Vedolizumab efficacy is associated with decreased intracolonic dendritic cells, not memory T cells [P444]
Background: Vedolizumab, an antibody blocking integrin a4ß7, is a safe and effective therapy for Crohn's disease and ulcerative colitis. Blocking a4ß7 from binding its cognate addressin MAdCAM-1 on intestinal blood vessel endothelial cells prevents T cells from migrating to the gut mucosa in animal models. However, data supporting this mechanism of action in humans is limited. Methods: We conducted a cross-sectional case-control study to evaluate the effect of vedolizumab on intestinal immune cell populations while avoiding the confounding effect resolving inflammation could have on the cellularity of the colonic mucosa in treatment-responsive patients. Colon biopsies from 71 case patients receiving vedolizumab were matched with biopsies from 71 control patients, similar in disease type, medications, anatomic location, and inflammation. Biopsies were analyzed by flow cytometry and full mRNA transcriptome sequencing of sorted T cells. Results: No difference was seen between vedolizumab recipients and controls in the quantity of any antigen-experienced lymphocyte subset, nor the quality of the transcriptome in any experienced T cell subset. Fewer naïve colonic B and T cells were seen in vedolizumab recipients than controls, regardless of response. The only immune population that was significantly reduced exclusively in the colonic mucosa of vedolizumab-responsive patients was CD1c+ (BDCA1+) dendritic cells. In blood, these dendritic cells ubiquitously express more a4ß7 per cell than almost any other circulating leukocyte, but rapidly downregulate a4ß7 expression upon vedolizumab exposure. Conclusions: The clinical efficacy of vedolizumab thus reveals integrin a4ß7-dependent dendritic cell migration to the intestinal mucosa to be central to IBD pathogenesis. Overall design: Cross-sectional case-control