A dysregulated mucosal immune response to normal intestinal bacteria may lead to human IBD. These diseases have increased substantially in industrialized regions over the last 75 years, and now are increasing quickly in developing countries. Unrecognized environmental factors clearly influence susceptibility for IBD. Our major hypothesis is that living in an exceedingly clean environment negatively effects immune development and predisposes to IBD. Moreover, we proposed that the modern day absence of exposure to intestinal helminths resulting from this hygiene is an important environmental factor contributing to IBD in industrialized societies. Helminths regulate their host's immune system and prevent excessive immune responses. Until the present era, nearly all children and adults harbored intestinal helminths. Substantial epidemiological data, and human and animal studies support this hypothesis. We and others have shown that helminths prevent or reverse intestinal inflammation in various animal models of IBD. This competing continuation proposal will continue to study how helminths help control IBD, hypothesizing that two newly discovered novel mechanisms of worm-induced, immune regulation involving dendritic cells and contra-regulatory T cells are important for disease control. The project will use a Rag-IL10 transfer murine model of IBD, characterized in our laboratory and a second model to confirm observations. The experiments will use various reporter mice and other transgenic animals, in vitro cell culture, adoptive cell transfer, cytokine inhibitors and various molecular and immunological techniques. Also employed will be Heligmosomoides polygyrus, an intestinal helminth of mice. Aim I will determine which cell types helminths modulate in the gut innate immune system to prevent colitis and how these cells function to accomplish the task. This aim will test the hypothesis that helminth exposure influences the function of intestinal dendritic cells rendering them less able to promote Th1 and Th17 responses, and colitis during subsequent immune challenges. Aim II will further study mechanisms by which DC down-modulate effector T cell responses in colitis. Aim III will determine if helminths inhibit contra-regulatory T cell activity. This aim will test the hypothesis that the gut normally contains specialized T cells (contra-regulatory T cells), which limit regulatory T cell function, and that helminths control contra-regulatory T cell function via modulation of DC function helping to limit intestinal inflammation. This investigation may provide fresh insight into the pathogenesis of IBD and lead to better treatment. PUBLIC HEALTH RELEVANCE: Several pharmaceutical companies are developing worm-based therapies, which are being tested extensively around the world and may be available for patients with various immunological diseases in the near future. This competing continuation proposal will continue to study how helminths help control IBD, hypothesizing that two newly discovered novel mechanisms of worm-induced, immune regulation involving innate immunity and contra-regulatory T cells are important for disease control. Results from this study could help improve the treatment of patients with IBD and other immunological disease.