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VisitVisit thethe NoPSCNoPSC webweb pages:pages: www.ous-research.no/nopscwww.ous-research.no/nopsc andand www.med.uio.no/klinmed/english/research/groups/primary-sclerosing-cholangitis/ 2 NoPSC ‌‌⁞ Annual report 2015

Content: Norwegian Primary Sclerosing Cholangitis 1 What is PSC? PAGE 3

Research Center (NoPSC) 2 Aims of the Center PAGE 3

Annual report 3 The Leader´s Corner PAGE 4

4 Overview of the Center PAGE 5 • Organization PAGE 5 • Monitoring Committee PAGE 6 2015 • Scientific Advisory Board PAGE 6 • Guest Professors PAGE 7 • Management PAGE 7 • Accounting PAGE 8

5 Highlights 2015 PAGE 9

6 Project Portfolio PAGE 12 • Experimental Group PAGE 12 • Genomics and Metagenomics Group PAGE 14 • Clinical Research Group PAGE 16

7 Awards PAGE 19

8 Biobank PAGE 20

Unit for Experimental 9 Gnotobiology PAGE 21

10 Networks PAGE 22

11 International lectures PAGE 25 NoPSC ANNUAL REPORT 2015

More information at the web pages: www.ous-research.no/nopsc PAGE 26 www.med.uio.no/klinmed/english/research/groups/ 12 IPSCSG Annual report primary-sclerosing-cholangitis/index.html Editors: Tom Hemming Karlsen and Julia Ferkis PUBLISHER: Oslo University Hospital 13 Publications PAGE 28 PRINT: Møklegaard Print Shop AS, 2016. SAMPLES: 150 ) r o t a r t llu s I NoPSC ⁞ Annual report 2015 3 I ud, C M ud, er o v T ) r o t a r t I llu s

What is PSC? I Primary sclerosing cholangitis (PSC) belongs to the group of autoimmune liver diseases.

I PSC is a chronic inflammatory disorder of the bile ducts. PSC ud, C M ud, er

leads to progressive strictures of the bile ducts and ultimately o v T to liver cirrhosis.

There is an increased risk of cancer of both the bile ducts (160-1500x) and the large bowel (5x). PSC is more common I in Northern Europe, where approximately 1:10.000 individuals are affected. There is no effective medical treatment available, and PSC is one of the most common indications for ) r o t liver transplantation in Scandinavia. a r t llu s I Affected individuals are typically young (30-40 years old) and

I have concurrent inflammatory bowel disease (IBD) in 60-80% ud, C M ud,

er of the cases. Disease course is highly variable from patient to o v T patient, but the median time from diagnosis to liver transplantation is 10-15 years. I

Primary Sclerosing Cholangitis (PSC) is a patchwork of different phenotypes in addition to the bile duct affection. Most important are inflammatory bowel disease (IBD), malignancy and other autoimmune diseases.

Aims of the PSC Research Center

• Ensure targeted and prudent management of the private donation • Motivate high-quality PSC research in Norway • Coordinate and distribute resources for PSC research in Norway • Establish international collaborations when needed • Establish and run Biobank and PSC Registry 4 NoPSC ‌‌⁞ Annual report 2015

The Leader´s Corner Professor Tom Hemming Karlsen

The year of 2015 was a special year in many aspects. As can be positions in key medical associations. This includes Prof. Lars seen, the publication list harbors a record number of 38 Aabakken (Oslo) serving as president of ESGE (European publications, with no less than 6 articles in Hepatology (for Society of Gastroenterological Endoscopy), Prof. Odd Helge many years the leading journal in Hepatology with an impact Gilja (Bergen) serving as president of EFSUMB (European Fede- factor of more than 11). Many other publications in top ration of Societies for Ultrasound in Medicine and Biology) and journals prove success of the ambition we have had within myself serving as vice secretary (“president elect”) of EASL NoPSC: to concentrate on quality – but still be able to deliver a (European Association for the Study of the Liver). The special considerable quantity of articles. It is important to recognize situation is a reflection of the many excellent research that a publication list already constitutes the past, and that the environments in gastroenterology within Norway, and we articles of 2015 represent work already performed. We should use the opportunity to establish closer collaborations therefore have to continue working hard and not rest on the at this strong national arena. laurels of these accomplishments. The international collaborations are a hallmark of NoPSC For this reason, it is reassuring to note that the year of 2015 and still as active as ever. Whilst imposing a significant has been a year of consolidating the research group structure travel burden to maintain and sometimes relatively complex within NoPSC. Importantly, the leaders of the genomic and project organizations, the close and friendly collabo- experimental groups (Johannes Roksund Hov and Espen rations within the International PSC study group (IPSCSG) are Melum) have obtained high-profile, independent funding for absolutely crucial for significant advances in a rare disease like themselves and key personnel in their groups. PSC to be made. In 2015, a major accomplishment within the The Norwegian Research Council “young talented researcher” IPSCSG was the conclusion of the Delphi consensus process on and the Helse Sør-Øst “career stipend” grants, respectively, endpoints for clinical trials in PSC. The process led to a close provide the basis for which these groups can continue to collaboration between regulators and scientists and formed develop into productive independence from the core center the basis of the decision by AASLD to host a 2 days joint funding. For the clinical group, a similar development has been conference in Maryland together with the FDA in March 2016 seen, with in 2015 the establishing of a formal working on the subject. These processes are important for the structure within the Section for Gastroenterology, headed by appropriate interpretation of the many ongoing clinical trials in Kirsten Muri Boberg. Multiple ongoing grant application PSC, from which the first data are anticipated to arrive initiatives aim to strengthen these activities. throughout 2016 and 2017.

Toward the end of 2015, the clinical group of NoPSC has made We are approaching “cruising altitude” with the NoPSC an important outreach to establish a national, collaborative initiative. With now close to 25 researchers and supporting network for autoimmune liver diseases, of which PSC personnel, we should only carefully grow the center size represents an important entity. Autoimmune liver diseases further. There is an ongoing process of consolidating the provide significant challenges for the practicing clinicians. In immunogenetics initiatives, particularly those focusing on the addition to the scientific value of such a network, a closer strong HLA association in PSC, within its own structure. collaboration at the clinical level will help the implementation Inherent to this is a strengthening of our relationship with the of new developments into everyday practice at Norwegian world-leading celiac disease environment in Oslo, led by Prof. hospitals. The Norwegian patient association for autoimmune Ludvig Sollid. This collaboration is an example of how liver diseases is closely involved in the initiative, providing questions deriving from PSC-specific research can be taken important directions for further clinical research. Furthermore, onward in novel constellations as projects dealing with general the clinical collaborations represent the national branch of a and fundamental biological issues. Similar directions can be European initiative to enhance quality of care in rare diseases seen for several areas of research within NoPSC at present (European Reference Networks), in which the involvement of (e.g. for the gut microbiota). PSC is anticipated. All taken together, we have a healthy situation for NoPSC at The international standing of Norwegian gastroenterology is present, forming the best possible platform for our embarking exceptionally strong right now, as evidenced by formal on the next 10-year period of research in 2017. NoPSC ⁞ Annual report 2015 5

Overview of the Norwegian PSC Research Center

NoPSC was established May 2008 at the Medical Department, Rikshospitalet, upon signing the contract between the University of Oslo and Rikshospitalet on the handling of funds from Canica A/S. The basis of this agreement was a donation from Stein Erik Hagen of NOK 100 millions made in September 2007 to substantially strengthen research related to basic and clinical aspects of the chronic liver disease Primary Sclerosing Cholangitis. Approaching the end of this donation period the Center is proud to announce that Canica A/S has provided another NOK 50 millions for a new ten-year period starting in 2017 on the basis of a contractual agreement between Canica A/S and the University of Oslo as of December 2014.

OrganiZation NoPSC has “center status” at the Medical Faculty, University of Oslo and is organized within Oslo University Hospital as a section (level 4 unit) within the Department of Transplantation Medicine at the Clinic for Surgery, Inflammatory Medicine and Transplantation. To maximize the translational opportunities of NoPSC, two of the three research groups comprising NoPSC is organized at the Research Institute of Internal Medicine, Oslo University Hospital (OUS) and one within the Section for Gastroenterology and Hepatology at the Department of Transplantation Medicine.

Internally, NoPSC is organised with an external Monitoring Committee, a Scientific Advisory Board (SAB), a Management, three Research groups and a Biobank.

Oslo University Hospital University of Oslo Clinic for Surgery, Inflammatory Medicine Institute of Clinical Medicine and Transplantation Monitoring committee

Scientific Advisory Norwegian PSC Research Center Board

Management/Administration Biobank Guest Professors

Experimental Hepatology Genomics, Clinical Research Group Metagenomics Group Group

On October 20th Tom H. Karlsen, together with a PSC patient representative, participated in the morning programme of the Norwegian 2nd Channel (TV2) and explained how PSC occurs and how this uncurable disease effects the lives of all concerned. Photo: T V2 Photo: 6 NoPSC ‌‌⁞ Annual report 2015

Monitoring Committee The Committee is supervising all official agreements and financial documents of the Center, and meets twice a year. Apart from presenting all activities, next year’s budget is discussed on the autumn meeting while the Annual report and the accounting are reviewed during the meeting in the summer.

Leader Prof. Ivar Prydz Gladhaug Head of the Institute of Clinical Medicine, University of Oslo

Hans Mossin Nina Paulsen Daniel Sørli Prof. Kristian Bjøro Prof. Pål Aukrust Adm. Head of the Canica A/S Canica A/S Div. of Surgery, Div. of Surgery, Institute of Clinical Inflammatory Medicine Inflammatory Medicine Medicine, and Transplantation, and Transplantation, University of Oslo OUS Rikshospitalet OUS Rikshospitalet

We at Canica are proud of all the work which had been performed by both the management and the researchers at the Norwegian PSC Research Center in 2015. The number of published articles is quite unique, but what is even more important that the research which is performed is innovative and of the highest international standard. The fact that numerous international scientists are affiliated with the Center bears witness of this. We are also impressed by the management’s ability to receive substantial external funding and hence secure the Center’s existence for a long time. We are looking forward to the continuation of this important work for the benefit of patients with primary sclerosing cholangitis. By Daniel Sørli.

Scientific Advisory Board In 2015 the Scientific Advisory Board (SAB) was formally established. The Center has great expectations regarding this highly competent board to evaluate the research being performed and the advice our scientists will receive on their professional development and career perspectives.

Prof. Terje Espevik Prof. Tore Kvien Prof. Herbert Tilg University of Science and University University of Technology (NTNU), of Oslo, Innsbruck, Austria Trondheim, Norway Norway NoPSC ⁞ Annual report 2015 7

Guest professors

Fredrik Bäckhed David Adams Institute of Medicine, Wallenberg College of Medical and Laboratory, University of Dental Sciences, Gothenburg, Sweden University of Birmingham, UK

Management It consists of the three research group leaders and the head of the Center. The Management, together with the Center´s administration, has the overall responsibility for the day-to-day work performed at the Center. Apart from all scientific and academic obligations, the Management, in close contact with the Monitoring Committee, the SAB and the guest professors, continuously plans all future activities and makes sure that all administrative routines are in place for the optimal functioning of the Center.

Prof. Tom Hemming Prof. Kirsten Muri Researcher Researcher Karlsen Boberg Espen Melum Johannes Roksund Hov Center leader Group leader Group leader Group leader t.h.karlsen@ [email protected] espen.melum@ j.e.r.hov@ medisin.uio.no medisin.uio.no medisin.uio.no

Julia Ferkis Merete Gunvor Hege Dahlen Sollid Cand.Philol, MHA, Gedde-Dahl MSc, Administrative Administrative MSc, Project coordinator, coordinator, coordinator, until Sept 2015 Since Sept 2015 Since Sept 2015 [email protected] [email protected] [email protected] 8 NoPSC ‌‌⁞ Annual report 2015

Accounting The core expenditures of the Center amounted to 18.728 mill NOK. Out of these 8.735 mill NOK wer from the Canica donation and 2.184 mill NOK were gift reinforcement provided by the Norwegian Research Council, adding to a total of 10.919 mill NOK of Canica-related expenditures in 2015. The remaining expenses of the 2015 budget were covered by a rapidly increasing number of independent grants (also including additional funds from the Norwegian Research Council), in accordance with our goal to build on the Canica funding to increase the external fraction of the overall Center funding which today amounts to somewhat more than 50%.

OSLO UNIVERSITY HOSPITAL UNIVERSITY OF OSLO INCOME EXPENSES INCOME EXPENSES TRANSFER FROM 2014 1 817 246 34 566 620 INTEREST 306 626 OTHER INCOME 532 237 262 699 TRANSFER FROM UiO 9 589 673 9 589 673 WAGES 4 585 898 1 810 139 OVERHEAD 284 781 232 116 INFRASTRUCTURE 731 076* OTHER OPERATING EXPENCES 3 003 716 118 910 TRANFER TO 2016 3 333 685 23 385 107

*Additional expenses of NOK 353 054,-for Germ Free Mouse Facility equipment will be presented in the 2016 budget.

This pie chart shows the expenditure distribution between the different funds:

Canica 8 735 S-E Norway Regional Health 4 217 Authorithy Norwegian Research Council 3 103 Jebsen Inflammation 770 Research Centre University of Oslo 686

Oslo University Hospital 445

Scientia Fellows (EU) 262

PSC Partners (USA) 260 West Norway Regional 250 Health Authority Thousand NOK 18 728 NoPSC ⁞ Annual report 2015 9

Highlights 2015

Dissertation of Sigrid Næss is one of the hosts. Dr. Brian Chung, has started his fellowship at the University of Birmingham on June On December 15th Sigrid Næss defended her thesis 1st 2015 and will spend two years there and finish his “The major histocompatibility complex association in fellowship at NoPSC in the following year. Dr. Schneditz Primary Sclerosing Cholangitis”. The trial lecture carried has joined the University of Cambridge on July 1st 2015 the title “Autoimmune leversykdommer: epidemiologi, and will stay there until June 30th 2017. As with Dr. diagnostikk og behandling”. The opponents, Professor Chung, Dr. Schneditz will finish his fellowship at NoPSC. Flemming Pociot, Herlev University Hospital, University For both candidates there is the long-term ambition of of Copenhagen, Dr. Magnhild Gangsøy Kristiansen, subsequent grant applications based upon the Scientia Institute of Clinical Medicine, University of Tromsø and Fellowship period to further the work and enhance the Professor Jørgen Jahnsen, Institute of Clinical Medicine, groups at NoPSC with new expertise. University of Oslo contributed to an interesting and fruitful scientific discussion with the candidate. Tom H. Guest professor meetings Karlsen, Johannes E. R. Hov and Benedicte A. Lie were These annual events are one of the most important Næss’ supervisors. scientific highlights in the life of NoPSC. Scientia Fellows During these visits all scientific projects are critically reviewed in relevant sub-groups under the leadership NoPSC participates in this international postdoctoral of a post doc or PhD candidate to enlarge the effect of fellowship programme in health sciences funded jointly knowledge transfer between these experienced by EU’s Marie Curie programme and the Faculty of Medicine, University of Oslo. Candidates are to spend time at the collaborating institutions, where NoPSC Photo Øystein H. Horgmo, University of O slo University H. Horgmo, Øystein Photo Guest Professor Bäckhed with PhD students Laura Valestrand and Elisabeth Schrumpf, Group Leader Espen Melum and post. doc. Georg Schneditz 10 NoPSC ‌‌⁞ Annual report 2015

scientists and the young researchers of the Center. Funding from Horizon2020 David Adams from the University of Birmingham and The project “DYNAFLOW: Dynamic bile flow modeling Fredrik Bäckhed from the University of Gothenburg and cellular sensing in primary sclerosing cholangitis” are both internationally renowned experts of their has received funding within the 1st Joint Transnational respective fields of immunology and microbiology, Call for Proposals for “European Research Projects to and have been serving as guest professors the past demonstrate the feasibility and benefits of systems few years. Fredrik Bäckhed´s term as visiting professor medicine” within the Horizon2020 programme. The ended in 2015, leaving a highly flourishing portfolio of consortium is headed by Professor Jochen Hampe, research related to the gut microbiota as proof of the University Clinic Dresden, Germany. Beside NoPSC usefulness of the activity. leader, Professor Tom H. Karlsen the members are Professor Michael Trauner, University of Vienna, Visits from collaborating Austria, Professor Marino Zerial, Max Planck Institute of scientists Cell Biology and Genetics, Dresden, Germany, Professor With increasing international profile, we experience a Josue Sznitman, Israel Institute of Technology, Dr. great interest in visiting the Norwegian PSC Research Patrick Delmas, CNRS AMU, Marseilles, France. The total Center, both for strategic and collaborative discussions. funding of the project is EURO 1,721,000 and serves to Visitors from 2015 include: strengthen key aspects of our research and the biobank March 24th: Professor Sebastian Zeisig, University clinic, collaborations with the Department of Pathology. Dresden June 16th: Professor Andre Franke, Christian Albrecht Second National Microbiota University, Kiel Conference June 30th – July 1st: Dr. Sebastian Jendrek, University NoPSC Group Leader Johannes R. Hov co-hosted the Clinic Schleswig – Holstein, Lubeck, Germany second national conference on “Gut Microbiota in November 3rd: Jean-Michel Pawlotsky, Hospital Henri Health and Disease” at Gardermoen on November 3rd Mondor, Paris, France 2015. The conference again became a success with 94 participants and 21 accepted abstracts for oral or poster . Hov Photo: Johannes E. R Johannes Photo: Interested participants on the 2nd National Microbiota Conference NoPSC ⁞ Annual report 2015 11

presentation. The first “Tore Midtvedt-price” for best related to the gut microbiota and immunology, and abstract was also presented at the meeting. NoPSC greatly appreciates participating in the well-run network platform of JIRC. NoPSC Scientific Retreat In September, the third annual NoPSC Scientific European Association for the Retreat was held at Hadeland Hotel. All members Study of the Liver (EASL) of NoPSC contributed with short presentations of In 2015, Tom H. Karlsen was elected vice secretary for their ongoing work and in depth discussions on the the steering committee of the European Association respective projects followed in smaller groups. The for the Study of the Liver as the first Norwegian management used this opportunity to present its possessing this position. More importantly, the election strategies for the coming year. The retreat gave also an is a recognition of the importance of the autoimmune excellent possibility to socialize and build relations. liver disease field within EASL, where the emphasis for many years have been predominantly concerned with Experimental liver immunology hepatitis C drug development. The engagement into workshop international liver research and health care politics There has for many years been a close collaboration is important, given the generally weaker standing of between Karolinska Huddinge and Rikshospitalet hepatology compared with other medical disciplines. starting with Erik Schrumpf and the late Ulrika EASL provides a key platform for engagement in Broomé. In the more recent years this collaboration European Union priorities as to both research funding evolved further focusing on clinical studies headed by programs and regulations. Annika Bergquist and Kirsten Muri Boberg. To further strengthen this collaboration, the Experimental Group International PSC study group visited the group of Niklas Björkström at Huddinge for (IPSCSG) the first joint Experimental Liver Immunology The engagement at the international arena resulting Workshop. There were approximately 20 participants from many years of research collaborations led to the that took active part in the informal discussions. We formation of the International PSC study group and already have one joint post.doc. working on a familial made the large genetics studies of NoPSC feasible. PSC disease (Xiaojun Jiang) and a new project focusing As in previous years, 2015 saw two official meetings on MAIT -cells were discussed and formed during the of the International PSC Study Group. The first one workshop. During the spring of 2016 we will host the in conjunction with the International Liver Congress second Experimental Liver Immunology workshop in (ILC/EASL) in Vienna on April 25th and the second one Oslo. in connection with the American Association of the Study of Liver Diseases (AASLD) annual Congress in th th K.G. Jebsen Inflammation San Francisco on November 15 . In Vienna the 5 Research Centre (JIRC) anniversary of this international, team-based and cutting-edge cooperation was celebrated. We sincerely The year of 2015 was an important year for the JIRC, hope that the network will continue its most valuable in which NoPSC leader Tom H. Karlsen serves as one of work and collaboration in the years to come. the Principal Investigators, since the evaluation done For more information on the IPSCSG, please see the would form the basis for a potential application of separate section on the IPSCSG on page 26 or the prolonged activities. The evaluation of the Center´s www.ipscsg.org webpages. activities was excellent, in line with a general perception of JIRC leader Guttorm Haraldsen being successful in bringing together the various inflammatory research environments atO slo University Hospital. Several new, local collaborations have been established as a result of JIRC, in particular for topics 12 NoPSC ‌‌⁞ Annual report 2015

Project portfolio // Research groups

Experimental Hepatology group Photo Øystein H. Horgmo, University of O slo University H. Horgmo, Øystein Photo From left to right: Laura Valestrand, Espen Melum, Xiaojun Jiang, Anne Pharo, Eva Kristine K. Henriksen (middle) and Natalie L. Berntsen (in the front)

GROUP LEADER: Natalie Lie Berntsen regulatory mechanisms involved in bile Espen Melum [email protected] duct inflammation by using different Eva Kristine Klemsdal Henriksen in vitro and in vivo assays. In January LAB MANAGER: [email protected] 2015 Anne Pharo started in a perma- Tonje Bjørnetrø (Jan-July 2015) Laura Valestrand nent position as a lab manager in our Anne Pharo [email protected] group. Anne has extensive experience [email protected] from the Institute of Immunology and In 2015 several large projects that have we were very fortunate that she POST DOC: been ongoing in the Research Group wanted to join us. In August 2015 Laura Jiang Xiaojun for Experimental Hepatology saw Valestrand, who is trained as an MD, [email protected] completion and publication in or started as a PhD student working on

submission to scientific journals. The the role of the immune system during PHD STUDENTS: main focus of the Group for Experimen- cholestasis with a particular focus on Elisabeth Schrumpf tal Hepatology is to understand the NKT cells. [email protected] NoPSC ⁞ Annual report 2015 13

In a project involving a familiar form of bile duct inflammation was completed NKT cells in this model by using bone PSC we have performed lymphocyte in 2014 and this model now constitutes marrow transplantation and knock-out RNAseq studies in collaboration of a unique asset for the group. Using this animals. In the same model we have Niklas Björkstöm at Karolinska and model, we have in 2015 demonstrated also demonstrated that the gut revealed mutation expression in that installation of the NKT cell microbiota is altered in mice with bile patients’ T cells at the mRNA level and activating hapten Oxazolone into the duct disease compared to mice with no found several mutation specific signal biliary tree induces bile duct inflamma- bile duct disease. Furthermore, we have proteins. Further signaling pathway tion that is likely driven by NKT cells. shown that the bile duct disease is not analysis is ongoing. Furthermore, Mice that lack NKT cells (CD1d as pronounced when the mice are functional assays to evaluate these knockout mice) and mice that are rederived into and house in a germ-free functions in T-cell has been set-up. treated with antibodies blocking NKT environment. We have also acquired knock-out mice cell activation seem to be partly and generated a knock-in mouse. protected from disease. Current studies Following the finding that cholangiocy- are aimed at further understanding the tes activate NKT-cells we have investiga- Using a unique collection of paired role of different lymphocyte subsets ted bile collect at the time of liver patient material, we have studied the and the characteristics of the inflam- transplantation. These studies have T-cell receptor repertoires of PSC-IBD matory process. To investigate the role demonstrated that biliary lipids activate affected livers and intestines. Our of the immune system during cholesta- NKT-hybridomas with a diverse range of findings suggest that a high proportion sis we will use a well-established antigen specificities. Of note, we have of the patients’ liver and gut memory T mouse model of cholestasis, where we demonstrated a clear dose-relationship cells are able to recognize the same induce cholestasis by bile duct ligation. between the grade of bile sample antigen(s) or antigen(s) that share The surgical technique is now up and dilution and the activation of the sequence or structural similarities. running, and we will start with NKT-hybridomas. Further experiments With this, we provide evidence in descriptive studies before we aim to are planned to elaborate the results and humans supporting the hypothesis that more closely investigate the role of NKT to characterise the lipid acting as an memory T cells migrate between the cells. Using a model of spontaneous antigen. inflamed gut and liver of PSC patients. bile duct inflammation (NOD.c3c4) we The development of a surgical model of have thoroughly investigated the role of

New Achievements 2015 • We have demonstrated that oxazolone cholangitis is CD1d restricted; • Accomplished successful development of our first CRISPR/Cas9 mouse model together with Applied StemCell; • Found differences in the microbiota in a murine model of bile duct inflammation and reduced inflammation in germ-free animals; Photo Øystein H. Horgmo, University of O slo University H. Horgmo, Øystein Photo Post. doc. Xiaojun Jiang during one of her experiments in the lab 14 NoPSC ‌‌⁞ Annual report 2015

Genomics and metagenomics Group Photo Øystein H. Horgmo, University of O slo University H. Horgmo, Øystein Photo From front and to the left: Silje Jørgensen, Johannes R. Hov, Cristiane Mayerhofer, Martin Kummen, Amandeep Kaur Dhillon, Gupta Udatha, Christopher Storm-Larsen, Kristian Holm and Liv Wenche Thorbjørnsen

GROUP LEADER: Amandeep Kaur Dhillon The PhD dissertation of Sigrid Næss Johannes R. Hov [email protected] on December 15th was a major event Silje Jørgensen (associated) in the Genomics and Metagenomics RESEARCHERS: [email protected] Group in 2015. Her thesis ”The major Marius Trøseid (associated) Cristiane Mayerhofer (associated) histocompatibility complex associati- [email protected] cristiane.caroline.mayerhofer@ on in primary sclerosing cholangitis” ous-hf.no comprised important studies focusing

POST DOCS: on the strong genetic associations Trine Folseraas (associated) BIOINFORMATICIAN: within the HLA complex in PSC, as [email protected] Kristian Holm well as in acute rejection after liver Gupta Udatha [email protected] transplantation. [email protected]

ENGINEER: The group contributed to a large PHD STUDENTS: Tonje Bjørnetrø number of publications in 2015. In Martin Kummen [email protected] genetics, the first genetic study on [email protected] (February-August 2015) the intriguing subgroup of PSC Sigrid Næss patients with increased IgG4 was [email protected] accepted in Gastroenterology, the NoPSC ⁞ Annual report 2015 15

top-ranking journal in the field, with the mucosal microbes and the New Achievements 2015 Natalie Lie Berntsen as first author functional content of the gut. • Finalization of our first papers of (now moved on to full PhD studies in Bacterial functions will also be gut microbiota profiling in human the Experimental Group). Besides characterised using profiling of micro- diseases based entirely on in-house this, the first definite reports using bial metabolites in peripheral blood. methodology, from sampling, lab sequencing-based gut microbiota The next step is application of gut preparations, bioinformatic and profiling were published in 2015. microbiota profiles and metabolo- statistical analyses. These include the first paper from our mics profiles in biomarker studies of • identification of a low diversity gut group on the microbiota of the disease activity and severity. Finally, microbiota in PSC, distinct from the intestinal mucosa in PSC (collaborati- clinical interventions targeting the microbiota of healthy individuals on with the Silverberg group in gut microbiota in PSC may provide and patients with ulcerative colitis Toronto), and contributions to two important evidence for a role of gut without liver disease. papers characterizing and treating the manipulation in the treatment of • identification of the gut microbial gut microbiota in HIV, important PSC. metabolite TMAO as a prognostic collaborations in the context of the factor in PSC Research Institute of Internal On the basic level, we have an Medicine and the K.G.Jebsen important collaboration with the

EDITORIAL Inflammation Research Center. Experimental Group regarding the Editorial Several major studies based entirely gut microbiota of mouse models The gut microbiota appears to play a role in a number of diseases. «Gut profiling» and «gut cocktails» on our in-house microbiota analysis of biliary disease, which may may become standard diagnostic tests and treatments in everyday clinical practice pipeline were also finished and hopefully translate into clinical Personalised medicine targeting submitted in 2015, with expected applications. In addition, the the gut microbiota?

publication early 2016. group is involved in a series of The recent national report on personalised medicine (1) devotes624 – 5 little space to microbiomics, that is, studies of the normal microbiota and its genes, owing to a limited existing knowledge base. cross-sectional and interventi- It is implied, however, that the field will acquire clinical signifi- There are many challenges remaining before terms like «gut micro- cance. What form might this take? biota medicine» or «gut microbiota disease» can become part of

Photo Øystein H. Horgmo, University of O slo University H. Horgmo, Øystein Photo clinical practice. The gut microbiota is affected by many known The Norwegian Research Council onal studies in population The gut microbiota varies greatly and has significant metabolic and unknown confounding factors, including diet and age. It is activity. The bacteria constitute a manipulable organ and therefore important that methods are standardised, as the conditions used can represent a potential therapeutic target. As more and more diseases greatly affect the results obtained. In Norway, optimal methods have are linked to disturbances of the gut microbiota, many of us will funded project “NORGUT” was controls or other inflamma- been established to only a limited degree, and the lack of facilities for find ourselves faced with the option of gut microbiota-directed research on germ-free animal models is a particular challenge. diagnostics or therapy. initiated in April 2015 and will run for tory conditions like immuno- Who will claim ownership of this new organ? Gastroenterologists Cross-sectional studies have revealed differences between diseased will be in a unique position, with endoscopic access to diagnosis and healthy individuals in the composition of their gut microbiota, and treatment, but it is difficult to envisage the development of a for example in type 2 diabetes (2). Whether it is single bacteria or four years, providing funding for the deficiencies and heart modern gut microbiota medicine without microbiologists and infec- the entire intestinal environment that plays a role, or whether the tious disease specialists. In order to conduct high quality studies observed changes are secondary to disease, is unclear. The studies of conditions such as obesity, diabetes and rheumatic diseases, to show, however, that the gut microbiota profile in itself has potential Group Leader, one PhD student and disease, aiming to under- name but a few, interdisciplinary collaboration will be required. as a diagnostic tool and may become clinically relevant. The first national microbiota conference, held in 2014, was a step in that direction, as was the foundation of a Norwegian Microbiota A better understanding of the relation between gut microbiota and several studies investigating the gut stand the relationship Society. disease will enable the use of personalised therapy. Trimethyla- mine-N-oxide (TMAO), a product of bacterial metabolism of cho- It is important not to get carried away. A thorough understanding of line and carnitine (in eggs and meat), is directly involved in athe- microbiota in conditions affecting the between gut microbiota the gut microbiota in different diseases is needed, and clinical trials rosclerosis, and is moreover a marker for cardiovascular events (3). will be required before implementation in clinical practice. The risk We have recently shown that plasma levels of this oxide are also of transmission of infectious diseases and a more theoretical risk related to survival in patients with heart failure (4). Identification intestine with a strong focus on PSC. and markers of inflammati- of transmission of a deleterious microbiota must be monitored and of specific environment-gut microbiota interactions such as these weighed up against presumed health benefits. We know little about could lead to novel therapeutic recommendations and lifestyle whether probiotics, for example, have positive effects in the long advice, based on either the gut microbiota profile or bacteria-related term, such that one can usefully refrain from such treatment given At the end of 2015 we were also on and microbial metabo- metabolites. that the benefits are not proven. All in all, there is still legitimate cause for optimism. By means of high- quality scientific studies of The efficacy and toxicity of drugs is affected by the gut microbiota. the gut microbiota, we can achieve better understanding of disease, happy to receive post. doc. funding lism, and how diet or Digoxin, for example, is inactivated in 10 % of us by the bacterium diagnosis and treatment in a personalised manner. Eggerthella lenta , while adverse effects of cytostatics can be reduced from the South-Eastern Norway drugs may manipulate by bacterial enzymes (5). Pharmacomicrobiomics may therefore Johannes Espolin Roksund Hov become part of personalised medicine. j.e.r.hov @medisin.uio.no Marius Trøseid The condition for which most progress has been made in this regard Regional Health Authority for projects this system. Finally, is Clostridium difficile recurrent disease can be colitis, regarded in whichas established faecal transplantation (6). A Dutch group for Johannes Espolin Roksund Hov (born 1977), PhD, specialty registrar in recently showed that faecal transplantation also improved insulin the Section of Gastroenterology and postdoctoral researcher at the Nor- focusing on the clinical application of following last year’s sensitivity in metabolic syndrome (7). Such data give rise to hopes wegian Primary Sclerosing Cholangitis Research Center at Oslo Univer- that targeted treatment of the gut microbiota can provide health sity Hospital, Rikshospitalet and the University of Oslo. He is head of a benefits also for conditions outside the intestines. research group studying genetics and the gut microbiota in inflammatory gut microbiota in PSC. success, the second diseases at the Research Institute for Internal Medicine. In Norway, there has been research into the relation between intes- The author has completed the ICMJE form and declares no conflicts tinal bacteria and health for some time (8). The gut microbiota has of interest. national conference on become a major field of research internationally, driven by new genetic methods that allow culture-independent analyses of the Marius Trøseid (born 1972), PhD, specialist in infectious diseases and microbiota, and by publicly funded projects in Europe (MetaHIT) senior consultant at Oslo University Hospital, Rikshospitalet. His research Research projects related to the gut microbiota was and the USA (the Human Microbiome Project). In addition, pionee- examines the significance of inflammation and the gut microbiota in HIV ring work in germ-free mice has directly linked the composition of infection and cardiovascular disease. the gut microbiota to factors such as obesity and behaviour (9, 10). The author has completed the ICMJE form and declares no conflicts concept “clinical microbiota medici- organized in Novem- of interest. ne” will be a major strategic goal of ber 2015. 624 © Copyright Tidsskrift for Den norske legeforening. Reprint not allowed. Downloaded from www.tidsskriftet.no 19.02.2016 the group in the years to come. The The event was once >>> Tidsskr Nor Legeforen nr. 7, 2015; 135 starting point is the ongoing in-depth more a great success, with more than characterisation of the gut microbiota twenty abstracts submitted and a in PSC using modern genetic methods, fully booked venue. which will include detailed studies of 16 NoPSC ‌‌⁞ Annual report 2015

Clinical Research group in Oslo and Bergen Photo Øystein H. Horgmo, University of O slo University H. Horgmo, Øystein Photo From front and to the left: Kristine Wiencke, Kirsten Muri Boberg, Trine Folseraas, Kristian Bjøro, Erik Schrumpf and Liv Wenche Thorbjørnsen

Group leader: Kristian Bjøro (associated) Kirsten Muri Boberg [email protected]

Post docs CORE STAFF: Mette Vesterhus Mona Bjørnstad [email protected] (until Sept) Trine Folseraas [email protected] [email protected] Liv Wenche Thorbjørnsen [email protected] RESEARCHERS: Jorunn Bratlie Kristine Wiencke (associated) (affiliated engineer; untilO ct) [email protected] Aud Sissel Hjartholm (associated) Erik Schrumpf [email protected] Kristin Kaasen Jørgensen(associated) [email protected] NoPSC ⁞ Annual report 2015 17

Biomarkers for prognosis or potential infectious components. Our group has in PSC participated in a drug trial with norursodeoxycholic acid. The study has been completed, but results are so far PSC is usually a slowly progressive disorder. Consequent- unknown. ly, the design of clinical trials of drugs that improve prognosis is hampered by the relatively low rate of clinically relevant endpoints. Appropriate surrogate Early detection of endpoints are lacking. An expert panel appointed by the cholangiocarcinoma IPSCSG and including members from NoPSC, has revie- PSC is strongly associated with cholangiocarcinoma (CCA) wed potential endpoints and performed a consensus development, which complicates the disease in 10 – 15% process to assess the currently available candidates of patients. The pathogenesis of PSC-related CCA is (Ponsioen CY el al, Hepatology 2015). It is evident that poorly understood. The lack of diagnostic methods for novel, preferably non-invasive, biomarkers as surrogate early detection and the limited therapeutic options once endpoints are urgently needed. The identification of such the tumor is diagnosed by available techniques, constitu- markers is a current focus of activities within the IPSCSG, te major challenges in the current handling of PSC as is the search for more potent prognostic markers. The patients. A main research focus is to detect biomarkers Mayo risk score has been the most widely used model for diagnosis of PSC-CCA at an early stage that might be for prediction of the disease course in PSC patients, but curable by radical surgery. DNA methylation analyses in novel biomarkers are also urgently needed to assess dise- biliary brush samples could potentially serve as supple- ase stage and activity as well as prognosis in PSC. A ment to conventional brush cytology. Building on our variety of potential prognostic markers are under study. previous identification of methylated DNA biomarkers in PSC is characterized by a fibrotic process involving the CCA tissue samples, we have now tested biliary brush bile ducts. In a study of the noninvasive, serum-based specimens for specific methylation patterns in 4 genes enhanced liver fibrosis (ELF) score in Norwegian patients, (CDO1, CNRIP1, SETP9, and VIM) and demonstrated a our group concluded that the ELF score was a potent sensitivity of 85% and specificity of 98% for CCA detecti- prognostic marker in PSC, independent of the Mayo risk on. Methylation profiling of this gene panel outperfor- score (Vesterhus et al, Hepatology 2015). These findings med the diagnostic accuracy of conventional brush will now be tested in independent patient cohorts from cytology (Andresen K et al, Hepatology 2015). Analysis of other IPSCSG centers. Furthermore, based on previous methylation profiles in bile samples are currently reports indicating that imaging of liver fibrosis by ongoing. ultrasound elastography might predict clinical outcome, we are investigating ultrasound elastography as a Targeted mutation prognostic biomarker in an ongoing prospective study as profiling in PSC-associated well as exploring the evaluation of liver fibrosis by a cholangiocarcinoma and novel multimodal MRI method. Further search for novel gallbladder carcinoma serum markers of PSC prognosis is also ongoing. In personalized medicine, screening for clinically relevant genetic tumor alterations is increasingly used to aid in Treatment of PSC prognostication and stratification of patients into targeted cancer therapy. Mutations in different tumor Whereas endoscopic treatment of strictures in PSC and suppressor genes and oncogenes have been detected in transplantation of selected patients are well established non-PSC CCA and gallbladder carcinoma (GBC), but treatment modalities, no drug has so far been shown to dedicated genetic studies in PSC-associated CCA and GBC improve the prognosis. This is partly due to the lack of are missing. NoPSC, in collaboration with the Depart- appropriate surrogate endpoints making drug trials ment of Pathology, University Hospital of Heidelberg, difficult to perform. Nevertheless, some studies are Germany, is leading a study in which genomic DNA ongoing - some are aiming at changing the bile composi- extracted from archived formalin fixed, paraffin embed- tion, some are directed against the development of ded (FFPE) PSC-associated CCA and GBC specimens is fibrosis, whereas some are directed against inflammation 18 NoPSC ‌‌⁞ Annual report 2015

analysed by targeted, massive parallel sequencing been implemented at Haukeland University Hospital (led covering hotspot mutations in cancer related genes. by post doc Mette Vesterhus) and at Oslo University Preliminary results are interesting, indicating several Hospital, Rikshospitalet (led by prof. Erik Schrumpf). druggable targets. In 2016 the study will be extended by Colleagues at all major hospitals in South-Eastern the inclusion of CCA and GBC specimens from several Norway have responded positively to the invitation to centers within the IPSCSG. join this collaborative effort. A similar action has also been asked for by patient organizations. We aim to Regional research and follow patients prospectively on a regular basis, with reference network in registration of predefined and standardized clinical, autoimmune liver disease (AILD) biochemical and radiological parameters at each visit. Data will be entered into a common database, with the PSC is commonly designated an autoimmune liver prospect of having a web-based version available by the disease (AILD), along with primary biliary cirrhosis (PBC) end of 2016. We also intend to prospectively collect and autoimmune hepatitis (AIH). These are all rare and biological material and will make the NoPSC sampling complex disorders with significant impact on patient procedures available, including the option to store health and with important areas of unmet needs. Apart samples in the NoPSC biobank at Oslo University from ongoing efforts to improve the understanding of Hospital. etiopathogenesis, there are challenges related to Providing a potential for improved diagnosis, treatment diagnostic difficulties, the definition of relevant prognos- and follow-up, this network will be useful for both tic markers, performance of clinical trials as well as clinicians and patients. It will also be an important better handling of patient symptoms, for all three resource for future clinical studies. A European Reference conditions. Furthermore, there is a need to ensure Network (ERN) program with the goal of improving quality and equality in patient care. clinical care in rare, complex liver diseases (including During 2015 NoPSC has taken the initiative to organize a AILD) across Europe, will be launched during 2016. We regional research- and reference network for AILD in the will be prepared to join the ERN, thereby contributing to South-Eastern Norway Health Region with a further aim and benefiting from this European joint action. to extend this network to a national undertaking. A syste-

matic, prospective follow-up of PSC patients has already

The figure shows the cumulative liver transplantation free survival in n=138 Norwegian PSC patients classified according to their enhanced liver fibrosis score, confirming its predictive potential. The figure is based on data from the study by Vesterhus et al. published in Hepatology 2015 NoPSC ⁞ Annual report 2015 19

NYTT FRA FAGMILJØENE GASTRONET 2828 Nasjonalt medisinsk kvalitetsregister 29 NYTT FRA FAGMILJØENE AwardsTekst: Thomas de Lange.

Besøk oss på: www.kreftregisteret.no/gastronet • the annual meeting of Henvendelserthe Norwegian til: [email protected] Gastro- HANS POPPER AWARD enteorological Society in February 2015 awarded

Figur 1. MartinKan vi stoleKummen på egen for best clinical work presented at the Tom Hemming Karlsen har fått oppfatning om kvalitet? Hans Popper Award som deles Members of the Prize Committee: Etter å ha skopert noen år lever nok de ut av Falk Foundation. Prisen er M. Colombo, Mailand (Italy) doteret med € 25.000. Seremonien M. Trauner, Vienna (Austria) meetingfleste i den trothat at de er ganskewas gode tilperfomed å skopører har samme at CIR aved screeninguniversity- hospital. Kummen fant sted under Falk Symposium M. Houghton, San Francisco (USA) skopere, men det er flere enn undertegnede skopier og kliniske skopier. Det viser seg nr. 200: M. Omata, Tokyo ( Japan) som har blitt negativt overrasket etter å ha også at skopiene gjennomføres skånsomt Highlights from Hepatology P. Ginès, Barcelona (Spain) has statedsett sine første Gastronet-resultater. that the Det gut (Figur microbiota 3 og 4). Dette på tross av atis mange different in patients with 14.-15. oktober, Freiburg, Tyskland. 2015, R. Perrillo, Dallas (USA) tyder vel på at man glemmer de dårlige undersøkelser er langvarige på grunn av

skopiene så fort som mulig. Dette nevnes mye terapi (mange og store polypper). PSC from healthy controls or patients suffering from - Jeg ser på prisen som en anerk- Hans Popper Award Winners 1989-2012: for å understreke at hovedmålet med Vi konstaterer at sluttresultatet av denne jennelse av det gode fagmiljøet ved 1989 - H. C. Thomas, London (Great Britain) Gastronet er å være hjelp til selvhjelp for strategien er god, men evalueringen er Norsk senter for PSC, sier prisvin- 1992 - M. Rizzetto, Turin (Italy) den enkelte og enheten i forbedringsarbei- ikke egnet til å avgjøre hvilke enkeltfak- Figur 2 inflammatory bowel disease. ner Tom Hemming Karlsen. 1995 - M. P. Manns, Hannover (Germany) det. Dessverre er det nok få enheter som torer som har vært mest utslagsgivende for 1999 - M. Houghton, Emeryville (USA) går gjennom sine data samlet, for å vurdere kvaliteten. Dekningsgraden i Gastronet Juryen trekker frem Karlsens fremragende bidrag til basal og eks- 2003 - S. L. Friedman, New York (USA) resultatene og om man bør gjøre noen innen screeningen er 99 %, og 85 % av perimentell hepatologi relatert til sykdommen Primær skleroseren- 2006 - P. Ginès, Barcelona (Spain) grep for å endre/forbedre egen og enhetens pasientene svarer på spørreskjemaet, så det de cholangitt (PSC). 2012 - J. Bruix, Barcelona (Spain) / J. M. Llovet, Barcelona (Spain) praksis. I det pågående screeningprosjektet er liten grunn til å tro at forskjellen i CIR • on harthe vi halvårlige same gjennomganger meeting av alles mellomNatalie totalen- og screeningsentrene Lie Berntsen was awarded resultater i et felles møte der fokus er hva skyldes rapporteringsbias. kan vi gjøre for å hjelpe hverandre å bli bedre. Anders Jahres Medisinske Pris 2015 with the prize for bestE-Gastronet presentation for her work in Endoskopikvaliteten i Bearbeidingen av innsamlede data i Figur 3 studien Bowel Cancer Gastronet Professor Ludvig M. Sollid fra Senter for immunregulering, establishingScreening in Norway a (BCSN) new surgical er svært animal arbeidskrevende, ogmodel for cholangitis. det ville lette om dataene kunne samles Universitetet i Oslo, og Avdeling for immunologi og transfusjon- Siden 2009 har det pågått to kolorek- inn elektronisk. I regi av et Norsk-Polsk smedisin, Oslo universitetssykehus, har fått utdelt “Anders Jahres talkreft-screeningstudier i Norge: NOR- samarbeid er det nylig startet en rando- Medisinske Pris 2015”. Han holdt Anders Jahres Forelesning den DICC og BCSN. I forbindelse med disse misert studie for å evaluere om det er 14. oktober med tittelen: “On autoimmunity: Lessons from celiac prosjektene har man i stor grad lærtth opp mulig å samle inn pasientbesvarelsene disease”. Seremonien med prisutdeling fant sted i universitetets • onendoskopører October fra bunnen av16 og kvaliteten Tom elektronisk. Hemming I denne studien randomiseres Karlsen was awarded aula 15. oktober. har fra start av blitt målt i Gastronet og pasientene enten til å få vanlig papirspørre- opplæringen har både vært basert på sys- skjema eller til E-Gastronet-armen. thetematikk, International tett supervisjon og høyt volum. HansI intervensjonsarmen Popper får de valget Awardmellom for his outstanding Sentrene har en cøkumintubasjonsrate å svare på vanlig papirskjema, få en auto- Figur 4 (CIR) på ca. 95 % eller over (Figur 1), matisk telefonoppringning eller en mail achievementsog variasjonen mellom den enkelte inendo -themed linkstudy til spørreskjemaet. of the Vi ønsker liver. å se This prestigious skopør er liten etter ett års praksis (Figur på hvilken metode som velges og om det 2). Foreløpige tall tyder også på at endo- vil foreligge en forskjell i svarprosenten prize is awarded oncemellom de in 3 alternativene. every third year, and this years’ jury underlined Dr. Karlsen’s meaningful results in basic NGF-nyttNGF-nytt 3 4• •2015 2015 and experimental hepatology related to PSC.

Foto: Yngve Vogt, UiO.

• elisabeth Schrumpf was awarded the first ever NGF-nytt 4 • 2015 ”Tore Midtvedt-Prize” for her presentation of the gut microbiome in the NOD.c3c4 biliary disease Facsimile from the Journal of the Norwegian Gastro-Forum model on the Second Microbiota Congress. Photo Øystein H. Horgmo, University of O slo University H. Horgmo, Øystein Photo Natalie L. Berntsen, Benedicte Stavik (Institute of Internal Medicine), Martin Kummen and Anne Pharo in the lab 20 NoPSC ‌‌⁞ Annual report 2015

Updates from the NoPSC Biobank

Liv Wenche Thorbjørnsen, Biobank Manager

By the end of 2015, a total of 1926 comprises patients with several types of prospective follow-up with annual individuals were registered in the liver diseases (autoimmune liver biobanking from a subgroup of the PSC NoPSC Biobank. diseases in particular) and various types patients. For some patients we are now of controls (including healthy controls). also able to collect new material up to The material amounts to approximately Patients with PSC have always been the five years after the first sample. Such 80 000 tubes of different types of “core business” of the biobanking long-term follow samples are extremely material (e.g. blood, bile, DNA, RNA activities. From 2010, this emphasis was important for longitudinal biomarker etc.). The total number of individuals strengthened and we introduced assessments.

1600 80000 1400 1200 60000 1000 800 40000 600

20000 400 200 0 0 2008 2009 2010 2011 2012 2013 2014 2015

Cumulative number of tubes in the NoPSC Biobank 2008 -‐2015

Cumulative number of registered persons, with collected materials, in the NoPSC Biobank 2008 -‐2015

NoPSC ⁞ Annual report 2015 21

Unit for Experimental Gnotobiology

Henrik Rasmussen, Head of the Departement of Comparative Medicine, OUS

Organisation • EG is a research unit for breeding and experimental use of gnotobiotic mice, located at Comparative Medicine (KPM) at Rikshospitalet. The collaboration between NoPSC and KPM was initiated in 2015 and the formal agreement between NoPSC and KPM was signed in February 2016. • NoPSC funded the isolators while UiO research funds from NoPSC, the Clinic for Cancer, Surgery and Transplantation and KPM funded the building of the animal room. KPM will be responsible for the daily operation, that is to be initiated Capacity at the beginning of 2016. • 4 breeding (5’x2’2’) and 4 experimental (3’x’2x2’) isolators in a 14 m2 animal room.

Remaining issues • defining a sterilant that can be readily used in our facility has emerged as an unexpected challenge. Clidox (formerly used in Sweden) is no longer available. While peracetic acid is a very effective sterilant, practical use • the facility will be open to all users. Projects will be is a challenge with respect to HMS in the KPM facility. prioritized by a Scientific Advisory Committee, focusing on • Validating optimal programs and chemical/biological NoPSC projects during startup (at least first year). User fees indicators for autoclaving of diet, bedding and water. will be charged per isolator per week. The EG unit is • optimal routines for regular confirmation of sterility approved by the Ministry of Agriculture and the Ministry of (monthly bacterial culture/16S PCR, quarterly fungal Health for housing of genetically modified mice. culture, yearly virology). 22 NoPSC ‌‌⁞ Annual report 2015

Networks

Key local is involved in several projects been crucial for the success collaborators related to the further of the initiative. We are characterization of the HLA particularly grateful to Dr. Research Institute for Internal association in PSC. The Andreas Abildgaard and Medicine (RIIM) Norwegian Sequencing Center Dr. Knut Brabrand for their The Institute is headed by hosts the NoPSC MiSeq next active contributions. Professor Bente Halvorsen and generation sequencing machine. the research groups led by Key national Espen Melum and Johannes E.R. Institute of Immunology collaborators Hov respectively are operational NoPSC has a longstanding at RIIM. Several collaborative collaboration with the Institute The IBSEN study group projects are established with of Immunology in our functional The biological material collected the other research groups. genetic projects. In particular, by Prof. Morten Vatn, Prof. Bjørn the good collaborations with Moum and several other Department of Transplantation Section of Transplantation co-workers of the IBSEN study Medicine Immunology, led by Prof. group is important for several of Department Head, Prof. Torstein Egeland and Prof. John the basic genetic and Pål-Dag Line, Prof. Aksel Foss, Torgils Vaage, and the research meta-genomic studies at NoPSC. Dr. Einar Martin Aandahl group of Fridtjof Lund-Johansen, Blood samples of patients and Head of the Section for are important in the activities of undergoing magnetic resonance Transplantation Surgery, Dr. NoPSC. cholangiography (MRC) at the Bjarte Fosby collaborate with 20 years follow-up consultation NoPSC on projects related to Department of Medical are deposited in the NoPSC liver transplantation in PSC Biochemistry Biobank. Dr. Anne Nergård and induced murine models of In conjunction with the and Dr. Aida Kapic Lunder cholangitis. establishment of the NoPSC are performing the MRCs at Biobank quality control Project Akershus University Hospital. Department of Pathology the collaboration with Dr. Dr. Kristin Kaasen Jørgensen Dr. Peter Jebsen, Prof. Tor Yngve Thomas Bliksrud is highly has entered a combined J. Eide, Dr. Henrik Reims appreciated. consultant–researcher position and Dr. Krzysztof Grzyb are at Akershus University Hospital involved in the histological Center for Cancer Biomedicine and continues her collaboration and immunohistochemical A collaboration with Prof. on PSC with the Center. evaluation of tissue samples Ragnhild Lothe and Prof. from PSC patients and samples Guro Lind at the Department Haukeland University Hospital from experimental mouse of Cancer Prevention, OUS and University of Bergen models. Through the K.G. Radiumhospitalet is the basis For the prospective PSC Jebsen InflammationR esearch for epigenetics-centered cohort and advanced imaging Centre (JIRC) we have several projects on early diagnosis of modalities there is a close ongoing projects with Prof. cholangiocarcinoma in PSC. collaboration with Prof. Odd Guttorm Haraldsen. Helge Gilja and several other Department of Radiology researchers at the Section Department of Medical The involvement of the for Gastroenterology and Genetics Department of Radiology at OUS the Norwegian Centre of The Immunogenetics group, led Rikshospitalet in the prospective Excellence in Gastrointestinal by Prof. Benedicte A. Lie follow-up of PSC patients has Ultrasonography at the Medical NoPSC ⁞ Annual report 2015 23

Department at Haukeland are being performed in the several projects related to the University Hospital in Bergen. Experimental Group. further characterization of the For the bile acid and microbiota HLA related immune response projects, Prof. Rolf Berge at the Cambridge Institute for Medical in PSC. Post.doc. and Scientia University of Bergen provides Research Fellow Brian Chung participates the serum lipid measurements. Cambridge, UK actively in these projects under The HLA association in PSC the daily supervision of Dr. Key international poses particular challenges, and Evaggelia Liaskou. collaborators the collaboration with Prof. John Trowsdale and senior researcher The Mayo Clinic, Rochester, Institute for Clinical and James Traherne and Vasilis USA Molecular Biology Kosmoliaptsis in Cambridge is Collaboration with Dr. Christian-Albrechts University, invaluable for the progress of Konstantinos Lazaridis at the Kiel, Germany several of our functional genetic Mayo Clinic in Rochester has Several co-workers of Prof. projects. been established within our Stefan Schreiber and Prof. projects on the genetics of PSC. Andre Franke’s group in the Dept of Medicine, University Via infrastructure at the Mayo German excellence cluster of Cambridge Addenbrooke’s Clinic, DNA from PSC patients in “Inflammation at interfaces” Hospital, Cambridge, UK USA and Canada are collected are involved in technically Prof. Arthur Kaser is Head of the and utilized in local projects advanced projects within the Division of Gastroenterology as well as for verification of genetic and metagenomic and Hepatology at findings in genetic studies at projects. Prof. Andre Franke has Addenbrooke’s Hospital, NoPSC. served as a loyal and dedicated Cambridge, UK. He served guest professor at NoPSC for 3 years as a NoPSC guest Brigham and Women’s Hospital for 5 years. In addition, Prof. professor and is still involved in Harvard Medical School, John Baines (joint position at one of the main translational Boston, USA Christian-Albrechts University work packages related to the Prof. Richard Blumberg is an and the Max Planck Institute of functional characterization of important collaborator in Dr. Evolutionary Biology in Plön) is one of the PSC risk genes. This Espen Melum’s projects related an important collaborator in the project is funded within the to NKT cells. He is also the metagenomic projects. Scientia Fellows’ program of the co-supervisor of PhD student University of Oslo and involves Elisabeth Schrumpf. Universitätsklinikum Dresden post.doc. Georg Schneditz and Dresden, Germany his daily supervisor Dr. Nicole Medical University of Vienna There is a growing collaborative Kaneider-Kaser. and Medical University of Graz, activity with Professors Jochen Austria Hampe and Sebastian Zeissig. University of Birmingham, In collaboration with Prof. Michael With Professor Hampe there Birmingham, UK Trauner and Prof. Peter Fickert, is a system biology project Prof. David Adams, a Guest ongoing projects aim at cross- under initiation, for which EU Professor at NoPSC since 2013, validating findings in mouse funding within the Horizon2020 and Dr. Gideon Hirschfield at models of PSC with human program has been obtained. the Center for Liver Research data. Prof. Michael Trauner has Professor Zeissig is participating at the Institute of Biomedical extensive experience in animal in the NKT-related projects that Research, University of models of PSC and serves as an Birmingham collaborate on important collaborator related to 24 NoPSC ‌‌⁞ Annual report 2015 om Henning Karlsen om Henning Photo: T Photo: Participants on the spring International PSC Study Group meeting in Vienna.

the development of a bile duct Helena Isoniemi), Stockholm Fredrik Bäckhed and Hanns- specific Cre mouse. (Prof. Bo-Göran Ericzon), Ulrich Marschall have been Gothenburg (Prof. William collaborators related to the The Nordic Liver Transplant Bennet) and Copenhagen (Dr. gut microbiota axis for several Group Allan Rasmussen) are involved years. Bäckhed, being a guest Collaborators in Helsinki (Prof. in several projects where data professor at NoPSC since 2012 Krister Höckerstedt, Prof. from the Nordic Liver Transplant is an expert on gut microbiota, Registry are required. metabolism and gnotobiotic animals and has been an Karolinska University Hospital, advisor and collaborator on Stockholm, Sweden gut microbiota studies in mice, Prof. Annika Bergquist is a while hepatologist Hanns-Ulrich close collaborator on clinical Marschall contributes with bile projects in PSC and has also acids expertise. participated in the genetics projects. Associate Professor Sapienza, Università di Roma, Niklas Björkström is involved Italy in projects relating to human Professors Eugenio Gaudio, immunology in PSC. Domenico Alvaro and co- workers are experts on stem- Molecular and Clinical cells in biliary tree, and the Medicine, Wallenberg NoPSC Biobank material is used

om Henning Karlsen om Henning Laboratory, University of to explore these in PSC. Gothenburg, Sweden Photo: T Photo: NoPSC ⁞ Annual report 2015 25

NoPSC International lectures 2015

Karlsen TH. Karlsen TH. Genome-wide association studies in hepatology Predicting susceptibility in cholestatic liver diseases and 48th Annual Meeting of the Italian Association for the Study gall stones of the Liver (A.I.S.F.) United European Gastroenterology Week Rome, February 17th – 19th 2015 Barcelona, Spain, October 24th – 28th 2015

Karlsen TH. Karlsen TH. Primary Sclerosing Cholangitis – Where are the Treatment State of the art introduction: Insights into cholestatic liver Targets? disease Grand Rounds, Beaujon Hospital United European Gastroenterology Week Paris, March 6th 2015 Barcelona, Spain, October 24th – 28th 2015

Karlsen TH. Karlsen TH. Evolution of the genetics of PSC and PBC Controversies in management of PSC Cholestasis: Past, Present and Future American Association for the Study of Liver Diseases Medical University of Vienna San Francisco, USA, November 13th – 17th 2015 Vienna, April 15th 2015 Karlsen TH. Karlsen TH. Genetic factors in autoimmune liver diseases Are there common genetic factors among the three American Association for the Study of Liver Diseases autoimmune liver diseases? San Francisco, USA, November 13th – 17th 2015 Falk Symposium “Autoimmune Diseases of the Liver” Lisbon, May 8th – 9th 2015 Karlsen TH. State of the art in primary schlerosing cholangitis Karlsen TH. 2nd Swiss Hepatology postgraduate Course MHC risk mapping – a holy grail of complex disease Ermatingen, Switzerland, November 26th – 28th 2015 genetics? 6th International Workshop on Genomic Epidemiology Karlsen TH. London, May 14th – 16th 2015 Cholestatic and metabolic liver diseases EASL Masterclass Karlsen TH. Pavia, Italy, December 3rd – 5th 2015 Approach to the cholestatic patient ASSA SAGES annual meeting Boberg KM. Durban, South Africa, August 8th 2015 Overlap syndromes between PSC or PBC and AIH 24th Conference of the Asian Pacific Association for the Karlsen TH. Study of the Liver (APASL) Management and treatment failures in autoimmune Istanbul, March 12th – 15th 2015 hepatitis ansd cholestatic liver disease ASSA SAGES annual meeting Boberg KM. Durban, South Africa, August 8th 2015 AIH-PSC variant syndromes EASL Monothematic Conference on Autoimmune Hepatitis Karlsen TH. London, September 4th – 5th 2015 GWAS in hepatology – What did we learn? Department of Biology, Henri Mondor University Hospital Boberg KM. Paris, September 14th 2015 The experience of the Norwegian PSC Research Center Morning GI Seminar Meeting, Mayo Clinic Karlsen TH. Rochester, USA, November 19th 2015 Cholestatic and autoimmune liver disease – from genetics to environment and back Falk Symposium “Therapeutic strategies in diseases of the digestive tract – 2015 and beyond” Freiburg, Germany, October 16th – 17th 2015 26 NoPSC ‌‌⁞ Annual report 2015

International PSC Study Group I( PSCSG) Annual report

In June 2010, a total of 45 active PSC researchers from Norway, Sweden, Finland, Germany, Switzerland, Austria, Italy, Spain, France, Belgium, the Netherlands, UK, Ireland, US and Canada met in Oslo and established the International PSC Study Group (IPSCSG). Entering 2016 the network consists of renowned scientists and clinicians from more than 57 different institutions in 22 countries working with autoimmune liver diseases.

Representation in the network is Vienna on April 25th where the 5th The second meeting was organized based on active participation in anniversary of this international, in connection with the AASLD at least one ongoing study, but team-based and cutting-edge Liver Meeting in San Francisco on intentionally kept low, informal- and cooperation was celebrated. In November 15th. The update meeting interest-driven. Every second year, addition to the project updates, a was concerned with the completion a two-day meeting is hosted by one key point for this meeting was to of several major undertakings in of the participating institutions, bring the group closer to joint grant the international PSC study group, in 2012 in Hamburg, and in 2014 applications within major funding for which papers are expected in Amsterdam. Two hour update bodies like the EU/Horizon2020 to appear in 2015. These include meetings are held twice a year and NIH. One step in this direction the genome-wide association during the International Liver is the leadership role taken within study meta-analysis (almost 5,000 CongressTM (ILC) organized by the the autoimmune liver disease arena patients), the Immunochip cross- European Association for the Study (IPSCSG included) to enter into an disease analysis (including more than of the Liver (EASL) and the annual application of a “European Reference 85,000 individuals and in addition meeting of the American Association Network” for rare liver diseases. to PSC patients with inflammatory for the Study of Liver Diseases Whilst a clinical initiative, a platform bowel disease, psoriasis and (AASLD). of an EU accredited clinical network ankylosing spondylitis), the clinical is also anticipated to be important database paper with clinical data In 2015 the first meeting took when reaching out for research from more than 7,000 patients, the place in conjunction with the EASL funding (e.g. within Horizon 2020). cholangiocarcinoma sequencing International Liver Congress in project, and the Immunochip sub- NoPSC ⁞ Annual report 2015 27

phenotype paper (more than 3,000 The IPSCSG Delphi consensus Members of the steering patients). Furthermore, several process on clinical endpoints committee clinical biomarker and intervention A key deliverable of the IPSCSG studies are underway, including in 2015 was the publishing of Prof. Ulrich H. Beuers, Amsterdam, the IPSCSG anchored FICUS study the Delphi consensus process on the Netherlands (elastography, Olivier Chazouillieres) endpoints in clinical trials in PSC Dr. Luca Fabris, Padua, Italy and DILSTENT2 study (endoscopic in Hepatology (see facsimile). The Prof. Martti Färkkilä, Helsinki, therapy, Cyriel Ponsioen). process resulted in the furthering of Finland the topic by the American Association Prof. Chris Bowlus, Sacramento, USA Both meetings attracted a full for Liver Diseases (AASLD) by the Prof. Olivier Chazouilleres, Paris, auditorium and the group has joint organizing of a workshop France all reason to be proud of its together with the FDA in Maryland Dr. Gideon Hirschfeld, Birmingham, UK achievements and most valuable in March of 2016. There are now Prof. Tom Hemming Karlsen, Oslo, work and collaboration. Planning many ongoing clinical trials in PSC, Norway is now ongoing for the 4th biennial targeting a broad range of potentially (coordinator/secretary) meeting in New Haven, for relevant targets (ranging from novel which Yale holds the organizing bile acid derivatives, immune- Planned meetings in 2016: responsibilities. Further details on targeted therapeutics, antibiotics projects and updated meeting details and antifibrotics). To be able to Barcelona in April 14th can be found at www.ipscsg.org. compare the results of all these trials, New Haven in June 26th – 27th robust endpoints and the consensus Boston in November initiative is sorely needed.

Internati onal International PSC Study PSC Study Group Reykjavik Group Network Network CANADA Alberta Australia Poland Calgary Helsinki Toronto Austria Spain Bergen Uppsala USA Oslo Belgium Switzerland Denver Stockholm Houston Canada Sweden Memphis Gothenburg Denmark The Netherlands Miami Newcastle New Haven Dublin Kiel Finland UK Philadelphia Groningen Szczecin Phoenix Birmingham Cambridge Hamburg France US Rochester Oxford Amsterdam Hannover Germany Sacramento London Düsseldorf Leuven JAPAN Bonn Homburg Heidelberg Greece More Tokyo Paris Vienna Ireland information on: Zurich AUSTRALIA Graz Adelaide Iceland www.ipscsg.org Milan Israel ISRAEL Padua Tel Aviv Italy Ancona

Japan Barcelona Norway

Athen 28 NoPSC ‌‌⁞ Annual report 2015

Publications 2015

1. Karlsen TH, Chung BK (2015) DC; International Inflammatory Bowel Disease Genetics Genetic Risk and the Development of Autoimmune Liver Consortium, Parkes M, Vermeire S, Rioux JD, Mansfield ,J Disease Silverberg MS, Radford-Smith G, McGovern DP, Barrett JC, Dig Dis, 33 Suppl 2, 13-24 Lees CW. (2015) Inherited determinants of Crohn’s disease and ulcerative 2. Thorsen T, Aandahl EM, Bennet W, Olausson M, Ericzon BG, colitis phenotypes: a genetic association study Nowak G, Duraj F, Isoniemi H, Rasmussen A, Karlsen TH, Lancet, 387 (10014), 156-67 Foss A (2015) Transplantation With Livers From Deceased Donors Older 9. Vukcevic D, Traherne JA, Næss S, Ellinghaus E, Kamatani Than 75 Years Y, Dilthey A, Lathrop M, Karlsen TH, Franke A, Moffatt M, Transplantation, 99 (12), 2534-42 Cookson W, Trowsdale J, McVean G, Sawcer S, Leslie S (2015) 3. Harbord M, Annese V, Vavricka SR, Allez M, Barreiro-de Imputation of KIR Types from SNP Variation Data Acosta M, Boberg K, Burisch J, De Vos M, De Vries AM, Am J Hum Genet, 97 (4), 593-607 Dick AD, Juillerat P, Karlsen T, Koutroubakis I, Lakatos P, Orchard T, Papay P, Raine T, Reinshagen M, Thaçi D, Tilg 10. Ponsioen CY, Chapman RW, Chazouillères O, Hirschfield H, Carbonnel F, European Crohn’s and Colitis Organisation GM, Karlsen TH, Lohse AW, Pinzani M, Schrumpf E, Trauner (ECCO) (2015) M, Gores GJ (2015) The First European Evidence-Based Consensus on Extra- Surrogate endpoints for clinical trials in primary sclerosing Intestinal Manifestations in Inflammatory Bowel Disease cholangitis; review and results from an International PSC J Crohns Colitis 10 (3), 239-54 Study Group consensus process Hepatology (early online) 4. Stiksrud ,B Nowak P, Nwosu FC, Kvale D, Thalme A, Sonnerborg A, Ueland PM, Holm K, Birkeland SE, Dahm AE, 11. Liaskou E, Henriksen EK, Holm K, Kaveh F, Hamm D, Fear J, Sandset PM, Rudi K, Hov JR, Dyrhol-Riise AM, Trøseid M Viken MK, Hov JR, Melum E, Robins H, Olweus J, Karlsen (2015) TH, Hirschfield GM (2015) Reduced Levels of D-dimer and Changes in Gut Microbiota High-throughput T-cell receptor sequencing across Composition After Probiotic Intervention in HIV-Infected chronic liver diseases reveals distinct disease-associated Individuals on Stable ART repertoires J Acquir Immune Defic Syndr, 70 (4), 329-37 Hepatology (early online)

5. Nowak P, Troseid M, Avershina E, Barqasho B, Neogi U, 12. Hov JR, Zhong H, Qin B, Anmarkrud JA, Holm K, Franke A, Holm K, Hov JR, Noyan K, Vesterbacka J, Svärd J, Rudi K, Lie BA, Karlsen TH (2015) Sönnerborg A (2015) The Influence of the Autoimmunity-Associated Ancestral Gut microbiota diversity predicts immune status in HIV-1 HLA Haplotype AH8.1 on the Human Gut Microbiota: A infection Cross-Sectional Study AIDS, 29 (18), 2409-18 PLoS One, 10 (7), e0133804

6. Kevans D, Tyler AD, Holm K, Jørgensen KK, Vatn MH, 13. Wannhoff A, Rupp C, Friedrich K, Brune M, Knierim Karlsen TH, Kaplan GG, Eksteen B, Gevers D, Hov JR, J, Flechtenmacher C, Sauer P, Stremmel W, Hov JR, Silverberg MS (2015) Schirmacher P, Weiss KH, Gotthardt DN (2015) Characterization of Intestinal Microbiota in Ulcerative Inflammation But Not Biliary Obstruction Is Associated Colitis Patients with and without Primary Sclerosing With Carbohydrate Antigen 19-9 Levels in Patients With Cholangitis Primary Sclerosing Cholangitis J Crohns Colitis, 10 (3), 330-7 Clin Gastroenterol Hepatol, 13 (13), 2372-9

7. Folseraas T, Boberg KM (2015) 14. Sampaziotis F, Cardoso de Brito M, Madrigal P, Bertero A, Cancer Risk and Surveillance in Primary Sclerosing Saeb-Parsy K, Soares FA, Schrumpf E, Melum E, Karlsen Cholangitis TH, Bradley JA, Gelson WT, Davies S, Baker A, Kaser A, Clin Liver Dis, 20 (1), 79-98 Alexander GJ, Hannan NR, Vallier L (2015) Cholangiocytes derived from human induced pluripotent 8. Cleynen I, Boucher G, Jostins L, Schumm LP, Zeissig S, stem cells for disease modeling and drug validation Ahmad T, Andersen V, Andrews JM, Annese V, Brand Nat Biotechnol, 33 (8), 845-52 S, Brant SR, Cho JH, Daly MJ, Dubinsky M, Duerr RH, Ferguson LR, Franke A, Gearry RB, Goyette P, Hakonarson 15. Thorsen T, Dahlgren US, Aandahl EM, Grzyb K, Karlsen TH, H, Halfvarson J, Hov JR, Huang H, Kennedy NA, Kupcinskas Boberg KM, Rydberg L, Naper C, Foss A, Bennet W (2015) L, Lawrance IC, Lee JC, Satsangi J, Schreiber S, Théâtre Liver transplantation with deceased ABO-incompatible E, van der Meulen-de Jong AE, Weersma RK, Wilson donors is life-saving but associated with increased risk of NoPSC ⁞ Annual report 2015 29

rejection and post-transplant complications 23. Hov JE, Trøseid M (2015) Transpl Int, 28 (7), 800-12 Personalised medicine targeting the gut microbiota? Tidsskr Nor Laegeforen, 135 (7), 624 16. Carpino G, Cardinale V, Renzi A, Hov JR, Berloco PB, Rossi M, Karlsen TH*, Alvaro D, Gaudio E (2015) (*Shared senior 24. Li J, Jørgensen SF, Maggadottir SM, Bakay M, Warnatz K, author) Glessner J, Pandey R, Salzer U, Schmidt RE, Perez E, Resnick Activation of biliary tree stem cells within peribiliary E, Goldacker S, Buchta M, Witte T, Padyukov L, Videm V, glands in primary sclerosing cholangitis Folseraas T, Atschekzei F, Elder JT, Nair RP, Winkelmann J Hepatol, 63 (5), 1220-8 J, Gieger C, Nöthen MM, Büning C, Brand S, Sullivan KE, Orange JS, Fevang B, Schreiber S, Lieb W, Aukrust 17. Folseraas T, Liaskou E, Anderson CA, Karlsen TH (2015) P, Chapel H, Cunningham-Rundles C, Franke A, Karlsen Genetics in PSC: what do the “risk genes” teach us? TH*, Grimbacher B*, Hakonarson H*, Hammarström L*, Clin Rev Allergy Immunol, 48 (2-3), 154-64 Ellinghaus E* (2015) (*Shared senior author) Association of CLEC16A with human common variable 18. Fosby B, Melum E, Bjøro K, Bennet W, Rasmussen A, immunodeficiency disorder and role in murine B cells Andersen IM, Castedal M, Olausson M, Wibeck C, Gotlieb Nat Commun, 6, 6804 M, Gjertsen H, Toivonen L, Foss S, Makisalo H, Nordin A, Sanengen T, Bergquist A, Larsson ME, Soderdahl G, Nowak 25. Schrumpf E, Boberg KM, Karlsen TH (2015) G, Boberg KM, Isoniemi H, Keiding S, Foss A, Line PD, Primary sclerosing cholangitis - the Norwegian experience Friman S, Schrumpf E, Ericzon BG, Höckerstedt K, Karlsen Scand J Gastroenterol, 50 (6), 781-96 TH. (2015) Liver transplantation in the Nordic countries - An 26. Olin P, Hausken J, Foss A, Karlsen TH, Melum E, Haugaa H intention to treat and post-transplant analysis from The (2015) Nordic Liver Transplant Registry 1982-2013 Continuous molecular adsorbent recirculating system Scand J Gastroenterol, 50 (6), 797-808 treatment in 69 patients listed for liver transplantation Scand J Gastroenterol, 50 (9), 1127-34 19. Schrumpf E, Tan C, Karlsen TH, Sponheim J, Björkström NK, Sundnes O, Alfsnes K, Kaser A, Jefferson DM, Ueno Y, Eide 27. Wittig M, Anmarkrud JA, Kässens JC, Koch S, Forster M, TJ, Haraldsen G, Zeissig S, Exley MA, Blumberg RS, Melum Ellinghaus E, Hov JR, Sauer S, Schimmler M, Ziemann M, E (2015) Görg S, Jacob F, Karlsen TH, Franke A (2015) The biliary epithelium presents antigens to and activates Development of a high-resolution NGS-based HLA-typing natural killer T cells and analysis pipeline Hepatology, 62 (4), 1249-59 Nucleic Acids Res, 43 (11), e70

20. Andreassen OA, Desikan RS, Wang Y, Thompson WK, 28. Maggadottir SM, Li J, Glessner JT, Li YR, Wei Z, Chang X, Schork AJ, Zuber V, Doncheva NT, Ellinghaus E, Albrecht Mentch FD, Thomas KA, Kim CE, Zhao Y, Hou C, Wang F, M, Mattingsdal M, Franke A, Lie BA, Mills IG, Aukrust P, Jørgensen SF, Perez EE, Sullivan KE, Orange JS, Karlsen TH, McEvoy LK, Djurovic S, Karlsen TH, Dale AM (2015) Chapel H, Cunningham-Rundles C, Hakonarson H (2015) Abundant genetic overlap between blood lipids and Rare variants at 16p11.2 are associated with common immune-mediated diseases indicates shared molecular variable immunodeficiency genetic mechanisms J Allergy Clin Immunol, 135 (6), 1569-77 PLoS One, 10 (4), e0123057 29. Andresen K, Boberg KM, Vedeld HM, Honne H, Jebsen P, 21. Karlsen TH, Lammert F, Thompson RJ (2015) Hektoen M, Wadsworth CA, Clausen OP, Lundin KE, Paulsen Genetics of liver disease: From pathophysiology to clinical V, Foss A, Mathisen Ø, Aabakken L, Schrumpf E, Lothe RA, practice Lind GE (2015) J Hepatol, 62 (1 Suppl), S6-S14 Four DNA methylation biomarkers in biliary brush samples accurately identify the presence of cholangiocarcinoma 22. Vesterhus M, Hov JR, Holm A, Schrumpf E, Nygård S, Hepatology, 61 (5), 1651-9 Godang K, Andersen IM, Naess S, Thorburn D, Saffioti F, Vatn M, Gilja OH, Lund-Johansen F, Syversveen T, Brabrand 30. Berntsen NL, Klingenberg O, Juran BD, Benito de Valle M, K, Parés A, Ponsioen CY, Pinzani M, Färkkilä M, Moum B, Lindkvist B, Lazaridis KN, Boberg KM, Karlsen TH, Hov JR Ueland T, Røsjø H, Rosenberg W, Boberg KM, Karlsen TH (2015) (2015) Association Between HLA Haplotypes and Increased Enhanced liver fibrosis score predicts transplant-free Serum Levels of IgG4 in Patients With Primary Sclerosing survival in primary sclerosing cholangitis Cholangitis Hepatology, 62 (1), 188-97 Gastroenterology, 148 (5), 924-927.e2 30 NoPSC ‌‌⁞ Annual report 2015

31. Goyette P, Boucher G, Mallon D, Ellinghaus E, Jostins KL, Raab M, Chen Q, Beauchemin N, Yazaki PJ, Pyzik M, L, Huang H, Ripke S, Gusareva ES, Annese V, Hauser Ostrowski MA, Glickman JN, Rudd CE, Ploegh HL, Franke A, SL, Oksenberg JR, Thomsen I, Leslie S; International Petsko GA, Kuchroo VK, Blumberg RS (Print 2015) Inflammatory Bowel Disease Genetics Consortium; CEACAM1 regulates TIM-3-mediated tolerance and Australia and New Zealand IBDGC; Belgium IBD Genetics exhaustion Consortium; Italian Group for IBD Genetic Consortium; Nature, 517 (7534), 386-90 NIDDK Inflammatory Bowel Disease Genetics Consortium; United Kingdom IBDGC; Wellcome Trust Case Control 35. Zeissig S, Petersen BS, Tomczak M, Melum E, Huc-Claustre Consortium; Quebec IBD Genetics Consortium, Daly MJ, E, Dougan SK, Laerdahl JK, Stade B, Forster M, Schreiber S, Van Steen K, Duerr RH, Barrett JC, McGovern DP, Schumm Weir D, Leichtner AM, Franke A, Blumberg RS (Print 2015) LP, Traherne JA, Carrington MN, Kosmoliaptsis V, Karlsen Early-onset Crohn’s disease and autoimmunity associated TH*, Franke A*, Rioux JD*. (2015) (*Shared senior author) with a variant in CTLA-4 High-density mapping of the MHC identifies a shared role Gut, 64 (12), 1889-97 for HLA-DRB1*01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis 36. Vedeld HM, Andresen K, Eilertsen IA, Nesbakken A, Seruca Nat Genet, 47 (2), 172-9 R, Gladhaug IP, Thiis-Evensen E, Rognum TO, Boberg KM, Lind GE (Print 2015) 32. Åberg F, Gissler M, Karlsen TH, Ericzon BG, Foss A, The novel colorectal cancer biomarkers CDO1, Rasmussen A, Bennet W, Olausson M, Line PD, Nordin ZSCAN18 and ZNF331 are frequently methylated across A, Bergquist A, Boberg KM, Castedal M, Pedersen CR, gastrointestinal cancers Isoniemi H (2015) Int J Cancer, 136 (4), 844-53 Differences in long-term survival among liver transplant recipients and the general population: a population-based 37. Andersen IM, Fosby B, Boberg KM, Clausen OPF, Jebsen P, Nordic study Melum E, Line PD, Foss A, Schrumpf E, Karlsen TH (2015) Hepatology, 61 (2), 668-77 Indications and outcomes in liver transplantation in patients with primary sclerosing cholangitis in Norway 33. Trøseid M, Ueland T, Hov JR, Svardal A, Gregersen I, Dahl Transplantation Direct 2015;1: e39 CP, Aakhus S, Gude E, Bjørndal B, Halvorsen B, Karlsen TH, Aukrust P, Gullestad L, Berge RK, Yndestad A (Print 2015) 38. Wannhoff A, Folseraas T, Brune M, Rupp C, Friedrich Microbiota-dependent metabolite trimethylamine-N- K, Knierim J, Weiss KH, Sauer P, Flechtenmacher C, oxide is associated with disease severity and survival of Schirmacher P, Stremmel W, Hov JR, Gotthardt DN (2015) patients with chronic heart failure A common genetic variant of fucosyltransferase 2 J Intern Med, 277 (6), 717-26 correlates with serum carcinoembryonic antigen levels and affects cancer screening in patients with primary 34. Huang YH, Zhu C, Kondo Y, Anderson AC, Gandhi A, Russell sclerosing cholangitis A, Dougan SK, Petersen BS, Melum E ,Pertel T, Clayton United European Gastroenterol J, 4 (1), 84-91

The diagram shows the Center’s publication development including Impact factor (IF). Publications are registered in the year they were first published. NoPSC ⁞ Annual report 2015 31 ) r o t a r t llu s I I ud, C M ud, er o v T I

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