Dual targeting of lymphocyte homing and retention through α4β7 and αEβ7 inhibition in inflammatory bowel disease

Anti-integrins are therapeutically effective for inflammatory bowel disease, yet the relative contribution of α4β7 and αEβ7 to gut lymphocyte trafficking is not fully elucidated. Here, we evaluate the effect of α4β7 and αEβ7 blockade using a combination of murine models of gut trafficking and longitudinal gene expression analysis in etrolizumab-treated patients with Crohn's disease (CD). Dual blockade of α4β7 and αEβ7 reduces CD8+ T cell accumulation in the gut to a greater extent than blockade of either integrin alone. Anti-αEβ7 reduces epithelial:T cell interactions and promotes egress of activated T cells from the mucosa into lymphatics. Inflammatory gene expression is greater in human intestinal αEβ7+ T cells. Etrolizumab-treated patients with CD display a treatment-specific reduction in inflammatory and cytotoxic intraepithelial lymphocytes (IEL) genes. Concurrent blockade of α4β7 and αEβ7 promotes reduction of cytotoxic IELs and inflammatory T cells in the gut mucosa through a stepwise inhibition of intestinal tissue entry and retention. [Display omitted] Blockade of α4β7 and αEβ7 reduces CD8+ T cells in the gut mucosa more than α4β7 aloneAnti-αEβ7 or -E-cadherin reduces retention and increases egress of T cells in the gutαEβ7+ intestinal T cells are proinflammatory and have little to no regulatory markersEtrolizumab reduces mucosal inflammatory T cell genes in patients with Crohn disease Dai et al. demonstrate the cooperative roles α4β7 and αEβ7 integrins have in CD8+ T cell accumulation in the gut mucosa in a mouse model of trafficking. Intestinal biopsies from patients with Crohn disease that has been treated with etrolizumab (anti-β7) show treatment-specific reductions in gene expression associated with CD8+ cytotoxic T cells.