DOP18 OSM neutralisation in IBD mucosal explant cultures reduces pro-inflammatory cytokine production

Abstract Background Oncostatin M (OSM) is a proinflammatory and profibrotic cytokine that has been implicated in the pathogenesis of inflammatory bowel disease (IBD). This is at least partly due to an ability to induce the secretion of cytokines and chemokines from intestinal stromal cells (West et al., Nat Med 2017). However, while mRNA expression is known to be elevated in inflamed bowel tissue from IBD patients, less is known about OSM protein levels and the effect of inhibiting OSM on cytokine production. The objective of this study was to measure OSM protein levels in serum and inflamed intestinal tissue from IBD patients, and to determine the effect of OSM neutralisation on cytokine production in an IBD mucosal explant model. Methods Serum and involved intestinal mucosa from patients with active moderate/severe ulcerative colitis (UC) or Crohn’s disease, along with corresponding samples from healthy volunteers, were obtained with patient informed consent in accordance with ICH GCP under an ethics committee-approved protocol. For the gut explant model, IBD mucosal biopsies from each individual donor were cultured ex vivo for 24 h with either anti-OSM antibody (10 or 40 µg/ml), isotype control antibody or prednisolone (1 µM). Cytokine concentrations were measured in serum, tissue lysates, and explant culture supernatants by ELISA. Results OSM protein was significantly (p < 0.001) increased in serum from Crohn’s and UC patients compared with healthy volunteer samples and significantly (p < 0.05) elevated in intestinal tissue from Crohn’s and UC patients compared with healthy control samples. Incubation of human IBD intestinal explants with an anti-OSM antibody reduced spontaneous pro-inflammatory cytokine production. In the UC mucosal explant assay (n = 9 donors), 10 and 40 µg/ml anti-OSM treatment resulted in a mean 49% and 48% inhibition of IL1β, 36% and 57% inhibition of IL6, and 27% and 43% inhibition of TNFα production, respectively. In the Crohn’s mucosal explant assay (n = 13 donors), 10 and 40 µg/ml anti-OSM treatment resulted in a mean 51% and 64% inhibition of IL1β, 57% and 42% inhibition of IL6, and 31% and 37% inhibition of TNFα production, respectively. This degree of cytokine inhibition was greater than that shown for the isotype control. Conclusions OSM protein is elevated in both serum and inflamed intestinal tissue from IBD patients. OSM neutralisation in the IBD mucosal explant assay reduced spontaneous pro-inflammatory cytokine produc