O13 Regulation and role of alphaE integrin in migration and retention of lymphocytes in intestinal mucosa

IntroductionTargeting integrins that mediate adhesion and migration of lymphocytes to the gastrointestinal (GI) tract is an effective therapy in inflammatory bowel disease (IBD). α4β7 and α4β1 are expressed on circulating lymphocytes that may mediate inflammation, while αEβ7 integrin is expressed primarily on a subset of T cells within the mucosa. Etrolizumab is a humanized monoclonal antibody that selectively binds the β7 subunit of the α4β7 and αEβ7 integrin heterodimers. The relative role of individual integrin heterodimers in lymphocyte migration and retention in the GI tract remains to be characterized.MethodspSMAD3, MAdCAM, VCAM and ICAM levels were measured in colonic and ileal biopsies. α4β7+ and α4β7- human T cells were induced to express αE integrin by TGF-β1 stimulation followed by qPCR array gene expression analysis. A murine photo-convertible reporter system was used to determine the effect of blockade of α4β7 and/or αEβ7 integrins on lymphocyte migration and retention. T cell-epithelial cell interactions were evaluated using intravital two-photon microscopy.ResultspSMAD3 was observed in the epithelium and lamina propria in IBD biopsies, suggesting active TGF-β signalling. Adhesion molecule expression was increased in inflamed biopsies. TGF-β1 stimulation induced αE integrin expression on both α4β7+ and α4β7- circulating T cells. αEβ7+ cells derived from α4β7+ and α4β7- progenitors had similar cytokine, chemokine, transcription factors and effector molecule gene expression. In a mouse model of T cell migration, combined blockade of both α4β7 and αEβ7 with anti-β7 (etrolizumab surrogate) led to a greater reduction of T cell accumulation in the intestinal mucosa and epithelium compared to single blockade of either α4β7 or αEβ7. Further intravital two-photon microscopy and photo-specific labelling experiments revealed that blockade of αEβ7 reduces T cell:epithelial cell interactions, increases the migratory speed of activated T cells in the intestinal mucosa, and facilitates effector T cell egress from the intestinal mucosa through lymphatic vessels.ConclusionsαEβ7 is induced by TGF-β1 on both α4β7+ or α4β7- T cells. Co-blockade of α4β7 and αEβ7 together leads to greater inhibition of T cell accumulation in gastrointestinal tissues through a stepwise inhibition of T cell migration and subsequent tissue retention.