (ASA) may be beneficial to prevent primary colorectal cancer due to reduced inflammation, our findings on the inhibitory effect of PGE2 on anti-tumor immunity led us to hypothesize that secondary prevention ASA may give even further benefit. This appears to hold true in a registry study with data on more than 23,000 patients from the Cancer Registry of Norway coupled with data from the Norwegian Prescription Database (Bains et al, J. Clin. Oncol., in press). We now plan a clinical intervention trial to assess this finding in a randomized and placebo-controlled setting.

JEBSEN INFLAMMATION RESEARCH CENTER (JIRC)

Protecting the heart from ischemia-reperfusion injury We examined beta-adrenergic signalling in the heart and specifically studied a PKAAKAP18-phospholamban signal complex that regulates Ca2+ re-uptake in sarcoplasmic reticulum and contractility. We hypothesised that perturbing the complex could be cardioprotective. By high-throughput screening and subsequent derivatisation of hits and characterization of compounds in cell-based studies as well as proof-of-concept studies in animals we have shown that a class of compounds specifically inhibits adrenergic pacing of the SERCA2 Ca2+ATPase and has a negative inotropic effect without introducing negative chronotropy, thereby isolating one beneficial effect of beta-blockers. Furthermore, we find that we can protect hearts from ischemia-reperfusion injury, reducing myocardial infarction size in rodents by up to 40% by blocking adrenergic pacing of compromised cardiomyocytes, thus preventing cell death, tissue damage and inflammation. Drug sensitivity screening and drug synergy analysis We are starting work with cancer drug sensitivity screening on patient samples looking for efficacious compounds and drug synergies on an individual basis, ultimately aim-

ing to assist clinical decisions in precision oncology and haematology. We are looking at CLL and MM cell signalling patterns and growth responses in a high throughput format in collaboration with Depts of Haematology (Tjønnfjord) and Immunology (Munthe). Cancer drug sensitivity screening with a panel of 400 cancer drugs is being established based on the assay development with the aim to support screening directly on patient samples to assist therapy choices in individualized or tailored medicine. We are expanding also to other cancers and are starting xenografting in zebrafish to support in vivo drug testing in a high-throughput format (collaboration NCMM/BiO PIs Staerk and Esguerra). We aim to have algorithms to predict effective therapy combinations to be tested in individualized clinical trials. CENTRAL PUBLICATIONS • Scott JD, Dessauer CW, Taskén K (2013) Creating order from chaos: Cellular regulation by kinase anchoring. Annu. Rev. Pharmacol. Toxicol., 53:187-210. • Lone AM, Taskén K. (2013) Proinflammatory and immunoregulatory role of eicosanoids in T cells. Front. Immunol. (T cell biology), 4:130, pp1-15, doi: 10.3389/fimmu.2013.00130. • Skånland SS, Moltu K, Berge T, Aandahl EM, Taskén K. (2014) T-cell co-stimulation through

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•

CD2 and CD28 induces distinct signaling responses. Biochem. J., 460:399-410. Landskron J, Helland Ø, Torgersen KM, Aandahl EM, Gjertsen BT, Bjørge L, Taskén K. (2015) Activated regulatory and memory T-cells accumulate in malignant ascites from ovarian carcinoma patients. Cancer Immunol. Immunother., 64: 337-47. Pidoux G, Gerbaud P, Dompierre J, Lygren B, Solstad T, Evain-Brion D, Taskén K. The A kinase anchoring protein ezrin interacts with connexin 43 to facilitate protein kinase A control of gap junction communication in cell fusion. J. Cell Sci., 127:4172-4185. Lieske NV, Tonby K, Kvale D, Dyrhol-Riise AM, Taskén K (2015) Targeting disease-specific regulatory T cells in chronic infectious diseases with MEK/ERK signaling pathway inhibitors. PLoS One, 10: e0141903, pp 1-19. doi:10.1371/ journal.pone.0141903. Chellappa S, Hugenschmidt H, Hagness M, Line PD, Labori KJ, Wiedswang G, Taskén K, Aandahl EM. (2016) Regulatory T cells that coexpress RORγt and FOXP3 are pro-inflammatory and immunosuppressive and expand in human pancreatic cancer. Oncoimmunology. 5(4):e1102828. Landskron J, Taskén K. (2016) Phosphoprotein detection by high-throughput flow cytometry. Methods in Molecular Biology,1355: 275-90. Chelappa S, Lieske NV, Hagness M, Line PD, Taskén K,# Aandahl EM# (2016) Activation status of human regulatory T cells controls TCR signaling and susceptibility to suppression in CD4+ T cells. J. Leukocyte Biol., in press in “Leading Edge Research” section. (#corresponding authors) Parente-Ribes A*, Skånland SS*, Bürgler S*, Os A, Wang D, Bogen B, Tjønnfjord GE, Taskén K$,#, Munthe LA$,# Spleen tyrosine kinase inhibitors block CD40L induced proliferation of chronic lymphocytic leukemia cells. Hematologica, in press. (*,$equal contributions, #corresponding authors) Bains SJ, Mahic M, Myklebust TÅ, Småstuen MC, Yaqub S, Dørum LM, Bjørnbeth BA, Møller B, Brudvik KW, Taskén K. Aspirin as Secondary Prevention in Patients with Colorectal Cancer - An Unselected Population-Based Study. J. Clin Oncol., in press.

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KEY ACHIEVEMENTS • Secondary preventive effect of ASA in colorectal cancer examined in a registrybased study with 23,000 patients and showing reduced cancer-specific and overall mortality (J. Clin. Oncol., 2016). • Level of activation of regulatory T cells control effector T cell signalling and their susceptibility to suppression (J. Leukocyte Biol. 2016). • A PKA-ezrin complex regulates opening and closing of Cx43 gap junctions (J. Cell Sci, 2014 and Inven2 innovation prize 2015) and this mechanism could have impact in heart myocardial infarction, Treg immunosuppression and cancer cell plasticity. • We have characterized regulatory T cells in various cancer types and assessed their involvement in tumor immune evasion (Cancer Immunol. Immunother. 2015a and 2015b; Oncoimmunology, 2016) • Some early reports from our cancer drug sensitivity screening approaches in chronic lymphatic leukemia and glioblastoma using phospho-flow cytometry to assess effect of targeted therapy drugs is also now out (J. Neuro-oncology, 2014; Hematologica, 2016) AMBITIONS FOR 2016–2017 • ASA intervention study fully funded and patient recruitment started. • Effect of small molecular compounds protecting the heart from ischemiareperfusion injury – studies finalised and reported. • Programme on regulatory T cells advanced to test emerging mechanisms for perturbing function. • Drug sensitivity screening programme advanced to predicting drug synergies and testing in xenograft models.

JEBSEN INFLAMMATION RESEARCH CENTER (JIRC)

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JEBSEN INFLAMMATION RESEARCH CENTER (JIRC)

activities

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JEBSEN INFLAMMATION RESEARCH CENTER (JIRC)

activities

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JEBSEN INFLAMMATION RESEARCH CENTER (JIRC)

The funding and establishment of the K.G. Jebsen Inflammation Research Centre has enabled several new discoveries and the initiation of cutting-edge collaborations. Crucial steps in achieving this level of collaboration has been (i) specific support of co-supervised projects that include the scientific contribution of at least two PIs; (ii) the cooperative selection of highly motivated postdoc candidates that want to spearhead such collaborative and interdisciplinary projects; (iii) ad hoc allocation of complementary expertise by PhD fellows, postdocs and senior scientists funded by other sources and their experimental contribution of crucial data to almost all new research collaborations; (iv) project exposure to all centre members at monthly research seminars where PIs alternate in their responsibility to present ongoing projects and at annual seminars with invited speakers but also an opportunity for all centre members to present their work orally or in the form of a poster. Most of the new research collaborations have all of these elements and would only have happened in the context of conceptualizing, financing and implementing JIRC, where a new focus and collaborative group have been put together.

NORIN seminars The Norwegian Inflammation Network (NORIN) is heavily engaged in public outreach to specific groups, such as patient organizations, industry, academics/ researchers and clinicians. As detailed at our website, we have already organized four very attractive and successful events since the onset of the network: 27. MAY 2014: “Kick-off” meeting 29. OCT 2014: “Sufficient options to treat inflammation? Looking at the pipeline of the pharmaceutical industry” 02. DEC 2014: “Limitations of today’s diagnosis and monitoring” 11. MAR 2015: “Bedre hverdag med kronisk inflammatorisk sykdom” 02. SEP 2015: “How to move academic innovation to the next level? Inspiration from Stanford’s SPARK Program” (co-organized with Oslo Cancer Cluster) 16. MAR 2016: “Morgendagens medisin” The events in March 2015 and 2016 were organized in collaboration with the NRF (Norsk Revmatikerforbund), LMF (Landsforening mot fordøyelsessykdomer) and Psoriasisog eksemforbundet. Importantly, they recruited as speakers leading clinicians in the field, as well as Anne Grethe Erlandsen, State Secretary of the Ministry of Health and Care Services, and Karita Bekkemellem, former Minister of Children, Equality and Social Inclusion in two cabinets, and currently Director of the Association of the Pharmaceutical Industry in Norway.

NORIN kick-off seminar

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Internal activities

Poster session at JIRC annual retreat

National Microbiota Conferences 2014–2015 NoPSC postdoc Johannes R. Hov and JIRC postdoc Marius Trøseid hosted the first national conference on “Gut Microbiota in health and Disease” at Gardermoen on 19 November 2014. More than 90 people attended the meeting. The speaker list included internationally renowned scientists, among these NoPSC Guest Professor Fredrik Bäckhed (Wallenberg Laboratory, University of Gothenburg) and Tore Midtvedt (Karolinska Institutet, Stockholm), but also several scientists from Norwegian research groups. Following the success of the first conference, they hosted the second national meeting on microbiota in health and disease on 3 November 2015. The focus was on the gut-brain axis and on the relevance of diet. There were open abstract sessions, providing a new forum for presentation of microbiota-related research in Norway.

PROJECT MEETINGS To keep members of the centre up to date on the research within the centre, project meetings are organized monthly. Each meeting is hosted by one of the eight research groups, responsible for presenting projects. Typically unpublished data from two projects are presented. Presentations range from questions of technical challenges, via preliminary data to publication-ready work. Ample time is reserved for discussion following the presentations and discussion is encouraged. At the end of the meeting snacks are served to promote interaction between research groups and to continue the discussion in a less formal atmosphere. The project meeting is an important event that facilitates collaboration, idea generation and critical discussion. Furthermore, the monthly project meeting provides a friendly venue for junior scientists less experienced in presenting their own work. The project meeting is also a vital activity aiming to build centre identity and a sense of community.

ANNUAL RETREAT The annual retreat is an important event that facilitates synergies, collaborations and exchange of ideas. We have organized annual centre retreats; all held at Thorbjørnrud in January 2014, 2015 and 2016. The organizing committee is composed of the JIRC postdoctoral fellows and the administrative coordinator overseeing all practicalities. The committee puts together the program with invited international speakers and plans and provides ample time for scientific discussion and social interaction. Over the past few years, the speakers have included Professors Boris Hinz, Göran Hansson, Peter Hunt and Kathy McCoy.

JIRC annual retreat at Thorbjørnrud

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s l l e le c

young investigator profiles

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ANNUAL REPORT 2015

CENTRE FOR IMMUNE REGULATION (CIR)

young investigator profiles

ANNUAL REPORT 2015

CENTRE FOR IMMUNE REGULATION (CIR)

Young investigators and career development Each research group has engaged in researcher training and the career progression of young scientists. This has ranged from the supervision of a total of 13 master students with more in the pipeline; contribution to the internal PhD program organized at the Research Institute of Internal Medicine; teaching graduate level PhD courses; and also participation in the Scientia Fellows program. Several centre members have advanced in their careers in 2013–2015. Three young JIRC scientists, Johannes R. Hov, Espen Melum, and Sigrid S. Skånland received a “Young talented researcher” grants from the Norwegian Research Council, a career grant from the South-Eastern Norway Regional Authority (HSØ) and a Career Grant from the Cancer Society, respectively. Johanna Hol Fosse, a former postdoc, was awarded a researcher grant from the South-Eastern Norway Regional Authority.

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Profile JIRC Young Investigators

JOHANNA HOL Johanna Hol received her veterinary degree from the University of Edinburgh in 2002 and completed her PhD at the Department of Pathology, University of Oslo in 2010. Her research is based in the Haraldsen group, where she is currently supported by a 4-year researcher grant from the Regional Health Authorities (2014–2018) combined with a grant from the National Association for Public Health (2016). Her research focus is to understand how phenotypic traits of endothelial cells affect their responsiveness to inflammatory stimuli. This is important because endothelial activation not only provides increased access to oxygen and nutrients but also

JEBSEN INFLAMMATION RESEARCH CENTER (JIRC)

controls immune cell recruitment to inflammatory lesions. Moreover, non-resolving inflammation may result in a dysfunctional endothelial phenotype and inappropriate activation, contributing to atherosclerosis and cardiovascular disease. Specifically, Johanna manages part of a common effort exploring how factors involved in contact inhibition control endothelial inflammatory activation. She is also leading the investigation into how the characteristic metabolic profile of endothelial cells may contribute to inflammation.

JOHANNES ROKSUND HOV Johannes Hov received his medical degree from the University of Oslo and his PhD in the genetics of primary sclerosing cholangitis in 2011. Currently, he is a researcher in the Karlsen group and also training as a gastroenterologist. His main research focus is the role of the gut microbiota in inflammatory diseases. Over the last three to four years he has established new methodologies and collected materials to perform microbial profiling using modern sequencing technology. His research interests, in addition to PSC, include the JIRC-relevant phenotypes immunodeficiencies, heart failure and diseases of the gut. The overall aim of the group is the development of clinical microbiota medicine, defining clinically relevant biomarkers based on microbial function (e.g. circulating metabolites) and performing proof-ofconcept studies targeting the gut microbiota. Johannes is currently funded by a RCN young talented researcher grant.

ESPEN MELUM Espen Melum received his MD at the University of Oslo in 2006. During medical school he got involved in clinical and basic research in hepatology with a focus on genetics and immunology. He defended his PhD thesis on the genetics of primary sclerosing cholangitis (PSC) in 2010 before training as a postdoctoral fellow in Richard Blumberg’s lab at Brigham and Women’s Hospital / Harvard in Boston where he worked with immunological models of inflammation. He is a member of the Karlsen group and leads the research group Experimental Hepatology which focuses on translational research relevant to PSC. In addition, he is training in clinical gastroenterology at Oslo University Hospital, Rikshospitalet. The research group consists of one postdoctoral fellow, four PhDstudents and one technician. The genetic risk factors so far uncovered in the genetic studies in PSC are mainly related to the function of the immune system, and his team is now focusing on understanding how the immunological process regulates inflammation in the bile ducts. They have demonstrated for the first time that the cholangiocytes lining the biliary tree in both mice and humans can present antigens to natural killer T (NKT) and to this end, they have developed a novel mouse model where a NKT activating antigen can be introduced into the biliary tree using surgical techniques and lead to development of cholangitis. Melum received a career grant from the South-Eastern Norway Regional Health Authority (HSØ) for his project “Regulation of bile duct inflammation.” This will finance his position as a researcher for 8 years in a 50% position where he will continue to combine group leadership with his clinical work.

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JEBSEN INFLAMMATION RESEARCH CENTER (JIRC)

DAG HENRIK REIKVAM Dag Henrik Reikvam received his medical degree from the University of Oslo and completed his PhD in mucosal immunology at Department of Pathology in 2011. He is a board-certified specialist in infectious diseases, consultant at Department of Infectious Diseases, and a part of the Kvale group. Reikvam’s research scope is a merger of his clinical interest in HIV infection and his scientific background in mucosal immunology. Specifically, his research addresses three overriding questions: i) How is chronic inflammation and gut mucosal barrier function in HIV infection linked?, ii) why do some HIV-infected patients have an insufficient immunological response despite persistent virological suppression? and ii) is enforcement of gut mucosal barrier a valid target for additional therapy in these patients - and maybe even for patients with other chronic inflammatory diseases? He has initiated a cross-sectional study comparing HIV-infected immunological nonresponder (INR) patients with immunological responders and HIV-negative controls. Furthermore, in an exploratory interventional study INR patients are treated with probiotics to enhance their gut mucosal barrier function. All study participants are subjected to colonoscopy and multiple biopsies collected for subsequent multidisciplinary analyses. As original and true translational projects they utilize the technology and competence of several of the JIRC partners and is a formal collaboration of the Kvale, Karlsen and Haraldsen groups, and Asle Medhus at the Department of Gastroenterology. Reikvam collaborates closely with co-JIRC Young Investigators Hov and Trøseid Reikvam is currently funded by the JIRC postdoctoral program and his project was awarded a three-year PhD grant by Helse Sør-Øst in 2016.

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SIGRID SKÅNLAND Sigrid S. Skånland is educated in biology at the University of Oslo. During her PhD with Prof Kirsten Sandvig at the Norwegian Radium Hospital she studied intracellular transport of protein toxins. She stayed in the field of cellular biology as an EMBO fellow in the lab of Prof Ivan Dikic in Frankfurt, Germany. Her work in this lab resulted in a Nature publication (Ikeda et al, Nature, 2011). From 2011, Skånland has been a member of the Taskén group at NCMM; since 2015 as a researcher funded by a Career Development Grant from the Norwegian Cancer Society. Her current research is on the establishment of a phosphoflow based approach for the assistance of clinical decisions in individualized therapy. Together with collaborators at the Oslo University Hospital, Skånland and colleagues aim to apply phosphoflow technology to identify signaling aberrations disease. Earlier this year, the team published a study showing that stimulation with soluble CD40 ligand induces phosphorylation of the BCR pathway transducer SYK (pY525/526) as well as cell proliferation. These effects could be reversed by the small molecular SYK inhibitors R406 or P505-15 (Parente-Ribes et al, Haematologica, 2016). Such identification of pathways amenable to inhibition will present drug candidates for the treatment of patients.

JEBSEN INFLAMMATION RESEARCH CENTER (JIRC)

MARIUS TRØSEID Marius Trøseid, a former JIRC postdoctoral fellow, has recently been appointed associate professor. He has background from clinical translational research within atherosclerosis, metabolic syndrome and infectious diseases, in particular HIV infection. He has investigated the potential influence of gut microbiota and related metabolites in these chronic inflammatory diseases. Several lines of evidence imply that fecal composition, transepithelial leakage and handling of inflammatory triggers in gut mucosa directly influence inflammatory processes in the circulation and in distant organs. Trøseid and coworkers have demonstrated that a low diversity of the gut microbiota in HIV-infected individuals is directly correlated with low CD4+ T cell count and elevated levels of lipopolysaccharide (LPS) in the peripheral blood, and furthermore that elevated LPS is closely associated with several cardiometabolic risk factors such as hypertension, dyslipidemia, insulin resistance and the metabolic syndrome. Trøseid has also been PI in one of the first studies to target the gut microbiota in HIV infection, showing that multistrain probiotics reduced levels of D-dimer and C-reactive protein. Currently, Trøseid and co-workers are investigating whether bacterial LPS with different inflammatory properties, are altered by probiotic intervention. Recently, the gut microbiota has been directly linked to atherosclerosis, through the gut microbiota-dependent marker trimethylamine-N-oxide (TMAO). TMAO is made from carnitine and phosphatidyl choline, which is abundant in red meat, and importantly, TMAO formation is completely blocked after a short course of antibiotics, implying the role of the gut microbiota.

Trøseid and coworkers have shown that elevated TMAO levels predict poor clinical outcome in heart failure patients. Based on these findings, a multi-center intervention study (GutHeart: Targeting the gut microbiota to treat Heart failure) has been started. Finally, Trøseid has contributed substantially to establishing a pipeline for sampling, sequencing and interpretation of gut microbiota at Oslo University Hospital, in collaboration with group leader Johannes Hov. Together, Trøseid and Hov have also established a regional research network and a national Gut microbiota society, which will host the third national Gut microbiota conference in November 2016 (www.mikrobiota.no).

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about JIRC

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JEBSEN INFLAMMATION RESEARCH CENTER (JIRC)

about JIRC

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JEBSEN INFLAMMATION RESEARCH CENTER (JIRC)

Facts and figures – overview of JIRC JIRC is affiliated with two organizations, the University of Oslo (UiO) and Oslo University Hospital (OUS). The centre is organized directly under the Faculty of Medicine and the Centre Director reports directly to the Dean. The Centre is headed by Professor Guttorm Haraldsen (Director) and Kjetil Taskén (Deputy Director). The centre management is supported by an administrative coordinator, Tara Sarin. JIRC consists of eight Principal Investigators (PI’s) headed by professors, Pål Aukrust, Guttorm Haraldsen, Tom Hemming Karlsen, Dag Kvale, Benedicte Lie, Tom Eirik Mollnes, Johanna Olweus and Kjetil Taskén and two Co-Principal Investigators, Einar Martin Aandahl and Arne Yndestad. A small management team consisting of Centre Director, Administrative Coordinator, Assistant Director (Kjetil Taskén), and one of the PIs (currently Pål Aukrust) assists in decisions of implementation, while the steering board, consisting of all PIs and Co-PIs, are called for major decisions, such as priorities of projects, implementation of advice given by the SAB, and financial models of funding JIRC postdocs. Two models that have been implemented as part of the scientific leadership strategy deserve specific mention: (i) One model is the collaborative strategy which involves shared financing of JIRC postdocs (K.G. Jebsen foundation/external sources granted to individual PIs) combined with a requirement of at least two PIs involved in supervision. Furthermore, this strategy of collaboration and the aim for cohesion across the group of PIs and Co-PIs in a true cross-disciplinary fashion, pervades the organisation of the JIRC research programme and is evident from the fact that all WP subsections have more than one PI involved, all JIRC postdocs have supervisors from at least

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two groups and where most new research collaborations and opportunities (NRCOs) result from such collaboration or from reaching out nationally/internationally from JIRC. This strategy has so far resulted in some 60 collaborative papers where more than one JIRC group leader is involved, testifying to the true collaborative spirit and the early success of this strategy. (ii) The second model is our involvement in the Marie Curie/COFUND program also designed to implement shared financing. These efforts not only implement scientific synergy but also efficiently amplify Jebsen funding. DECISIONS AND OPPORTUNITIES TO ADJUST STRATEGIES are inherent to the model to finance projects by means of K.G. Jebsen funding. The budget of 4 years that includes additional support from both UiO and OUH allows us to finance a total of 24 postdoc years. Our initial allocation from that budget offered 7 co-supervised postdoc positions, each financed for 2 years and amounting to 14 postdoc years, yet positions were offered for 3 years with the implication that projects are re-evaluated after 2 years and subject to reallocation to other JIRC projects or PI-driven financing of the final year from other sources. Likewise, the opportunity to co-fund JIRC-postdocs via the recently awarded Scientia Fellows program of UiO, a Marie Curie COFUND action, has allowed us to again select several projects of co-supervision (scientists labelled in the list of JIRC staff). In addition, the overall positive evaluation of our Scientific Advisory Board has also suggested directional adjustments that will be carefully evaluated by our steering committee. Thus, although several activities will be pursued as described in the original project description, NRCOs now

JEBSEN INFLAMMATION RESEARCH CENTER (JIRC)

developing will be subject to careful comparison and prioritization. Moreover, these plans and also the results of this midterm evaluation will provide an excellent backdrop for further SAB evaluation scheduled for 2016/2017. SCIENTIFIC ADVISORY BOARD JIRC has a scientific advisory board (SAB) consisting of European world-class scientists. The SAB’s mandate is to critically evaluate and advice on the centre’s scientific performance and progress.

The board visited Oslo in fall 2014 and evaluated the JIRC program, results and activities. They have provided very positive feedback and consider the K.G. Jebsen funding ‘to represent excellent value for the money spent’. Likewise, very useful, constructive feedback to increase research focus and synergy beyond current collaborations has been given. All elements of the report have been subject to analysis and discussion of implementation in the JIRC steering committee, and a new SAB visit will be planned in late 2016/early 2017.

The scientific advisory board has four members: • Professor Nancy Hogg, London, United Kingdom • Professor Rikard Holmdahl, Stockholm, Sweden • Professor Arthur Kaser, Cambridge, United Kingdom • Professor Alberto Mantovani, Milan, Italy

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JIRC Staff Leaders Research Groups

DIRECTOR Guttorm Haraldsen DEPUTY DIRECTOR Kjetil Taskén

PRINCIPAL INVESTIGATOR Pål Aukrust

HEAD OF ADMINISTRATION Tara Sarin

RESEARCHERS Arne Yndestad, Co-PI Bente Halvorsen, Professor Trine Ranheim

*= K.G. Jebsen funded postdoctoral fellows

POSTDOCTORAL FELLOWS Tuva B. Dahl Ida Gregersen Sverre Holm Xiang Yi Kong Knut Husø Lauritzen *Mieke Louwe (in collab. with TEM group) Øystein Sandanger

®= Scientia Fellows program postdoctoral fellows

PHD FELLOWS Linn E. Fosshaug Yangchen Holmen Ståle Haugset Nymo Maria Belland Olsen Negar Shahini Marina Sokolova Kuan Yang RESEARCH TECHNICIAN Azita Rashidi Katrine Alfsnes Jonas Øgaard MEDICAL STUDENT Margrethe F. Holt

PRINCIPAL INVESTIGATOR

Guttorm Haraldsen

RESEARCHERS Johanna Hol Monika Kasprzycka Anita Kavlie Denis Khnykin Helge Scott, Professor POSTDOCTORAL FELLOWS ®Nicola Bassi *Francesca Gatti (in collab. with THK/BL group) Lars la Cour Poulsen ®Peter Lundbäck (in collab. with KT group) ®Sobuj Mia ®Anastasia Renzi (in collab. with THK group) Eirik Sundlisæter Monika Szymanska PHD FELLOWS Clara Hammarström Stig Krüger Tor Espen Bendvold Wojciech Pietka Olav Sundnes RESEARCH TECHNICIANS Aaste Aursjø Sara Halmøy Bakke Kathrine Hagelsten Kjersti Thorvaldsen Hagen Dahn Phung Linda Solfjell MSC STUDENT Jonas Aakre Wik

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JEBSEN INFLAMMATION RESEARCH CENTER (JIRC)

PRINCIPAL INVESTIGATOR

RESEARCHERS Kristin Muri Boberg Johannes R. Hov Espen Melum Erik Schrumpf

RESEARCHERS Anne Ma Dyrhol-Riise Kjetil Taskén, adjunct position via NCMM-UIO

POSTDOCTORAL FELLOWS Andreas Baratt-Due Bernt Chr. Hellerud Ebbe Billmann Thorgersen Per H. Nilsson Søren Pischke

Tom Hemming Karlsen

POSTDOCTORAL FELLOWS Mette Vesterhus *Xiaojun Jiang (in collab. with GH group) Gupta Udatha ®Brian K. Chung ®Georg Schneditz PHD FELLOW Trine Folseraas Kristin Kaasen Jørgensen Bjarte Fosby Elisabeth Schrumpf Martin Kummen Natalie Lie Berntsen Eva Kristine Klemsdal Henriksen Laura Valestrand Amandeep Kaur Dhillon ADMINISTRATION Julia Ferkis Merete Gedde-Dahl RESEARCH TECHNICIANS Anne Pharo Liv Wenche Throbjørnsen

Dag Kvale

POSTDOCTORAL FELLOWS *Dag Henrik Reikvam (in collab. with THK/PA group) Synne Jenum Kristina Berg Lorvik (joint DK/KT groups) Kristian Tonby

MEDICAL STUDENT Christopher Storm Larsen

PHD FELLOWS Alice Gustavsen Hilde Lang-Orrem Kiki Johnson MSC STUDENTS Camilla Schjalm Karin Ekholt

PHD FELLOWS Kristin Brekke Birgitte Stiksrud Christian Prebensen Else Quist Paulsen Siri Feruglio Malin Meyer-Myklestad

PRINCIPAL INVESTIGATOR Johanna Olweus RESEARCHER Terhi Kärpänen

SENIOR CONSULTANTS Marius Trøseid Vidar Ormaasen Torgun Wæhre Mette Sannes

POSTDOCTORAL FELLOWS Shraddha Kumari *Adi Mehta (in collab. with THK/BL group) Mateusz Walczak

RESEARCH TECHNICIANS Helene Gjelsås Linda Gail Skeie Kjerstin Røstad

PRINCIPAL INVESTIGATOR BIOINFORMATICS Kristian Holm

Tom Eirik Mollnes

Benedicte Lie

TECHNICIANS Siri T. Flåm Helle Akselsen POSTDOCTORAL FELLOWS Marte K. Viken *Fatemeh Kaveh (in collab. with THK group) Hanna Helgeland

PHD FELLOWS Muhammad Ali Maxi-Lu Böschen Zsofia Földväri Eirini Giannakopoulou Erlend Strønen Eli Taraldsrud RESEARCH TECHNICIANS Cathrine F. Knetter Dorthea Tollefsrud Gjølberg Weiwen Yang

PHD FELLOWS Ingvild Gabrielsen Kari Guderud Line H. Sunde Fatima Heinicke Maria Dehli Vigeland Asgeir Lande

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JEBSEN INFLAMMATION RESEARCH CENTER (JIRC)

PRINCIPAL INVESTIGATOR Kjetil Taskén

Collaboration

RESEARCHERS Einar Martin Aandahl, Co-PI Johannes Landskron Sigrid Strand Skånland

National

POSTDOCTORAL FELLOWS Ana Isabel Costa Calejo ®Dinh-Toi Chu Sorina Dinescu Lena Eroukhmanoff Guro Mørk Johnsen Anna Mari Lone Kristina Berg Lorvik Maria-Niki Mylonakou Deepak Balaji Thimiri Govinda Raj *Vanessa Wehbi (in collab. with DK group) PHD FELLOWS Simer Jit Bains Aleksandra Dukic Stalin Chellappa Gunasekaran Nora V. Lieske Kristine Moltu Ellen Østensen RESEARCH TECHNICIANS Marianne Enger Jorun Solheim Martine Schrøder Gladys Tjørhom CHEMICAL BIOLOGY PLATFORM (BIO, AFFILIATED KT GROUP): Anne Jorunn Stokka, head Paal Berg Eirin Solberg David W. McClymont

NTNU, DEPARTMENT OF CANCER RESEARCH AND MOLECULAR MEDICINE: Magnar Bjørås; Terje Espevik; Anders Sundan OSLO UNIVERSITY HOSPITAL, ULLEVÅL: Ivar Sjaastad, Geir Ø. Andersen and Andreas Lossius, Institute of Experimental Medical Research, Department of Immunology and Transfusion Medicine and Department of Neurology Asle W. Medhus, Department of Gastroenterology OSLO UNIVERSITY HOSPITAL, RIKSHOSPITALET: Alexandre Corthay and Klaus Beiske, Department of Pathology Halvor Rollag, Department of Microbiology Håvard Attramadal, Institute for Surgical Research Ludvig Munthe, Institute of Immunology Børre Fevang and Stig Frøland, Research Institute of Internal Medicine Yngvar Fløisand and Geir Tjønnfjord, Department of Hematology Øyvind Molberg, Dept of Rheumatology Hanne Harbo, John Anker Zwart, Dept of Neurology Bjørn Atle Bjørnbeth and Sheraz Yaqub, Gastrosurgical Department Geir E. Tjønnfjord and Ingunn Dybedahl, Department of Hematology Annetine Staff, Department Obstetrics/ Gynaekology OSLO UNIVERSITY HOSPITAL, RADIUMHOSPITALET: June Myklebust and Kalle Malmberg, Department of Immunology, Institute for Cancer Research Harald Holte, Department of Oncology Gunnar Kvalheim, Department of Cellular Therapies ØSTFOLD HOSPITAL TRUST: Waleed Ghanima LILLEHAMMER HOSPITAL FOR RHEUMATIC DISEASES: Ivana Hollan

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UNIVERSITY OF OSLO: Trond Vidar Hansen, School of Pharmacy Tore Kvien, Institute for Clinical Medicine/ Diakonhjemmet Oddmund Bakke, Inger Sandlie and Geir Åge Løset, Department of Molecular Biosciences and Centre for Immune Regulation Camila Esguerra Bernd Thiede, Judith Staerk and J. Preben Morth, Biotechnology Centre / NCMM Heidi Kiil Blomhoff, Philippe Collas, Jo Klaveness, Arnoldo Frigessi, Kirsten Holven, Bjørn Skålhegg, Institute for Basic Medicine Ragnhild Lothe (*the Director of the K.G. Jebsen Center for colorectal cancer research) and Guro Lind, Center for Cancer Biomedicine Jørgen Jahnsen, Department of Gastroenterology, AHUS UNIVERSITY OF BERGEN: Rolf K. Berge; Institute of Medicine, Section of Medical Biochemistry James B. Lorens, Department of Biomedicine UNIVERSITY OF TROMSØ: John-Bjarne Hansen and Jon Florholmen, Institute for Clinical Medicine Jeanette Hammer Andersen, Marbio CANCER REGISTRY OF NORWAY: Bettina Kulle Andreassen Bjørn Møller Tor-Åge Myklebust AKERSHUS UNIVERSITY HOSPITAL: Trygve Holmøy, Department of Neurology HAUKELAND UNIVERSITY HOSPITAL: Lars Akslen, Bjørn Tore Gjertsen, Helga Salvesen and Line Bjørge Norwegian Institute of Public Health: Lars Christian Stene, Dept of Epidemiology SINTEF: Geir Klinkenberg

International Ralph Adams, Max-Planck Institute, Muenster Peter Andersen, Else Marie Agger and Morten Ruhwald, Statens Serum Institute, Denmark Annika Bergquist and Niklas Gjorkstrom, Karolinska University Hospital, Stockholm, Sweden Eric A. Biessen, University Hospital Maastricht, Netherlands Richard Blumberg, Brigham and Women’s Hospital, Harvard Medical School, Boston, US Matthew Brown, University of Queensland Diamantina Institute, Princess Alexandra Hospital, Australia Kenneth Caidahl, Karolinska Institute, Stockholm, Sweden Mary Carrington, Center for Cancer Research, National Institute of Health, US Marco Conti, University of California, San Francisco, US Department of Medical Microbiology and Virology, University of the Free State, South Africa Mikael Elofsson, MIMS, Umeå, Sweden Sven Enerbäck, Gothenburg University, Sweden Peter Garred, Copenhagen, Denmark Daniel Gotthardt, University Hospital of Heidelberg, Germany Bodo Grimbacher, Freiburg University, Germany Hakon Hakonarson, Center for Applied Genomics and Department of Pediatrics, The Children’s Hospital of Philadelphia, US Gøran Hansson, Karolinska Institutet, Stockholm, Sweden Albert Heck, The Netherlands Proteomics Centre, Utrecht, The Netherlands Friedrich Herberg, Universität Kassel, Germany Bert van den Heuvel, Nijmegen, The Netherlands Gideon Hirschfield, Centre for Liver Research, NIHR Birmingham Liver Biomedical Research Unit, University of Birmingham, Birmingham, UK, University Pietro Invernizza and Ana Lleo, IRCSS Instituto Clinico Humanitas, Milan, Italy Arthur Kaser, Department of Medicine, University of Cambridge, Addenbrook’s Hospital, Cambridge, UK Martin Knofler, University of Vienna, Austria Markus Huber-Lang, Ulm, Germany Joshua LaBaer, Arizona State University, Arizona, US

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Riitta Lahesmaa, University of Turku, sFinland Eicke Latz, University of Bonn, Germany Konstantinos Lazaridis, The Mayo Clinic, Rochester, US Joe Lewis, Chemical Biology Unit, EMBL, Germany Egil Lien, University of Massachusetts, Worcester, US Javier Martin, Instituto de Parasitologia y Biomedicina Lopez-Neyra, CSIC, Spain Kim Midwood, Oxford University, UK MMH Hospital Zanzibar, Tanzania Michel Moutschen, Liege, Belgium Susanne Dam Nielsen, Rigshospitalet, Denmark Bo Nilsson, Uppsala, Sweden The Nordic Liver Transplant Group Klaus Okkenhaug, Babraham Institute, Cambridge, US Leonid Padyukov, Karolinska Institute, Sweden Guillaume Pidoux, Université Paris Süd, Paris, France Tatiana Petrova, Helsinki University, Finland Stefan Pflanz, Merck Research labs (former DNAX), Palo Alto, US Alberto Pugliese, Diabetes Research Institute Foundation, US Harlan Robins, Divisions for Public Health and Human Biology, Fred Hutchinson Cancer Research Center, Seattle, US Julio Saez-Rodrigues, EMBL-EBI, Hinxton, UK Stefan Schreiber and Andre Franke, Institute for Clinical and Molecular Biology, Christian-Albrechts University, Kiel, Germany Ton N. Schumacher, Division of Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands John D. Scott, University of Washington, Seattle, US Chris Siebel, Genentech Inc, South San Francisco Mario Strazzabosco and Luca Rabris, Liver Center, Yale University, New Haven, US and University of Padova, Italy Anders Sonnerborg, Karolinska Institute, Sweden Michael Trauner and Peter Fickert, Medical University of Vienna and Medical University of Graz, Austria Johan Trowsdale, James Traherne and Vasilis Kosmoliaptsis, Cambridge Institute for Medical Research, Cambridge, UK Krister Wennerberg, FIMM, Helsinki, Finland Manuela Zaccolo, University of Oxford, UK Lars Østergård, University of Aarhus, Denmark

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Funding In addition to the K.G Jebsen funding of 4 million NOK per year for four years JIRC has received contributions from the University of Oslo (2m NOK/y) and Oslo University Hospital (1 m NOK/y). The centre has also raised a dedicated network grant (IRNet) from Health Region South East that complements the K.G. Jebsen funding and has helped develop both a focused centre and a broader network of clinical collaborators that enables expansion to a wider set of inflammatory disease, specifically the Norwegian Inflammation Network (NORIN). JIRC scientists have received exceptional funding since establishment of the centre. JIRC extramural funding in the form of grants to the group leaders was approx. 95 mNOK in 2013 and 130 mNOK in 2014. This includes grants from the Norwegian Research Council, Norwegian Cancer Society, the South-Eastern Norway Regional Health Authority (HSØ), Western Norway Regional Health Authority (HelseVest), European Commission, Norwegian Diabetes Foundation, National Association for Public Health (Nasjonalforeningen for

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folkehelsen), and private foundations and organizations such as Canica A/S, Jahre Foundation (Jahrefondet), Novo Nordic Foundation, Roche Switzerland and others. Moreover, we currently hold 4 grants from the RCN Biotek2021 Optimization program, two JIRC projects were selected for funding 2015–2017 among a total of 5 funded in biomedicine nationwide. Most PIs receive highly competitive independent project support ("åpen prosjektstøtte") from the Regional Health Authority of Southeastern Norway. The Tom Hemming Karlsen group was granted a 75 mNOK expansion of private funding allocated to PSC research (Canica) over the next 10 years.

JEBSEN INFLAMMATION RESEARCH CENTER (JIRC)

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JEBSEN INFLAMMATION RESEARCH CENTER (JIRC)

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JEBSEN INFLAMMATION RESEARCH CENTER (JIRC)

PUBLICATIONS The list highlights 2013–2015 publications in which the K.G. Jebsen Centre or the foundation is mentioned/credited. ®= Publications with contributions from more than one research group within the centre. 1. ®Stiksrud B, Nowak P, Nwosu FC, Kvale D, Thalme A, Sonnerborg A, Ueland PM, Holm K, Birkeland SE, Dahm AE, Sandset PM, Rudi K, Dsc, Hov JR, Dyrhol-Riise AM, Trøseid M. Reduced Levels of D-dimer and Changes in Gut Microbiota Composition after Probiotic Intervention in HIV-infected Individuals on Stable ART. J Acquir Immune Defic Syndr. 2015 Aug 6. [Epub ahead of print] PubMed PMID: 26258571. 2. ®Liaskou E, Henriksen EK, Holm K, Kaveh F, Hamm D, Fear J, Viken MK, Hov JR, Melum E, Robins H, Olweus J, Karlsen TH, Hirschfield GM. High-throughput T-cell receptor sequencing across chronic liver diseases reveals distinct disease-associated repertoires. Hepatology. 2015 Aug 7. doi: 10.1002/hep.28116. [Epub ahead of print] PubMed PMID: 26257205. 3. Landsem A, Fure H, Christiansen D, Nielsen EW, Østerud B, Mollnes TE, Brekke OL. The key roles of complement and tissue factor in Escherichia coli-induced coagulation in human whole blood. Clin Exp Immunol. 2015 Jun 9. doi: 10.1111/cei.12663. [Epub ahead of print] PubMed PMID: 26241501. 4. ®Fosshaug LE, Dahl CP, Risnes I, Bohov P, Berge RK, Nymo S, Geiran O, Yndestad A, Gullestad L, Aukrust P, Vinge LE, Øie E. Altered levels of fatty acids and inflammatory and metabolic mediators in epicardial adipose tissue in patients with systolic heart failure. J Card Fail. 2015 Jul 28. pii: S1071-9164(15)00630-2. doi:10.1016/j.cardfail.2015.07.014. [Epub ahead of print] PubMed PMID: 26231517. 5. Norum HM, Gullestad L, Abraityte A, Broch K, Aakhus S, Aukrust P, Ueland T. Increased serum levels of the Notch ligand DLL1 are associated with diastolic dysfunction, reduced exercise capacity and adverse outcome in chronic heart failure. J Card Fail. 2015 Jul 23. pii: S1071-9164(15)00623-5. doi:10.1016/j.cardfail.2015.07.012. [Epub ahead of print] PubMed PMID: 26211721. 6. ®Hov JR, Zhong H, Qin B, Anmarkrud JA, Holm K, Franke A, Lie BA, Karlsen TH. The Influence of the Autoimmunity-Associated Ancestral HLA Haplotype AH8.1 on the Human Gut Microbiota: A Cross-Sectional Study. PLoS

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One. 2015 Jul 24;10(7):e0133804. doi: 10.1371/ journal.pone.0133804. eCollection 2015. PubMed PMID: 26207384; PubMed Central PMCID: PMC4514645. 7. Wannhoff A, Rupp C, Friedrich K, Brune M, Knierim J, Flechtenmacher C, Sauer P, Stremmel W, Hov JR, Schirmacher P, Weiss KH, Gotthardt DN. Inflammation but not Biliary Obstruction is Associated With Level of CA19-9 in Patients with Primary Sclerosing Cholangitis. Clin Gastroenterol Hepatol. 2015 Jul 17. pii: S15423565(15)00972-6. doi: 10.1016/j.cgh.2015.07.014. [Epub ahead of print] PubMed PMID: 26192140. 8. Raslan Z, Magwenzi S, Aburima A, Taskén K, Naseem KM. Targeting of type I protein kinase A to lipid rafts is required for platelet inhibition by the 3',5'-cyclic adenosine monophosphate-signaling pathway. J Thromb Haemost. 2015 Jul 14. doi: 10.1111/jth.13042. [Epub ahead of print] PubMed PMID: 26176741. 9. ®Sampaziotis F, Cardoso de Brito M, Madrigal P, Bertero A, Saeb-Parsy K, Soares FA, Schrumpf E, Melum E, Karlsen TH, Bradley JA, Gelson WT, Davies S, Baker A, Kaser A, Alexander GJ, Hannan NR, Vallier L. Cholangiocytes derived from human induced pluripotent stem cells for disease modeling and drug validation. Nat Biotechnol. 2015 Aug;33(8):845-52. doi: 10.1038/nbt.3275. Epub 2015 Jul 13. PubMed PMID: 26167629. 10. Gaardbo JC, Trøsied M, Stiksrud B, Midttun Ø, Ueland PM, Ullum H, Nielsen SD. Increased Tryptophan Catabolism is Associated with Increased Frequency of CD161+Tc17/MAIT Cells, and Lower CD4+ T cell Count in HIV-1 infected Patients on cART after Two Years of Follow-up. J Acquir Immune Defic Syndr. 2015 Jul 11. [Epub ahead of print] PubMed PMID: 26181815. 11. Volokhina EB, Bergseth G, van de Kar NC, van den Heuvel LP, Mollnes TE. Eculizumab treatment efficiently prevents C5 cleavage without C5a generation in vivo. Blood. 2015 Jul 9;126(2):278-9. doi: 10.1182/blood-2015-03637645. PubMed PMID: 26160188. 12. ®Otterdal K, Haukeland JW, Yndestad A, Dahl TB, Holm S, Segers FM, Gladhaug IP, Konopski Z, Damås JK, Halvorsen B, Aukrust P. Increased Serum Levels of LIGHT/TNFSF14 in Nonalcoholic Fatty Liver Disease: Possible Role in Hepatic Inflammation. Clin Transl Gastroenterol. 2015 Jul 2;6:e95. doi:10.1038/ctg.2015.23. PubMed PMID: 26133108. 13. ®Carpino G, Cardinale V, Renzi A, Hov JR, Berloco PB, Rossi M, Karlsen TH, Alvaro D, Gaudio E. Activation of biliary tree stem cells

JEBSEN INFLAMMATION RESEARCH CENTER (JIRC)

within peribiliary glands in primary sclerosing cholangitis. J Hepatol. 2015 Jun 25. pii: S01688278(15)00410-9. doi: 10.1016/j.jhep.2015.06.018. [Epub ahead of print] PubMed PMID: 26119688. 14. ®Prebensen C, Ueland T, Michelsen AE, Lind A, Pettersen FO, Mollnes TE, Aukrust P, Dyrhol-Riise AM, Kvale D. High MIP-1β Levels in Plasma Predict Long-Term Immunological Nonresponse to Suppressive Antiretroviral Therapy in HIV Infection. J Acquir Immune Defic Syndr. 2015 Aug 1;69(4):395-402. doi:10.1097/ QAI.0000000000000617. PubMed PMID: 26115437. 15. Volokhina EB, van de Kar NC, Bergseth G, van der Velden TJ, Westra D, Wetzels JF, van den Heuvel LP, Mollnes TE. Sensitive, reliable and easy-performed laboratory monitoring of eculizumab therapy in atypical hemolytic uremic syndrome. Clin Immunol. 2015 Jun 23;160(2):237-243. doi:10.1016/j. clim.2015.05.018. [Epub ahead of print] PubMed PMID: 26111482. 16. Khan F, Pharo A, Lindstand JK, Mollnes TE, Tønnessen TI, Pischke SE. Effect of perfusion fluids on recovery of inflammatory mediators in microdialysis. Scand J Immunol. 2015 Jun 22. doi: 10.1111/sji.12332. [Epub ahead of print] PubMed PMID: 26099791. 17. Lappegård KT, Bjørnstad H, Mollnes TE, Hovland A. Effect of cardiac resynchronization therapy on inflammation in congestive heart failure: a review. Scand J Immunol. 2015 Jun 22. doi: 10.1111/sji.12328. [Epub ahead of print] PubMed PMID: 26099323. 18. ®Hovland A, Jonasson L, Garred P, Yndestad A, Aukrust P, Lappegård KT, Espevik T, Mollnes TE. The complement system and toll-like receptors as integrated players in the pathophysiology of atherosclerosis. Atherosclerosis. 2015 Aug;241(2):480-94. doi: 10.1016/j.atherosclerosis.2015.05.038. Epub 2015 Jun 5. Review. PubMed PMID: 26086357. 19. Bergstrøm B, Aune MH, Awuh JA, Kojen JF, Blix KJ, Ryan L, Flo TH, Mollnes TE, Espevik T, Stenvik J. TLR8 Senses Staphylococcus aureus RNA in Human Primary Monocytes and Macrophages and Induces IFN-β Production via a TAK1-IKKβ-IRF5 Signaling Pathway. J Immunol. 2015 Aug 1;195(3):1100-11. doi: 10.4049/jimmunol.1403176. Epub 2015 Jun 17. PubMed PMID: 26085680.

1759(15)30010-7. doi: 10.1016/j.jim.2015.06.006. [Epub ahead of print] PubMed PMID: 26079729. 21. Niyonzima N, Samstad EO, Aune MH, Ryan L, Bakke SS, Rokstad AM, Wright SD, Damås JK, Mollnes TE, Latz E, Espevik T. Reconstituted High-Density Lipoprotein Attenuates Cholesterol Crystal-Induced Inflammatory Responses by Reducing Complement Activation. J Immunol. 2015 Jul 1;195(1):257-64. doi: 10.4049/jimmunol.1403044. Epub 2015 May 29. PubMed PMID: 26026058. 22. Pedersen KK, Eiersted MR, Gaardbo JC, Pedersen M, Gerstoft J, Troseid M, Nielsen SD. Lower self-reported Quality of Life in HIV-infected patients on cART and with low co-morbidity compared to healthy controls. J Acquir Immune DeficSyndr. 2015 May 21. [Epub ahead of print] PubMed PMID: 26017659. 23. ®Berg A, Otterdal K, Patel S, Gonca M, David C, Dalen I, Nymo S, Nilsson M, Nordling S, Magnusson PU, Ueland T, Prato M, Giribaldi G, Mollnes TE, Aukrust P, Langeland N, Nilsson PH. Complement Activation Correlates With Disease Severity and Contributes to Cytokine Responses in Plasmodium falciparum Malaria. J Infect Dis. 2015 May 15. pii: jiv283. [Epub ahead of print] PubMed PMID: 25980034. 24. ®Andreassen OA, Desikan RS, Wang Y, Thompson WK, Schork AJ, Zuber V, Doncheva NT, Ellinghaus E, Albrecht M, Mattingsdal M, Franke A, Lie BA, Mills IG, Aukrust P, McEvoy LK, Djurovic S, Karlsen TH, Dale AM. Correction: Abundant Genetic Overlap between Blood Lipids and Immune-Mediated Diseases Indicates Shared Molecular Genetic Mechanisms. PLoS One. 2015 May 15;10(5):e0128048. doi: 10.1371/ journal.pone.0128048. eCollection 2015. PubMed PMID: 25978331; PubMed Central PMCID: PMC4433198. 25. Hope S, Hoseth E, Dieset I, Mørch RH, Aas M, Aukrust P, Djurovic S, Melle I, Ueland T, Agartz I, Ueland T, Westlye LT, Andreassen OA. Inflammatory markers are associated with general cognitive abilities in schizophrenia and bipolar disorder patients and healthy controls. Schizophr Res. 2015 Jul;165(2-3):188-94. doi: 10.1016/j.schres.2015.04.004. Epub 2015 May 5. PubMed PMID: 25956633.

20. Tadesse FG, Mensali N, Fallang LE, Walseng E, Yang W, Olweus J, Wälchli S. Unpredicted phenotypes of two mutants of the TcR DMF5. J Immunol Methods. 2015 Jun 14. pii: S0022-

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26. Egge KH, Thorgersen EB, Pischke SE, Lindstad JK, Pharo A, Bongoni AK, Rieben R, Nunn MA, Barratt-Due A, Mollnes TE. Organ inflammation in porcine Escherichia coli sepsis is markedly attenuated by combined inhibition of C5 and CD14. Immunobiology. 2015 Aug;220(8):999-1005. doi: 10.1016/j. imbio.2015.04.002. Epub 2015 Apr 27. PubMed PMID: 25956456. 27. Ueland T, Caidahl K, Askevold ET, Karlsson T, Hartford M, Aukrust P. Secreted FrizzledRelated Protein 3 (sFRP3) in acute coronary syndromes. Int J Cardiol. 2015 Jul 1;190:217-9. doi: 10.1016/j.ijcard.2015.03.401. Epub 2015 Apr 8. PubMed PMID: 25920031.

33. ®Neupane SP, Lien L, Ueland T, Mollnes TE, Aukrust P, Bramness JG. Serumbrainderived neurotrophic factor levels in relation to comorbid depression and cytokine levels in Nepalese men with alcohol-use disorders. Alcohol. 2015 Aug;49(5):471-8. doi: 10.1016/j. alcohol.2015.01.012. Epub 2015 Mar 22. PubMed PMID: 25873205.

28. ®Thorsen T, Aandahl EM, Bennet W, Olausson M, Ericzon BG, Nowak G, Duraj F, Isoniemi H, Rasmussen A, Karlsen TH, Foss A. Transplantation With Livers from Deceased Donors Older Than 75 Years. Transplantation. 2015 Apr 24. [Epub ahead of print] PubMed PMID: 25909464.

34. Olin P, Hausken J, Foss A, Karlsen TH, Melum E, Haugaa H. Continuous molecular adsorbent recirculating system treatment in 69 patients listed for liver transplantation. Scand J Gastroenterol. 2015 Sep;50(9):1127-34. doi: 10.3109/00365521.2015.1027262. Epub 2015 Apr 11. PubMed PMID: 25865318.

29. Egge KH, Barratt-Due A, Nymo S, Lindstad JK, Pharo A, Lau C, Espevik T, Thorgersen EB, Mollnes TE. The anti-inflammatory effect of combined complement and CD14 inhibition is preserved during escalating bacterial load. Clin Exp Immunol. 2015 Apr 23. doi: 10.1111/ cei.12645. [Epub ahead of print] PubMed PMID: 25907631.

35. ®Schrumpf E, Tan C, Karlsen TH, Sponheim J, Björkström NK, Sundnes O, Alfsnes K, Kaser A, Jefferson DM, Ueno Y, Eide TJ, Haraldsen G, Zeissig S, Exley MA, Blumberg RS, Melum E. The biliary epithelium presents antigens to and activates natural killer T cells. Hepatology. 2015 Apr 8. doi: 10.1002/hep.27840. [Epubahead of print] PubMed PMID: 25855031.

30. ®Li J, Jørgensen SF, Maggadottir SM, Bakay M, Warnatz K, Glessner J, Pandey R, Salzer U, Schmidt RE, Perez E, Resnick E, Goldacker S, Buchta M, Witte T, Padyukov L, Videm V, Folseraas T, Atschekzei F, Elder JT, Nair RP, Winkelmann J, Gieger C, Nöthen MM, Büning C, Brand S, Sullivan KE, Orange JS, Fevang B, Schreiber S, Lieb W, Aukrust P, Chapel H, CunninghamRundles C, Franke A, Karlsen TH, Grimbacher B, Hakonarson H, Hammarström L, Ellinghaus E. Association of CLEC16A with human common variable immunodeficiency disorder and role in murine B cells. Nat Commun. 2015 Apr 20;6:6804. doi: 10.1038/ncomms7804. PubMed PMID: 25891430; PubMed Central PMCID: PMC4444044.

36. ®Andreassen OA, Desikan RS, Wang Y, Thompson WK, Schork AJ, Zuber V, Doncheva NT, Ellinghaus E, Albrecht M, Mattingsdal M, Franke A, Lie BA, Mills I, Aukrust P, McEvoy LK, Djurovic S, Karlsen TH, Dale AM. Abundant genetic overlap between blood lipids and immune-mediated diseases indicates shared molecular genetic mechanisms. PLoS One. 2015 Apr 8;10(4):e0123057. doi:10.1371/journal.pone.0123057. eCollection 2015. PubMed PMID: 25853426; PubMed Central PMCID: PMC4390360.

31. Holter JC, Müller F, Bjørang O, Samdal HH, Marthinsen JB, Jenum PA, Ueland T, Frøland SS, Aukrust P, Husebye E, Heggelund L. Etiology of community-acquired pneumonia and diagnostic yields of microbiological methods: a 3-year prospective study in Norway. BMC Infect Dis. 2015 Feb 15;15:64. doi: 10.1186/s12879-015-08035. PubMed PMID: 25887603; PubMed Central PMCID: PMC4334764.

32. Walseng E, Wälchli S, Fallang LE, Yang W, Vefferstad A, Areffard A, Olweus J. Soluble T-cell receptors produced in human cells for targeted delivery. PLoS One. 2015 Apr 13;10(4):e0119559. doi: 10.1371/journal.pone.0119559. eCollection 2015. PubMed PMID: 25875651; PubMed Central PMCID: PMC4395278.

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37. Bryn V, Halvorsen B, Ueland T, Isaksen J, Kolkova K, Ravn K, Skjeldal OH. Brain derived neurotrophic factor (BDNF) and autism spectrum disorders (ASD) in childhood. Eur J Paediatr Neurol. 2015 Jul;19(4):411-4. doi: 10.1016/j. ejpn.2015.03.005. Epub 2015 Mar 18. PubMed PMID: 25847750. 38. ®Vesterhus M, Hov JR, Holm A, Schrumpf E, Nygård S, Godang K, Andersen IM, Naess S, Thorburn D, Saffioti F, Vatn M, Gilja OH, Lund-Johansen F, Syversveen T, Brabrand K, Parés A, Ponsioen CY, Pinzani M, Färkkilä M, Moum B, Ueland T, Røsjø H, Rosenberg W, Boberg KM, Karlsen TH. Enhanced liver fibrosis

JEBSEN INFLAMMATION RESEARCH CENTER (JIRC)

score predicts transplant-free survival in primary sclerosing cholangitis. Hepatology. 2015 Jul;62(1):188-97. doi: 10.1002/hep.27825. Epub 2015 Apr 28. PubMed PMID:25833813. 39. Persson LJ, Aanerud M, Hiemstra PS, Michelsen AE, Ueland T, Hardie JA, Aukrust P, Bakke PS, Eagan TM. Vitamin D, vitamin D binding protein, and longitudinal outcomes in COPD. PLoS One. 2015 Mar 24;10(3):e0121622. doi: 10.1371/journal.pone.0121622. eCollection 2015. PubMed PMID: 25803709; PubMed Central PMCID: PMC4372215. 40. Blom AM, Österborg A, Mollnes TE, Okroj M. Antibodies reactive to cleaved sites in complement proteins enable highly specific measurement of soluble markers of complement activation. Mol Immunol. 2015 Aug;66(2):16470. doi: 10.1016/j.molimm.2015.02.029. Epub 2015 Mar 18. PubMed PMID: 25795308. 41. Kasprzycka M, Hammarström C, Haraldsen G. Tenascins in fibrotic disorders-from bench to bedside. Cell Adh Migr. 2015;9(1-2):83-9. doi :10.4161/19336918.2014.994901. PubMed PMID: 25793575. 42. Øynebråten I, Barois N, Bergeland T, Küchler AM, Bakke O, Haraldsen G. Oligomerized, filamentous surface presentation of RANTES/CCL5 on vascular endothelial cells. Sci Rep. 2015 Mar 20;5:9261. doi: 10.1038/ srep09261. PubMed PMID: 25791723; PubMed Central PMCID: PMC4367157. 43. Tonby K, Ruhwald M, Kvale D, Dyrhol-Riise AM. IP-10 measured by Dry Plasma Spots as biomarker for therapy responses in Mycobacterium Tuberculosis infection. Sci Rep. 2015 Mar 18;5:9223. doi: 10.1038/srep09223. PubMed PMID: 25783975; PubMed Central PMCID: PMC4363864. 44. Arora S, Andreassen AK, Andersson B, Gustafsson F, Eiskjaer H, Bøtker HE, Rådegran G, Gude E, Ioanes D, Solbu D, Sigurdardottir V, Dellgren G, Erikstad I, Solberg OG, Ueland T, Aukrust P, Gullestad L; SCHEDULE (SCandinavian Heart transplant everolimus De novo stUdy with earLy calcineurin inhibitors avoidancE) Investigators. The Effect of Everolimus Initiation and Calcineurin Inhibitor Elimination on Cardiac Allograft Vasculopathy in De Novo Recipients: One-Year Results of a Scandinavian Randomized Trial. Am J Transplant. 2015 Jul;15(7):1967-75. doi: 10.1111/ajt.13214. Epub 2015 Mar 17. PubMed PMID: 25783974. 45. Røsjø E, Myhr KM, Løken-Amsrud KI, Bakke SJ, Beiske AG, Bjerve KS, Hovdal H, Lilleås F, Midgard R, Pedersen T, Šaltytė Benth

J, Torkildsen Ø, Wergeland S, Michelsen AE, Aukrust P, Ueland T, Holmøy T. Vitamin D status and effect of interferon-β1a treatment on MRI activity and serum inflammation markers in relapsing-remitting multiple sclerosis. J Neuroimmunol. 2015 Mar 15;280:21-8. doi: 10.1016/j. jneuroim.2015.02.001. Epub 2015 Feb 11. PubMed PMID: 25773151. 46. Sveaas SH, Berg IJ, Provan SA, Semb AG, Olsen IC, Ueland T, Aukrust P, Vøllestad N, Hagen KB, Kvien TK, Dagfinrud H. Circulating levels of inflammatory cytokines and cytokine receptors in patients with ankylosing spondylitis: a cross-sectional comparative study. Scand J Rheumatol. 2015;44(2):118-24. doi: 10.3109/03009742.2014.956142. PubMed PMID: 25756521. 47. ®Wittig M, Anmarkrud JA, Kässens JC, Koch S, Forster M, Ellinghaus E, Hov JR, Sauer S, Schimmler M, Ziemann M, Görg S, Jacob F, Karlsen TH, Franke A. Development of a high-resolution NGS-based HLA-typing and analysis pipeline. Nucleic Acids Res. 2015 Jun 23;43(11):e70. doi: 10.1093/nar/gkv184. Epub 2015 Mar 9. PubMed PMID: 25753671; PubMed Central PMCID: PMC4477639. 48. Sundnes O, Pietka W, Loos T, Sponheim J, Rankin AL, Pflanz S, Bertelsen V, Sitek JC, Hol J, Haraldsen G, Khnykin D. Epidermal Expression and Regulation of Interleukin-33 during Homeostasis and Inflammation: Strong Species Differences. J Invest Dermatol. 2015 Jul;135(7):177180. doi: 10.1038/jid.2015.85. Epub 2015 Mar 4. PubMed PMID: 25739051. 49. ®Thorsen T, Dahlgren US, Aandahl EM, Grzyb K, Karlsen TH, Boberg KM, Rydberg L, Naper C, Foss A, Bennet W. Liver transplantation with deceased ABO-incompatible donors is life-saving but associated with increased risk of rejection and post-transplant complications. Transpl Int. 2015 Jul;28(7):800-12. doi: 10.1111/ tri.12552. PubMed PMID: 25736519. 50. Lindenskov PH, Castellheim A, Saugstad OD, Mollnes TE. Meconium aspiration syndrome: possible pathophysiological mechanisms and future potential therapies. Neonatology. 2015;107(3):225-30. PubMed PMID: 25721501. 51. Skarpengland T, Laugsand LE, Janszky I, Luna L, Halvorsen B, Platou CG, Wang W, Vatten LJ, Damås JK, Aukrust P, Bjørås M, Åsvold BO. Genetic variants in the DNA repair gene NEIL3 and the risk of myocardial infarction in a nested case-control study. The HUNT Study. DNA Repair (Amst). 2015 Apr;28:21-7. doi: 10.1016/j. dnarep.2015.01.013. Epub 2015 Feb 2. PubMed PMID: 25703835.

TWO YEARS OF OPERATION

JEBSEN INFLAMMATION RESEARCH CENTER (JIRC)

52. Maggadottir SM, Li J, Glessner JT, Li YR, Wei Z, Chang X, Mentch FD, Thomas KA, Kim CE, Zhao Y, Hou C, Wang F, Jørgensen SF, Perez EE, Sullivan KE, Orange JS, Karlsen TH, Chapel H, Cunningham-Rundles C, Hakonarson H. Rare variants at 16p11.2 are associated with common variable immunodeficiency. J Allergy Clin Immunol. 2015 Jun;135(6):1569-77. doi: 10.1016/j. jaci.2014.12.1939. Epub 2015 Feb 10. PubMed PMID: 25678086; PubMed Central PMCID: PMC4461447. 53. ®Berntsen NL, Klingenberg O, Juran BD, Benito de Valle M, Lindkvist B, Lazaridis KN, Boberg KM, Karlsen TH, Hov JR. Association Between HLA Haplotypes and Increased Serum Levels of IgG4 in Patients With Primary Sclerosing Cholangitis. Gastroenterology. 2015 May;148(5):924-927.e2. doi: 10.1053/j. gastro.2015.01.041. Epub 2015 Feb 2. PubMed PMID: 25655558; PubMed Central PMCID: PMC4409500. 54. Abbas A, Gregersen I, Holm S, Daissormont I, Bjerkeli V, Krohg-Sørensen K, Skagen KR, Dahl TB, Russell D, Almås T, Bundgaard D, Alteheld LH, Rashidi A, Dahl CP, Michelsen AE, Biessen EA, Aukrust P, Halvorsen B, Skjelland M. Interleukin 23 levels are increased in carotid atherosclerosis: possible role for the interleukin 23/ interleukin 17 axis. Stroke. 2015 Mar;46(3):7939. doi: 10.1161/STROKEAHA.114.006516. Epub 2015 Feb 3. PubMed PMID: 25649806. 55. Asprusten TT, Fagermoen E, Sulheim D, Skovlund E, Sørensen Ø, Mollnes TE, Wyller VB. Study findings challenge the content validity of the Canadian Consensus Criteria for adolescent chronic fatigue syndrome. Acta Paediatr. 2015 May;104(5):498-503. doi: 10.1111/apa.12950. Epub 2015 Mar 23. PubMed PMID: 25640602. 56. ®Wergeland I, Pullar N, Assmus J, Ueland T, Tonby K, Feruglio S, Kvale D, Damås JK, Aukrust P, Mollnes TE, Dyrhol-Riise AM. IP-10 differentiates between active and latent tuberculosis irrespective of HIV status and declines during therapy. J Infect. 2015 Apr;70(4):381-91. doi: 10.1016/j.jinf.2014.12.019. Epub 2015 Jan 15. PubMed PMID: 25597826. 57. Goyette P, Boucher G, Mallon D, Ellinghaus E, Jostins L, Huang H, Ripke S, Gusareva ES, Annese V, Hauser SL, Oksenberg JR, Thomsen I, Leslie S; International Inflammatory Bowel Disease Genetics Consortium; Australia and New Zealand IBDGC; Belgium IBD Genetics Consortium; Italian Group for IBD Genetic Consortium; NIDDK Inflammatory Bowel Disease Genetics Consortium; United Kingdom IBDGC; Wellcome Trust Case Control Consortium; Quebec IBD Genetics Consortium, Daly MJ, Van Steen K,

TWO YEARS OF OPERATION

Duerr RH, Barrett JC, McGovern DP, Schumm LP, Traherne JA, Carrington MN, Kosmoliaptsis V, Karlsen TH, Franke A, Rioux JD. High-density mapping of the MHC identifies a shared role for HLA-DRB1*01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis. Nat Genet. 2015 Feb;47(2):172-9. doi: 10.1038/ng.3176. Epub 2015 Jan 5. PubMed PMID: 25559196; PubMed Central PMCID: PMC4310771. 58. Wyller VB, Sørensen Ø, Sulheim D, Fagermoen E, Ueland T, Mollnes TE. Plasma cytokine expression in adolescent chronic fatigue syndrome. Brain Behav Immun. 2015 May;46:80-6. doi: 10.1016/j.bbi.2014.12.025. Epub 2014 Dec 31. PubMed PMID: 25555530. 59. ®Næss S, Lie BA, Melum E, Olsson M, Hov JR, Croucher PJ, Hampe J, Thorsby E, Bergquist A, Traherne JA, Schrumpf E, Boberg KM, Schreiber S, Franke A, Karlsen TH. Refinement of the MHC risk map in a scandinavian primary sclerosing cholangitis population. PLoS One. 2014 Dec 18;9(12):e114486. doi:10.1371/ journal.pone.0114486. eCollection 2014. PubMed PMID: 25521205; PubMed Central PMCID: PMC4270690. 60. ®Berg A, Patel S, Gonca M, David C, Otterdal K, Ueland T, Dalen I, Kvaløy JT, Mollnes TE, Aukrust P, Langeland N. Cytokine network in adults with falciparum malaria and HIV-1: increased IL-8 and IP-10 levels are associated with disease severity. PLoS One. 2014 Dec 11;9(12):e114480. doi: 10.1371/journal.pone.0114480. eCollection 2014. PubMed PMID: 25503583; PubMed Central PMCID: PMC4263737. 61. Ueland T, Olarescu NC, Jørgensen AP, Otterdal K, Aukrust P, Godang K, Lekva T, Bollerslev J. Increased serum and bone matrix levels of the secreted Wnt antagonist DKK-1 in patients with growth hormone deficiency in response to growth hormone treatment. J Clin Endocrinol Metab. 2015 Feb;100(2):736-43. doi: 10.1210/ jc.2014-2912. Epub 2014 Dec 2. PubMed PMID: 25459913. 62. ®Eskesen AN, Bjøro K, Aandahl EM, Line PD, Melum E. Low use of surveillance and early diagnosis of hepatocellular carcinoma in Norway--a population-based cohort study. Cancer Epidemiol. 2014 Dec;38(6):741-7. PubMed PMID: 25454262. 63. Abraityte A, Gullestad L, Askevold ET, Nymo S, Dahl CP, Aakhus S, Aukrust P, Ueland T. The Notch ligand Delta-like 1 is elevated and associated with mortality in patients with symptomatic aortic stenosis. Int J Cardiol. 2015

JEBSEN INFLAMMATION RESEARCH CENTER (JIRC)

Feb 1;180:18-20. doi: 10.1016/j.ijcard.2014.11.111. Epub 2014 Nov 18. PubMed PMID: 25438200.

PMID: 25268365; PubMed Central PMCID: PMC4182541.

64. ®Landskron J, Helland Ø, Torgersen KM, Aandahl EM, Gjertsen BT, Bjørge L, Taskén K. Activated regulatory and memory T-cells accumulate in malignant ascites from ovarian carcinoma patients. Cancer Immunol Immunother. 2015 Mar;64(3):337-47. doi: 10.1007/s00262-014-16366. Epub 2014 Nov 22. PubMed PMID: 25416072.

70. Rogne M, Taskén K. Compartmentalization of cAMP signaling in adipogenesis, lipogenesis, and lipolysis. Horm Metab Res. 2014 Nov;46(12):833-40. doi: 10.1055/s-0034-1389955. Epub 2014 Sep 23. Review. PubMed PMID: 25247872.

65. ®Finsen AV, Ueland T, Sjaastad I, Ranheim T, Ahmed MS, Dahl CP, Askevold ET, Aakhus S, Husberg C, Fiane AE, Lipp M, Gullestad L, Christensen G, Aukrust P, Yndestad A. The homeostatic chemokine CCL21 predicts mortality in aortic stenosis patients and modulates left ventricular remodeling. PLoS One. 2014 Nov 14;9(11):e112172. doi: 10.1371/journal. pone.0112172. eCollection 2014. PubMed PMID: 25398010; PubMed Central PMCID: PMC4232360. 66. ®Trøseid M, Ueland T, Hov JR, Svardal A, Gregersen I, Dahl CP, Aakhus S, Gude E, Bjørndal B, Halvorsen B, Karlsen TH, Aukrust P, Gullestad L, Berge RK, Yndestad A. Microbiota-dependent metabolite trimethylamine-N-oxide is associated with disease severity and survival of patients with chronic heart failure. J Intern Med. 2015 Jun;277(6):717-26. doi: 10.1111/joim.12328. Epub 2014 Dec 1. PubMed PMID: 25382824. 67. Engberg AE, Nilsson PH, Huang S, Fromell K, Hamad OA, Mollnes TE, Rosengren-Holmberg JP, Sandholm K, Teramura Y, Nicholls IA, Nilsson B, Ekdahl KN. Prediction of inflammatory responses induced by biomaterials in contact with human blood using protein fingerprint from plasma. Biomaterials. 2015 Jan;36:55-65. doi: 10.1016/j.biomaterials.2014.09.011. Epub 2014 Oct 5. PubMed PMID: 25292422. 68. Husebø GR, Bakke PS, Aanerud M, Hardie JA, Ueland T, Grønseth R, Persson LJ, Aukrust P, Eagan TM. Predictors of exacerbations in chronic obstructive pulmonary disease--results from the Bergen COPD cohort study. PLoS One. 2014 Oct 3;9(10):e109721. doi: 10.1371/ journal.pone.0109721. eCollection 2014. PubMed PMID: 25279458; PubMed Central PMCID: PMC4184893. 69. Sveaas SH, Berg IJ, Provan SA, Semb AG, Hagen KB, Vøllestad N, Fongen C, Olsen IC, Michelsen A, Ueland T, Aukrust P, Kvien TK, Dagfinrud H. Efficacy of high intensity exercise on disease activity and cardiovascular risk in active axial spondyloarthritis: a randomized controlled pilot study. PLoS One. 2014 Sep 30;9(9):e108688. doi: 10.1371/journal. pone.0108688. eCollection 2014. PubMed

71. Pedersen KK, Manner IW, Seljeflot I, Kvale D, Os I, Gerstoft J, Nielsen SD, Trøseid M. Monocyte activation, but not microbial translocation, is independently associated with markers of endovascular dysfunction in HIV-infected patients receiving cART. J Acquir Immune Defic Syndr. 2014 Dec 1;67(4):370-4. doi: 10.1097/ QAI.0000000000000339. PubMed PMID: 25226210. 72. Pettersen PS, Brox IK, Naman E, Bruun JN, Dyrhol-Riise AM, Trøseid M, Johannessen A. Antiretroviral treatment failure predicts mortality in rural Tanzania. Int J STD AIDS. 2015 Aug;26(9):633-9. doi: 10.1177/0956462414548460. Epub 2014 Aug 13. PubMed PMID: 25122578. 73. Smedbråten YV, Sagedal S, Mjøen G, Hartmann A, Fagerland MW, Rollag H, Mollnes TE, Thiel S. High ficolin-3 level at the time of transplantation is an independent risk factor for graft loss in kidney transplant recipients. Transplantation. 2015 Apr;99(4):791-6. doi: 10.1097/TP.0000000000000422. PubMed PMID: 25222012. 74. ®Ueland T, Gullestad L, Nymo SH, Yndestad A, Aukrust P, Askevold ET. Inflammatory cytokines as biomarkers in heart failure. Clin Chim Acta. 2015 Mar 30;443:71-7. doi: 10.1016/j. cca.2014.09.001. Epub 2014 Sep 6. PubMed PMID: 25199849. 75. Hein E, Munthe-Fog L, Thiara AS, Fiane AE, Mollnes TE, Garred P. Heparin-coated cardiopulmonary bypass circuits selectively deplete the pattern recognition molecule ficolin-2 of the lectin complement pathway in vivo. Clin Exp Immunol. 2015 Feb;179(2):294-9. doi: 10.1111/ cei.12446. PubMed PMID: 25174443; PubMed Central PMCID: PMC4298406. 76. ®Ohm IK, Gao E, Belland Olsen M, Alfsnes K, Bliksøen M, Øgaard J, Ranheim T, Nymo SH, Holmen YD, Aukrust P, Yndestad A, Vinge LE. Toll-like receptor 9-activation during onset of myocardial ischemia does not influence infarct extension. PLoS One. 2014 Aug 15;9(8):e104407. doi: 10.1371/journal.pone.0104407.eCollection 2014. PubMed PMID: 25126943; PubMed Central PMCID: PMC4134200.

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JEBSEN INFLAMMATION RESEARCH CENTER (JIRC)

77. Ohm IK, Alfsnes K, Belland Olsen M, Ranheim T, Sandanger Ø, Dahl TB, Aukrust P, Finsen AV, Yndestad A, Vinge LE. Toll-like receptor 9 mediated responses in cardiac fibroblasts. PLoS One. 2014 Aug 15;9(8):e104398. doi: 10.1371/journal.pone.0104398. eCollection 2014. PubMed PMID: 25126740; PubMed Central PMCID: PMC4134207. 78. Lossius A, Johansen JN, Vartdal F, Robins H, Jūratė Šaltytė B, Holmøy T, Olweus J. Highthroughput sequencing of TCR repertoires in multiple sclerosis reveals intrathecal enrichment of EBV-reactive CD8+ T cells. Eur J Immunol. 2014 Nov;44(11):3439-52. doi: 10.1002/ eji.201444662. Epub 2014 Sep 16. PubMed PMID: 25103993. 79. Volokhina EB, Westra D, van der Velden TJ, van de Kar NC, Mollnes TE, van den Heuvel LP. Complement activation patterns in atypical haemolytic uraemic syndrome during acute phase and in remission. Clin Exp Immunol. 2015 Aug;181(2):306-13. doi: 10.1111/cei.12426. PubMed PMID: 25079699; PubMed Central PMCID: PMC4516446. 80. Spurgeon BE, Aburima A, Oberprieler NG, Taskén K, Naseem KM. Multiplexed phosphospecific flow cytometry enables largescale signaling profiling and drug screening in blood platelets. J Thromb Haemost. 2014 Oct;12(10):1733-43. doi: 10.1111/jth.12670. Epub 2014 Sep 18. PubMed PMID: 25056834. 81. Nymo S, Niyonzima N, Espevik T, Mollnes TE. Cholesterol crystal-induced endothelial cell activation is complementdependent and mediated by TNF. Immunobiology. 2014 Oct;219(10):786-92. doi: 10.1016/j. imbio.2014.06.006. Epub 2014 Jul 5. PubMed PMID: 25053140. 82. Pidoux G, Gerbaud P, Dompierre J, Lygren B, Solstad T, Evain-Brion D, Taskén K. A PKAezrin-Cx43 signaling complex controls gap junction communication and thereby trophoblast cell fusion. J Cell Sci. 2014 Oct 1;127(Pt 19):417285. doi: 10.1242/jcs.149609. Epub 2014 Jul 22. PubMed PMID: 25052094. 83. ®Lappegård KT, Garred P, Jonasson L, Espevik T, Aukrust P, Yndestad A, Mollnes TE, Hovland A. A vital role for complement in heart disease. Mol Immunol. 2014 Oct;61(2):126-34. doi: 10.1016/j.molimm.2014.06.036. Epub 2014 Jul 16. Review. PubMed PMID: 25037633. 84. Gustavsen MW, Viken MK, Celius EG, Berge T, Mero IL, Berg-Hansen P, Aarseth JH, Myhr KM, Søndergaard HB, Sellebjerg F, Oturai AB, Hillert J, Alfredsson L, Olsson T, Kockum I, Lie BA, Harbo HF. Oligoclonal band phenotypes in MS differ in their HLA class II association, while specific KIR ligands at HLA class I show association to MS in general. J Neuroimmunol. 2014 Sep 15;274(1-2):174-9. doi: 10.1016/j.

TWO YEARS OF OPERATION

jneuroim.2014.06.024. Epub 2014 Jul 6. PubMed PMID: 25037176. 85. ®Neupane SP, Lien L, Martinez P, Aukrust P, Ueland T, Mollnes TE, Hestad K, Bramness JG. High frequency and intensity of drinking may attenuate increased inflammatory cytokine levels of major depression in alcohol-use disorders. CNS Neurosci Ther. 2014 Oct;20(10):898-904. doi: 10.1111/cns.12303. Epub 2014 Jul 3. PubMed PMID: 24995667; PubMed Central PMCID: PMC4257130. 86. Ueland T, Rollag H, Hartmann A, Jardine A, Humar A, Bignamini AA, Åsberg A, Aukrust P. Increased osteoprotegerin predicts poor virological outcome during anticytomegalovirus therapy in solid organ transplant recipients. Transplantation. 2015 Jan;99(1):100-5. doi: 10.1097/TP.0000000000000227. PubMed PMID: 24983306. 87. Hirschfield GM, Karlsen TH. Genetic risks link autoimmune hepatitis to other autoimmune liver disease. Gastroenterology. 2014 Aug;147(2):270-3. doi: 10.1053/j. gastro.2014.06.020. Epub 2014 Jun 25. PubMed PMID: 24973678. 88. Trøseid M, Ditlevsen S, Hvid T, Gerstoft J, Grøndahl T, Pedersen BK, Nielsen SD, Lindegaard B. Reduced trunk fat and triglycerides after strength training are associated with reduced LPS levels in HIVinfected individuals. J Acquir Immune Defic Syndr. 2014 Jun 1;66(2):e52-4. doi: 10.1097/ QAI.0000000000000132. PubMed PMID: 24608893. 89. Pandya AD, Leergaard TB, Dissen E, Haraldsen G, Spurkland A. Expression of the T cellspecific adapter protein in human tissues. Scand J Immunol. 2014 Sep;80(3):169-79. doi: 10.1111/ sji.12199. PubMed PMID: 24910151. 90. Narverud I, Retterstøl K, Iversen PO, Halvorsen B, Ueland T, Ulven SM, Ose L, Aukrust P, Veierød MB, Holven KB. Markers of atherosclerotic development in children with familial hypercholesterolemia: a literature review. Atherosclerosis. 2014 Aug;235(2):299-309. doi: 10.1016/j.atherosclerosis.2014.05.917. Epub 2014 May 20. Review. PubMed PMID:24908240. 91. Tveita AA, Schjesvold FH, Sundnes O, Haabeth OA, Haraldsen G, Bogen B. Indirect CD4+ T-cell-mediated elimination of MHC II(NEG) tumor cells is spatially restricted and fails to prevent escape of antigen-negative cells. Eur J Immunol. 2014 Sep;44(9):2625-37. doi: 10.1002/eji.201444659. Epub 2014 Jun 20. PubMed PMID: 24846412. 92. Ostvik AE, Granlund Av, Gustafsson BI, Torp SH, Espevik T, Mollnes TE, Damås JK, Sandvik AK. Mucosal toll-like receptor 3-dependent synthesis of complement factor B and systemic

JEBSEN INFLAMMATION RESEARCH CENTER (JIRC)

complement activation in inflammatory bowel disease. Inflamm Bowel Dis. 2014 Jun;20(6):9951003. doi: 10.1097/MIB.0000000000000035. PubMed PMID: 24739633. 93. ®Halvorsen B, Smedbakken LM, Michelsen AE, Skjelland M, Bjerkeli V, Sagen EL, Taskén K, Bendz B, Gullestad L, Holm S, Biessen EA, Aukrust P. Activated platelets promote increased monocyte expression of CXCR5 through prostaglandin E2-related mechanisms and enhance the anti-inflammatory effects of CXCL13. Atherosclerosis. 2014 Jun;234(2):352-9. doi: 10.1016/j.atherosclerosis.2014.03.021. Epub 2014 Mar 31. PubMed PMID: 24732574. 94. Røsjø E, Myhr KM, Løken-Amsrud KI, Bakke SJ, Beiske AG, Bjerve KS, Hovdal H,Lilleås F, Midgard R, Pedersen T, Benth JS, Torkildsen Ø, Wergeland S, Michelsen AE, Aukrust P, Ueland T, Holmøy T. Increasing serum levels of vitamin A, D and E are associated with alterations of different inflammation markers in patients with multiple sclerosis. J Neuroimmunol. 2014 Jun 15;271(1-2):60-5. doi: 10.1016/j.jneuroim.2014.03.014. Epub 2014 Mar 24. PubMed PMID: 24713402. 95. ®Skånland SS, Moltu K, Berge T, Aandahl EM, Taskén K. T-cell co-stimulation through the CD2 and CD28 co-receptors induces distinct signalling responses. Biochem J. 2014 Jun 15;460(3):399-410. doi: 10.1042/BJ20140040. PubMed PMID: 24665965. 96. Ovchinnikova OA, Folkersen L, Persson J, Lindeman JH, Ueland T, Aukrust P, Gavrisheva N, Shlyakhto E, Paulsson-Berne G, Hedin U, Olofsson PS, Hansson GK. The collagen crosslinking enzyme lysyl oxidase is associated with the healing of human atherosclerotic lesions. J Intern Med. 2014 Nov;276(5):525-36. doi: 10.1111/ joim.12228. Epub 2014 Mar 24. PubMed PMID: 24588843. 97. ®Naess S, Björnsson E, Anmarkrud JA, Al Mamari S, Juran BD, Lazaridis KN, Chapman R, Bergquist A, Melum E, Marsh SG, Schrumpf E, Lie BA, Boberg KM, Karlsen TH, Hov JR. Small duct primary sclerosing cholangitis without inflammatory bowel disease is genetically different from large duct disease. Liver Int. 2014 Nov;34(10):1488-95. doi: 10.1111/liv.12492. Epub 2014 Mar 7. PubMed PMID: 24517468; PubMed Central PMCID: PMC4128902. 98. Manner IW, Baekken M, Oektedalen O, Kvale D, Nowak P, Nielsen SD, Os I, Trøseid M. Plasma lipopolysaccharide and triglycerides are independently associated and both markers correlate with the development of metabolic syndrome in HIV infection. J Acquir Immune Defic Syndr. 2014 Apr 1;65(4):e158-61. doi: 10.1097/QAI.0000000000000055. PubMed PMID: 24577189.

99. Bossini Henriksen EK, Melum E, Karlsen TH. Update on primary sclerosing cholangitis genetics. Curr Opin Gastroenterol. 2014 May;30(3):310-9. doi: 10.1097/ MOG.0000000000000052. Review. PubMed PMID: 24565892. 100. Bossini-Castillo L, de Kovel C, Kallberg H, van 't Slot R, Italiaander A, Coenen M, Tak PP, Posthumus MD, Wijmenga C, Huizinga T, van der Helm-van Mil AH, Stoeken-Rijsbergen G, Rodriguez-Rodriguez L, Balsa A, GonzálezÁlvaro I, González-Gay MÁ, Gómez-Vaquero C, Franke B; LifeLines Cohort Study, Vermeulen S, van der Horst-Bruinsma Ie, Dijkmans BA, Wolbink GJ, Ophoff RA, Maehlen MT, van Riel P, Merriman M, Klareskog L, Lie BA, Merriman T, Crusius JB, Brouwer E, Martin J, de Vries N, Toes R, Padyukov L, Koeleman BP. A genomewide association study of rheumatoid arthritis without antibodies against citrullinated peptides. Ann Rheum Dis. 2015 Mar;74(3):e15. doi: 10.1136/annrheumdis-2013-204591. Epub 2014 Feb 14. PubMed PMID: 24532677. 101. Trøseid M, Manner IW, Pedersen KK, Haissman JM, Kvale D, Nielsen SD. Microbial translocation and cardiometabolic risk factors in HIV infection. AIDS Res Hum Retroviruses. 2014 Jun;30(6):514-22. doi: 10.1089/AID.2013.0280. Epub 2014 Mar 25. Review. PubMed PMID: 24521167; PubMed Central PMCID: PMC4046217. 102. ®Halvorsen B, Dahl TB, Smedbakken LM, Singh A, Michelsen AE, Skjelland M, Krohg-Sørensen K, Russell D, Höpken UE, Lipp M, Damås JK, Holm S, Yndestad A, Biessen EA, Aukrust P. Increased levels of CCR7 ligands in carotid atherosclerosis: different effects in macrophages and smooth muscle cells. Cardiovasc Res. 2014 Apr 1;102(1):148-56. doi: 10.1093/cvr/cvu036. Epub 2014 Feb 11. PubMed PMID: 24518141. 103. Skjeflo EW, Christiansen D, Espevik T, Nielsen EW, Mollnes TE. Combined inhibition of complement and CD14 efficiently attenuated the inflammatory response induced by Staphylococcus aureus in a human whole blood model. J Immunol. 2014 Mar 15;192(6):2857-64. doi: 10.4049/jimmunol.1300755. Epub 2014 Feb 10. PubMed PMID: 24516199. 104. ®Askevold ET, Gullestad L, Dahl CP, Yndestad A, Ueland T, Aukrust P. Interleukin-6 signaling, soluble glycoprotein 130, and inflammation in heartfailure. Curr Heart Fail Rep. 2014 Jun;11(2):146-55. doi: 10.1007/s11897-014-0185-9. Review. PubMed PMID: 24477903. 105. Vik R, Busnelli M, Parolini C, Bjørndal B, Holm S, Bohov P, Halvorsen B, Brattelid T, Manzini S, Ganzetti GS, Dellera F, Nygård OK, Aukrust P, Sirtori CR, Chiesa G, Berge RK. An immunomodulating fatty acid analogue targeting mitochondria exerts anti-atherosclerotic effect beyond plasma cholesterollowering activity in apoe(-/-) mice. PLoS One.

TWO YEARS OF OPERATION

JEBSEN INFLAMMATION RESEARCH CENTER (JIRC)

2013 Dec 4;8(12):e81963. doi: 10.1371/journal. pone.0081963. eCollection 2013. PubMed PMID: 24324736; PubMed Central PMCID: PMC3852987. 106. Holven KB, Retterstøl K, Ueland T, Ulven SM, Nenseter MS, Sandvik M, Narverud I, Berge KE, Ose L, Aukrust P, Halvorsen B. Subjects with low plasma HDL cholesterol levels are characterized by an inflammatory and oxidative phenotype. PLoS One. 2013 Nov 11;8(11):e78241. doi: 10.1371/journal.pone.0078241 eCollection 2013. PubMed PMID: 24244297; PubMed Central PMCID: PMC3823918. 107. ®Taraldsrud E, Fevang B, Aukrust P, Beiske KH, Fløisand Y, Frøland S, Rollag H, Olweus J. Common variable immunodeficiency revisited: normal generation of naturally occurring dendritic cells that respond to Toll-like receptors 7 and 9. Clin Exp Immunol. 2014 Mar;175(3):439-48. doi: 10.1111/cei.12239. PubMed PMID: 24237110; PubMed Central PMCID: PMC3927904. 108. Nenseter MS, Aukrust P, Ose L, Holven KB. Low level of inflammatory marker in hyperhomocysteinemic patients on statin therapy. Scand J Clin Lab Invest. 2014 Jan;74(1):1-7. doi: 10.3109/00365513.2013.854926. Epub 2013 Nov 18. PubMed PMID: 24236948. 109. ®Andersen IM, Tengesdal G, Lie BA, Boberg KM, Karlsen TH, Hov JR. Effects of coffee consumption, smoking, and hormones on risk for primary sclerosing cholangitis. Clin Gastroenterol Hepatol. 2014 Jun;12(6):1019-28. doi: 10.1016/j.cgh.2013.09.024. Epub 2013 Sep 25. PubMed PMID: 24076415. 110. Lone AM, Taskén K. Proinflammatory and immunoregulatory roles of eicosanoids in T cells. Front Immunol. 2013 Jun 4;4:130. doi: 10.3389/fimmu.2013.00130. eCollection 2013. PubMed PMID: 23760108; PubMed Central PMCID: PMC3671288.

TWO YEARS OF OPERATION

JEBSEN INFLAMMATION RESEARCH CENTER (JIRC)

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8 Trykksak 6

Redaktør: Tara Sarin, UiO Foto©UiO: Øystein Horgmo og Kristin Ellefsen, UiO Foto: Terje Heiestad, Millimeterpress Design: Millimeterpress/Merete Dagsgard. Trykk: Rolf Ottesen

K.G. JEBSEN INFLAMMATION RESEARCH CENTRE (JIRC) Visiting address Department of pathology Oslo University Hospital - Rikshospitalet Sognsvannsveien 20 N-0027 Oslo Mailing address K.G. Jebsen Inflammation Research Centre Department of Pathology Oslo University Hospital - Rikshospitalet P.O. Box 4956 Nydalen N-0424 Oslo Norway PHONE (+47) 23071492 FAX (+47) 23071511 www.med.uio.no/jebseninflammation http://norinnetwork.no/