Tyrosine kinase 2 signalling drives pathogenic T-cells in colitis.

De Vries, L C S; Ghiboub, M; van Hamersveld, P H P; Welting, O; Verseijden, C; Bell, M J; Rioja, I; Prinjha, R K; Koelink, P J; Strobl, B; Müller, M; D'Haens, G R; Wildenberg, M E; De Jonge, W J

BACKGROUND AND AIMS Tyrosine kinase 2 (TYK2) is required for signalling of key cytokines in the pathogenesis of inflammatory bowel disease (IBD). We assessed the efficacy of a novel selective TYK2 inhibitor (TYK2i) in experimental colitis using pharmacological and genetic tools. METHODS At onset of T-cell transfer colitis RAG1 -/- mice received vehicle or TYK2i daily by oral gavage. T-cells lacking TYK2 kinase activity (TYK2 KE) were used to confirm selectivity of the inhibitor. To this end RAG1 -/- or RAG1 -/-TYK2 KE animals were transferred with either wild type (WT) or TYK2 KE-CD45RB high colitogenic T-cells. Loss of bodyweight, endoscopic disease, the disease activity index (DAI) and histopathology scores were recorded. Tissues were analysed ex vivo for lymphocyte populations by flow cytometry. The impact of TYK2 inhibition on human DC-T-cell interactions were studied using autologous Revaxis specific T-cell assays. RESULTS TYK2i (70 mg/kg) prevented weight loss and limited endoscopic activity during T-cell transfer colitis. TYK2i (70 mg/kg) decreased DAI. While transfer of WT T-cells into RAG -/-TYK2 KE hosts induced colitis, TYK2 KE T-cells transferred into RAG1 -/-TYK2 KErecipients failed to do so. Ex vivo analysis showed a decrease in colon tissue Th1 cells and an increase in Th17 cells upon transfer of TYK2 KE-CD45RB high cells. In human antigen triggered T-cells, TYK2i displayed reduced Th1 differentiation similar to murine Th1 cells. CONCLUSION Oral administration of TYK2i, as well as transfer of T-cells lacking TYK2 activity, reduced human Th1 differentiation and ameliorated the course of murine T-cell transfer colitis. We conclude that TYK2 is a promising drug target for the treatment of IBD.