T cell-associated α4 β7 but not α4 β1 integrin is required for the induction and perpetuation of chronic colitis

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Abstract

Anti-adhesion therapies that target α 4 integrins (e.g., natalizumab) are thought to work by blocking T-cell recruitment to the intestinal tissues in patients with Crohn's disease (CD); however, little direct evidence is available to confirm this contention. We wished to evaluate the importance of T cell-associated α4 integrins in a chronic colitis model in mice and to determine the effect of natalizumab treatment on intestinal tissue T-cell accumulation in human CD. Adoptive transfer of T cells lacking α 4 (α4-/-) but not β1 integrin into immunodeficient mice produced significantly attenuated disease. This was correlated with reduced numbers of colon CD4 T cells compared with the control mice; however, tissue distribution of T helper type 1 (Th1) and T helper type 17 (Th17) cells and regulatory T cells (Tregs) was not affected by the lack of α4. Furthermore, α4-/- T cells demonstrated defective homing to the chronically inflamed small intestines and colons. Finally, patients treated with natalizumab showed significant reduction in mucosal CD4 T cells and no skewing in the foxp3 + Treg or T-bet + Th1 fractions thereof. These results demonstrate a direct role for T cell-associated α4 β7 but not α4 β 1 integrins during initiation and perpetuation of chronic colitis. Moreover, our data demonstrated that natalizumab treatment reduced mucosal CD4 T-cell accumulation in CD patients.

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Kurmaeva, E., Lord, J. D., Zhang, S., Bao, J. R., Kevil, C. G., Grisham, M. B., & Ostanin, D. V. (2014). T cell-associated α4 β7 but not α4 β1 integrin is required for the induction and perpetuation of chronic colitis. Mucosal Immunology, 7(6), 1354–1365. https://doi.org/10.1038/mi.2014.22

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