DCs as clinical targets of anti-integrin therapy in IBD

PROJECT SUMMARY/ABSTRACT Anti-integrin α4β7 therapy (vedolizumab) has demonstrated outstanding safety and efficacy for the treatment of inflammatory bowel disease (IBD), a relatively common, chronic, incurable pair of idiopathic immune-mediated diseases of the intestines (Crohn’s disease and ulcerative colitis) that typically strike in youth to early adulthood to produce lifelong suffering and disability. However, for unknown reasons, many IBD patients do not respond to even this therapy. We recently generated evidence that this therapy selectively affects the intestinal migration of dendritic cells (DC) rather than T cells, as had been widely presumed. We therefore seek to demonstrate that directly observing the nature of these DC, and their response to vedolizumab, will improve our currently limited clinical tools for predicting and optimizing the efficacy of this therapy. Additionally, by demonstrating that DC are the actual target of this profoundly specific yet effective therapy, we have implicated them directly in the pathogenesis of IBD, which to date remains poorly understood. We therefore propose to perform a detailed analysis on DC from the blood and colonic mucosa of IBD patients to correlate their phenotype and diversity with the presence or absence of inflammation, and more specifically how vedolizumab induces remission in IBD. By doing so, we will not only improve our existing tools for helping IBD patients, but also reveal for new strategies to treat or even cure this significant public health problem.