P371 Vedolizumab is associated with changes in innate rather than T-cell immunity in patients with inflammatory bowel disease. (16th January 2018)

• Record Type: Journal Article
• Authors: Zeissig, S; Rosati, E; Dowds, C M; Aden, K; Bethge, J; Schulte, B; Pan, W H; Falk-Paulsen, M; Conrad, C; Schuldt, D; Sinha, A; Nikolaus, S; Arlt, A; Kabelitz, D; Ellrichmann, M; Rosenstiel, P; Franke, A; Schreiber, S
• Is Part Of: Journal of Crohn's and colitis. Volume 12:Number 1(2018:Jan.)Supplement 1
• Page Start: S292
• Page End: S292
• Publication Date: 2018-01-16
• Subjects: Inflammatory bowel diseases -- Periodicals; 616.344005
• DOI: 10.1093/ecco-jcc/jjx180.498
• Languages: English
• ISSNs: 1873-9946

Abstract

Abstract: Background: Vedolizumab, a monoclonal antibody directed against the integrin α4β7, is approved for the treatment of inflammation in Crohn's disease (CD) and ulcerative colitis (UC). The efficacy of vedolizumab has been suggested to result from inhibition of intestinal T-cell trafficking although human data to support this conclusion are scarce. We therefore performed a comprehensive analysis of vedolizumab-induced alterations in mucosal immunity in patients with inflammatory bowel disease (IBD), using anti-inflammatory therapy with the TNF antibody infliximab as control. Methods: Peripheral blood and biopsies from sigmoid colon obtained from patients with CD ( n = 17) and UC ( n = 21) before and at 2, 6, and 14 weeks of first time treatment with vedolizumab ( n = 18) or infliximab ( n = 20) were subjected to immunophenotyping, T-cell receptor (TCR) sequencing, and RNA sequencing. In vivo trafficking of indium- and fluorescein-labelled leukocytes was investigated using single photon emission computed tomography (SPECT) and endomicroscopy. Results: Vedolizumab did not affect the abundance or activation of lamina propria T cells and had no discernible effect on the mucosal T-cell repertoire as determined by TCR sequencing. In contrast, infliximab led to rapid alterations in mucosal T-cell abundance. Indium111 studies of intestinal leukocyte trafficking in patients with CD demonstrated unaltered leukocyte migration in vivo in the presence of vedolizumab. Surprisingly, however, vedolizumab elicited pronounced changes in innate mucosal immunity including alterations in the expression of innate effector molecules, microbial sensors and chemokines. These effects were specific to α4β7 targeting and associated with clinical efficacy. Conclusions: Our findings in IBD patients differ from previous results in animal models and suggest that the mechanism of action of vedolizumab involves modulation of innate immunity more than regulation of intestinal T-cell recruitment.