Th226 - Successful Anti-integrin alpha4/beta7 Therapy Reduces Intracolonic Dendritic Cells, Not Effector T Cells in Inflammatory Bowel Disease

Astrid Clarke – Scientist, SeaGen; Duncan Hindmarch – Technician, Translational Research, Benaroya Research Institute; Ramya Kongala – Technician, Translational Research, Benaroya Res. Inst., Virginia Mason; Donna Shows – Senior Technician, Translational Research, Benaroya Research Institute

Abstract Text: Vedolizumab controls intestinal inflammation in Crohn’s disease and ulcerative colitis by preventing integrin α4β7 on circulating immune cells from binding the addressin MaDCAM-1 on vascular endothelial cells in inflamed intestinal lamina propria. This was believed to achieve remission by preventing migration of effector T cells into tissue. We tested this hypothesis by evaluating the blood and colonic mucosal immune cells of 13 vedolizumab recipients before and during therapy. We found no changes in effector T cell frequency, mRNA transcriptome, or T cell receptor repertoire overlap between circulating and mucosal T cells to follow vedolizumab initiation, regardless of clinical efficacy. Instead we found a precipitous drop in mucosal CD1c+ dendritic cells (DCs), particularly in treatment-responsive patients. To determine if this was a unique effect of α4β7 blockade rather than simply a nonspecific effect of resolving inflammation, we evaluated 71 biopsies from vedolizumab recipients and 71 control biopsies from inflammatory bowel disease patients not on vedolizumab, matched 1:1 in terms of anatomic location, disease type, inflammation, and concomitant IBD therapy (other than vedolizumab). Again, we found no differences in effector T cell frequency or mRNA transcriptome profile associated with vedolizumab use. Instead, we found significantly fewer CD1c+ DCs exclusively in the biopsies of treatment-responsive patients. Indeed, circulating DCs express more α4β7 than any T cell and more dramatically down-regulate it upon exposure to vedolizumab in vitro. We thus strongly suggest that vedolizumab controls Crohn’s disease and ulcerative colitis by blocking the migration of DCs, not effector T cells, to the inflamed mucosa.