Blockade of αEβ7 integrin suppresses accumulation of CD8+ and Th9 lymphocytes from patients with IBD in the inflamed gut in vivo

Objective Therapeutically targeting lymphocyte adhesion is of increasing relevance in IBD. Yet, central aspects of the action of antiadhesion compounds are incompletely understood. We investigated the role of alpha E beta 7 and alpha 4 beta 7 integrins and their blockade by vedolizumab and etrolizumab for trafficking of IBD T lymphocytes in an in vivo model of homing to and retention in the inflamed gut. Design We explored integrin expression in patients with IBD by flow cytometry and immunohistochemistry, while regulation of integrins was studied in T cell cultures. The functional relevance of integrins was assessed by adhesion assays and a recently established humanised mouse model in dextran sodium sulfate-treated immunodeficient mice. Results High expression of alpha E beta 7 was noted on CD8(+) and CD4(+) Th9 cells, while alpha 4 beta 7 was expressed on CD8+, Th2 and Th17 cells. T cell receptor stimulation and transforming growth factor beta were key inducers of alpha E beta 7 on human T cells, while butyric acid suppressed alpha E beta 7. In comparison to alpha 4 beta 7 blockade via vedolizumab, blockade of beta 7 via etrolizumab surrogate antibody superiorly reduced colonic numbers of CD8+ and Th9 cells in vivo after 3 hours, while no difference was noted after 0.5 hours. AE beta 7 expression was higher on CD8+ T cells from patients with IBD under vedolizumab therapy. Conclusions AE beta 7 is of key relevance for gut trafficking of IBD CD8(+) T cells and CD4(+) Th9 cells in vivo and mainly retention might account for this effect. These findings indicate that blockade of alpha E beta 7 in addition to alpha 4 beta 7 may be particularly effective in intestinal disorders with expansion of CD8(+) and Th9 cells such as IBD.