Human IBD probably results from a dysregulated mucosal immune response to normal intestinal bacteria. The frequency of Crohn's disease (CD) has increased substantially over the last 50 years in industrialized, temperate regions. CD and ulcerative colitis (UC) are rare in less developed countries. Environmental factors influence the worldwide distribution of IBD. Helminths regulate their host's immune system and prevent excessive immune responses. Until the present era, nearly all children and adults harbored intestinal helminths. Our major hypothesis is that the modern day absence of exposure to intestinal helminths is an important environmental factor contributing to the growth of lBD. There now are substantial human epidemiologic data, and human and animal studies supporting this hypothesis. Others and we showed that helminths prevent TNBS-induced colitis and the colitis of IL 10 deficient animals. We have exciting data suggesting that helminths strongly induce regulatory T cells. Using two IBD models (TNBS and IL 10 KO colitis) and normal WT mice, we will study the immunologic mechanisms used by helminths to prevent and reverse IBD as outlined in the 3 specific aims of this proposal. Experiments will use the murine intestinal helminth Heligrnosomoides polygyrus, which only inhabits the duodenum of the host. Also employed will be transgenic mice, in vitro cell culture methods, adoptive cell transfer, cytokine inhibitors and various other molecular and immunologic techniques. Aim I derives from studies showing that H. polygyrus prevents TNBS-induced colitis. Aim I will explore the hypothesis that helminths avert mucosal inflammation by enhancing IL10, TGFbeta, IL4, IL 13 and/or PgE2 regulatory circuits locally in the intestinal mucosa. Aim II will pursue the hypothesis, supported by preliminary data, that intestinal helminths induce regulatory T cells in the MLN, which migrate to the gut to limit immune responses. This aim will characterize these regulatory cells and study mechanisms leading to their development. Aim III will determine how intestinal helminths reverse ongoing colitis in IL 10-/- mice. Helminths use many regulatory circuits to modulate immune responses. This study could lead to new therapies for human IBD and provide insight into disease pathogenesis. Double blind clinical studies have proven the utility of helminths for the treatment of IBD.