P007 Oral tyrosine kinase 2 inhibitor ameliorates T cell transfer colitis

Abstract

Background: Several Janus Kinase (JAK) inhibitors selectively targeting one JAK-family member are currently under development for the treatment of inflammatory bowel diseases (IBD). Tyrosine Kinase 2, one of the JAK family members, mediates signalling of pro-inflammatory cytokines involved in the pathogenesis of IBD including IL6, IL12, IL23 and interferon gamma (IFNγ). The aim of this study was to investigate the potency of an oral TYK2 inhibitor (TYK2i) in vivo in a murine colitis model. Methods: T cell transfer colitis was induced by adoptive transfer of wild type CD45RBhigh T lymphocytes into RAG1KO mice. After onset of endoscopic disease (day 36), animals were administered with placebo or TYK2i (10, 30, 70 mg/kg/day) daily by oral gavage. Upon sacrifice, colon weight, colon length and disease activity index (DAI, consisting of diarrhoea, oedema and occult blood, score 0–7) were recorded. Colon tissue was analysed by histology (score 0–12) and protein and transcriptional analyses of various cytokines were performed. Results: In the T cell transfer colitis model, daily administration of TYK2i prevented loss of bodyweight at all doses tested. Both endoscopic and clinical disease activity were decreased by TYK2i in a dose-dependent manner, with animals receiving 70mg/kg displaying disease activity comparable to healthy controls (median activity 0, 1.75 and 0 for healthy controls, placebo and 70mg/kg respectively). Histologically, animals receiving 70 mg/kg showed significantly decreased colitis when compared to placebo treated animals, although some residual inflammation was apparent (median score 1, 5.25 and 1.5 for healthy controls, placebo and 70mg/kg respectively). Analysis of the affected colon revealed decreased expression of IFNγ and IL6 both at the mRNA and protein level, as well as decreased protein expression of TNFα. Conclusions: Our results show that oral administration of a TYK2 inhibitor ameliorates the course of T cell transfer colitis, suggesting TYK2 as a potential therapeutic target in the treatment of IBD.