Crohn's disease (CD) is a debilitating condition of unknown etiology that affects up to 1 million individuals in North America. An accepted hypothesis suggests that CD may represent a dysregulated immune response to antigens derived from the commensal flora in a genetically predisposed host. Our recent studies have shown that SAMP1/YitFc (SAMP) mice are able to develop an attenuated form of ileitis and spontaneous colitis when raised under germ-free conditions. This suggests that mechanisms independent of the intestinal flora may also be involved in the pathogenesis of CD. The present renewal application will therefore focus on the mechanisms of chronic intestinal inflammation in SAMP mice lacking colonization with commensal flora. The central hypothesis of this proposal is that normal intestinal bacteria are important, but not essential for the initiation and perpetuation of immune responses in the gut of SAMP mice, and that this model provides a unique opportunity to characterize bacterial-independent mechanisms of chronic intestinal inflammation. We have developed three specific aims designed to explore this hypothesis: 1. Characterize the effect of dietary antigens on the development of disease in SAMP mice. We will define and manipulate the antigenic composition of the diet of these mice through comparison of regular diet with elemental and ultra-filtered diets, to determine which elements are important in the development and severity of disease in germ-free (GF) mice. 2. Determine the possible role of autoimmunity in the pathogenesis of gut inflammation in SAMP mice. We will perform a series of experiments to test the presence of auto- antibodies and intestinal self-antigens in the intestinal mucosa of SAMP mice, as well as performing passive transfer experiments to prove a direct role of auto-antibodies in pathogenicity. These studies will help us to understand how auto-antigens may induce chronic gut inflammation in this model. 3. Determine the role of the regulatory component of the immune system in SAMP mice. We will perform a series of adoptive transfer experiments and mono-association studies with specific bacterial strains, to precisely define the components of the commensal flora that are important in the development of T regs. The overall objective in this research proposal is to further understand the basic mechanism(s) underlying chronic intestinal inflammation in CD, with the ultimate goal of beginning to develop a cure for this devastating disease.
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