Intestinal T cells and microbiota as therapeutic targets in autoimmune uveitis

Project Summary Chronic autoimmune uveitis represents a medical management conundrum, which left untreated, is a significant cause of blindness in the US and worldwide. Yet due to an incomplete understanding of its pathogenesis, treatment has often required use of non-specific anti-inflammatory agents that can have untoward side effects. Emerging evidence links the intestinal microbiota to extraintestinal autoimmune diseases like uveitis, providing new clues into pathogenesis, and novel avenues for therapeutic targeting. Our goal is to investigate how the intestinal microbiota can be manipulated to re-establish intestinal and thus systemic immune homeostasis that has gone awry during the course of autoimmune uveitis. To do this, we are using a quintessential T-cell mediated model, experimental autoimmune uveitis (EAU). We will utilize two different interventions to alter the intestinal microbiota, antibiotics and short chain fatty acid (SCFA) metabolites of intestinal bacterial fermentation of dietary fiber, in EAU. Enhancement of intestinal Tregs (cells that usually suppress the immune system) by these microbiota-altering interventions will be tested by adoptive transfer of Tregs and in vitro Treg suppression assays. The impact of microbiota-altering interventions on intestinal immune cell migration to peripheral lymphoid tissues and the eye during EAU will also be investigated. Direct microbiota effects on enhancement of intestinal Treg abundance and uveitis severity will be tested by fecal microbial transplantation from antibiotic or SCFA-pre-treated animals. These results are expected to yield novel insights into autoimmune uveitis pathogenesis as well as lay groundwork for new treatment strategies targeting the intestinal microbiota to re-establish immune homeostasis.