title: Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor-neutralizing therapy in patients with inflammatory bowel disease.
abstract: Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are complex chronic inflammatory conditions of the gastrointestinal tract that are driven by perturbed cytokine pathways. Anti-tumor necrosis factor-α (TNF) antibodies are mainstay therapies for IBD. However, up to 40% of patients are nonresponsive to anti-TNF agents, which makes the identification of alternative therapeutic targets a priority. Here we show that, relative to healthy controls, inflamed intestinal tissues from patients with IBD express high amounts of the cytokine oncostatin M (OSM) and its receptor (OSMR), which correlate closely with histopathological disease severity. The OSMR is expressed in nonhematopoietic, nonepithelial intestinal stromal cells, which respond to OSM by producing various proinflammatory molecules, including interleukin (IL)-6, the leukocyte adhesion factor ICAM1, and chemokines that attract neutrophils, monocytes, and T cells. In an animal model of anti-TNF-resistant intestinal inflammation, genetic deletion or pharmacological blockade of OSM significantly attenuates colitis. Furthermore, according to an analysis of more than 200 patients with IBD, including two cohorts from phase 3 clinical trials of infliximab and golimumab, high pretreatment expression of OSM is strongly associated with failure of anti-TNF therapy. OSM is thus a potential biomarker and therapeutic target for IBD, and has particular relevance for anti-TNF-resistant patients.
authors.affiliation: Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.|Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Nathaniel R
authors.identifier: http://orcid.org/0000-0001-9991-0503
authors.initials: NR
authors.lastname: West
authors.affiliation: Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.|Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Ahmed N
authors.initials: AN
authors.lastname: Hegazy
authors.affiliation: Somerville College, University of Oxford, Oxford, UK.
authors.forename: Benjamin M J
authors.initials: BMJ
authors.lastname: Owens
authors.affiliation: Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Bullers
authors.affiliation: Janssen Research and Development, Raritan, New Jersey, USA.
authors.forename: Bryan
authors.initials: B
authors.lastname: Linggi
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
authors.forename: Sofia
authors.initials: S
authors.lastname: Buonocore
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
authors.forename: Margherita
authors.initials: M
authors.lastname: Coccia
authors.affiliation: Institute of Biochemistry and Molecular Biology, RWTH Aachen University, Aachen, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Görtz
authors.affiliation: Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Sébastien
authors.initials: S
authors.lastname: This
authors.affiliation: Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.|Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Krista
authors.initials: K
authors.lastname: Stockenhuber
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
authors.forename: Johanna
authors.initials: J
authors.lastname: Pott
authors.affiliation: Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
authors.forename: Matthias
authors.initials: M
authors.lastname: Friedrich
authors.affiliation: Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
authors.forename: Grigory
authors.initials: G
authors.lastname: Ryzhakov
authors.affiliation: Janssen Research and Development, Raritan, New Jersey, USA.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Baribaud
authors.affiliation: Janssen Research and Development, Raritan, New Jersey, USA.
authors.forename: Carrie
authors.initials: C
authors.lastname: Brodmerkel
authors.affiliation: Medical Department, Division of Gastroenterology, Infectiology and Rheumatology, Charité-Universitätsmedizin Berlin, Germany.
authors.forename: Constanze
authors.initials: C
authors.lastname: Cieluch
authors.affiliation: OPPF-UK, The Research Complex at Harwell, Rutherford Appleton Laboratory, Harwell, Oxford, UK.
authors.forename: Nahid
authors.initials: N
authors.lastname: Rahman
authors.affiliation: Institute of Biochemistry and Molecular Biology, RWTH Aachen University, Aachen, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Müller-Newen
authors.affiliation: OPPF-UK, The Research Complex at Harwell, Rutherford Appleton Laboratory, Harwell, Oxford, UK.|Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Owens
authors.affiliation: Medical Department, Division of Gastroenterology, Infectiology and Rheumatology, Charité-Universitätsmedizin Berlin, Germany.
authors.forename: Anja A
authors.initials: AA
authors.lastname: Kühl
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Maloy
authors.affiliation: Janssen Research and Development, Raritan, New Jersey, USA.
authors.forename: Scott E
authors.initials: SE
authors.lastname: Plevy
authors.affiliation: Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Satish
authors.initials: S
authors.lastname: Keshav
authors.affiliation: Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Simon P L
authors.identifier: http://orcid.org/0000-0002-2690-4361
authors.initials: SPL
authors.lastname: Travis
authors.affiliation: Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.|Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Fiona
authors.initials: F
authors.lastname: Powrie
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D016022:Case-Control Studies; D018925:Chemokines; D003092:Colitis / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D005765:Gastrointestinal Agents / Q000627:therapeutic use; D020869:Gene Expression Profiling; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D007249:Inflammation; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D000069285:Infliximab / Q000627:therapeutic use; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D053683:Oncostatin M / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D053681:Oncostatin M Receptor beta Subunit / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D018925:Chemokines; D005765:Gastrointestinal Agents; C508600:IL6 protein, human; D015850:Interleukin-6; C508351:OSM protein, human; C508348:OSMR protein, human; D053681:Oncostatin M Receptor beta Subunit; C508352:Osm protein, mouse; C508349:Osmr protein, mouse; D014409:Tumor Necrosis Factor-alpha; D053683:Oncostatin M; D018799:Intercellular Adhesion Molecule-1; C529000:golimumab; D000069285:Infliximab