West, N. R. et al. (2017) Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor–neutralizing therapy in patients with inflammatory bowel disease. Nature Medicine, 23(5), pp. 579-589. (doi: 10.1038/nm.4307) (PMID:28368383) (PMCID:PMC5420447)
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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.
Item Type: | Articles |
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Additional Information: | We gratefully acknowledge the contributions of the Oxford Radcliffe and GI Biobanks and the Oxford IBD cohort study, which are supported by the NIHR Oxford Biomedical Research Centre (grant no. HBRWAE04 Task HB81.G). N.R.W. was supported by an Irvington Institute Postdoctoral Fellowship (Cancer Research Institute). A.N.H. was supported by a European Molecular Biology Organization (EMBO) long-term fellowship (ALTF 116-2012) and a Marie Curie fellowship (FP7-PEOPLE-2012-IEF, proposal 330621). R.J.O. and N.R. are supported by Medical Research Council grant no. MR/K018779/1. K.J.M. is supported by the Wellcome Trust (Investigator Award 102972). |
Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Maloy, Professor Kevin |
Authors: | West, N. R., Hegazy, A. N., Owens, B. M.J., Bullers, S. J., Linggi, B., Buonocore, S., Coccia, M., Gortz, D., This, S., Stockenhuber, K., Pott, J., Freidrich, M., Ryzhakov, G., Baribaud, F., Brodmerkel, C., Cieluch, C., Rahman, N., Muller-Newen, G., Owens, R. J., Kuhl, A. A., Maloy, K. J., Plevy, S. E., Oxford IBD Cohort Investigators, , Keshav, S., Travis, S. P.L., and Powrie, F. |
College/School: | College of Medical Veterinary and Life Sciences > School of Infection & Immunity |
Journal Name: | Nature Medicine |
Publisher: | Nature Research |
ISSN: | 1078-8956 |
ISSN (Online): | 1546-170X |
Published Online: | 03 April 2017 |
Copyright Holders: | Copyright © 2017 Nature America, Inc. |
First Published: | First published in Nature Medicine |
Publisher Policy: | Reproduced in accordance with the publisher copyright policy |
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