Abstract
SummaryAnti-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.
Highlights
To mount an efficient immune response, lymphocytes travel between secondary lymphoid organs and mucosal tissues to enable antigen recognition, leading to activation and expansion
In the mesenteric lymph node, activated T lymphocytes are imprinted in a specialized microenvironment that results in increased expression of integrin a4b7 and CCR9.2,3 Elevated a4b7 enables T cells to have an increased capacity to adhere to mucosal addressin cell adhesion molecule 1 (MAdCAM-1) on endothelial venules in the lamina propria (LP).[4]
Consistent with that, we demonstrate a significant reduction of genes associated with cytotoxic intraepithelial lymphocytes (IEL) in patients with Crohn’s disease (CD) enrolled in a placebo-controlled study of etrolizumab (ClinicalTrials.gov: NCT02394028), which showed efficacy in an exploratory subcohort analysis.[26]
Summary
To mount an efficient immune response, lymphocytes travel between secondary lymphoid organs and mucosal tissues to enable antigen recognition, leading to activation and expansion. Gut-resident T cells express CD69 to repress S1PR1-dependent tissue egress into lymphatics through CD69:S1P1 complex formation, another mechanism of lymphocyte retention in tissue.[11,12]
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