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Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor–neutralizing therapy in patients with inflammatory bowel disease

An Erratum to this article was published on 06 June 2017

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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.

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Figure 1: OSM and OSMR are highly expressed in the inflamed intestinal tissue of patients with IBD.
Figure 2: OSM is associated with response to anti-TNF therapy.
Figure 3: Nonhematopoietic stromal cells are prevalent in inflamed intestinal tissue and express high levels of OSMR.
Figure 4: OSM promotes inflammatory behavior in human intestinal stroma.
Figure 5: The OSM–stromal cell axis is conserved in a preclinical model of anti-TNF-resistant IBD.
Figure 6: OSM promotes anti-TNF-resistant colitis in vivo.

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  • 11 April 2017

    In the version of this article initially published, there were two typographical errors in the Abstract. The unnecessary ‘h’ in the line “Furthermore, h according to…..” has been deleted. The line “OSM is thus a potential biomarker of and therapeutic target for IBD,….” was changed to read “OSM is thus a potential biomarker and therapeutic target for IBD…”. These errors have been corrected in the HTML and PDF versions of the article. A coding error that inadvertently resulted in incorrect ordering of the authors in the HTML version was also corrected.

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Acknowledgements

We thank J. Middleton, S. Rogatti Granados, C. Arancibia, P. Siddhanathi, J. Chivenga, N. Charumbira, J. Schulthess, C. Pearson, and S. Spieckermann for excellent technical support, patient-sample collection, and lab management. We thank H. Uhlig and all members of the laboratory for valuable discussions and support. We also thank V. Malmstrom and E. Thompson for critical review of this manuscript. We thank V. Cerundolo for providing IL-1R1 knockout mice. 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). We thank the flow cytometry core-facility staff at the University of Oxford Translational Gastroenterology Unit and Kennedy Institute of Rheumatology, as well as the staff of the Kennedy Institute histology core facility for excellent tissue preparation. We thank all volunteers, patients, and their families for agreeing to contribute to this study. 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). B.M.J.O. is a lecturer at Somerville College, University of Oxford. S.T. was supported by the Ecole Normale Supérieure of Lyon and the French Ministry of Education. R.J.O. and N.R. are supported by Medical Research Council grant no. MR/K018779/1. M.C. and K.J.M. were supported by the Edward Penley Abraham Trust. K.J.M. is supported by the Wellcome Trust (Investigator Award 102972). F.P. is supported by the Wellcome Trust and Foundation Louis Jeantet.

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N.R.W., A.N.H., B.M.J.O., and F.P. contributed to study conception and design, data analysis, and manuscript production. N.R.W. and A.N.H. designed, executed, and analyzed experiments. S.J.B., C.C., and A.A.K. performed histological assays. B.L., F.B., C.B., and S.E.P. contributed clinical trial data and analysis. S.B., M.C., and K.J.M. provided data on the cytokine requirements of the Hh + α-IL-10R model of IBD. D.G. and G.M.-N. designed the OR-Fc protein construct. N.R. and R.J.O. designed the strategy for OR-Fc production and generated the final protein. S.T. contributed to intestinal stromal cell experiments. K.S. and G.R. contributed to preclinical mouse experiments. J.P. conducted mouse intestinal organoid experiments. M.F. contributed to the establishment of human intestinal stromal cell cultures. S.K. and S.P.L.T. provided clinical guidance and contributed to patient-sample collection. All authors read and approved the final manuscript.

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Correspondence to Fiona Powrie or Fiona Powrie.

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Competing interests

N.R.W., A.N.H., B.M.J.O., and F.P. are inventors of patents relating to OSM as a therapeutic target for IBD. S.K. has received honoraria and/or research support from Allergan, Abbvie, Astra-Zeneca, ChemoCentryx Inc., Dr Falk Pharma, Ferring, Gilead, GSK, Merck, Mitsubishi-Tanabe Pharma, Pfizer, and Vifor Pharma. S.P.L.T. has received research support from Abbvie, IOIBD, Lilly, UCB, Vifor, and the Norman Collison Foundation. S.P.L.T. receives consulting fees from Abbvie, Amgen, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Chemocentryx, Cosmo, Ferring, Giuliani SpA, GSK, Lilly, MSD, Neovacs, NovoNordisk, Norman Collison Foundation, Novartis, NPS Pharmaceuticals, Pfizer, Proximagen, Receptos, Shire, Sigmoid Pharma, Takeda, Topivert, UCB, VHsquared, and Vifor Pharma. S.P.L.T. has received speaker fees from Abbvie, Biogen, Ferring, and Takeda. B.L., F.B., C.B., and S.E.P. are employees of Janssen Research and Development LLC. S.B. and M.C. are currently employees of GSK. F.P. has received research support or consultancy fees (unrelated to this work) from Eli Lilly, Janssen, GSK, Medimmune, Compugen and UCB.

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West, N., Hegazy, A., Owens, B. et al. Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor–neutralizing therapy in patients with inflammatory bowel disease. Nat Med 23, 579–589 (2017). https://doi.org/10.1038/nm.4307

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