The etiology of inflammatory bowel disease (IBD) is unknown but genetic and environmental factors appear to be important. During the current funding period we demonstrated that luminal bacteria and bacterial cell wall polymers can initiate and potentiate chronic colitis and systemic inflammation in genetically susceptible rats using 4 separate experimental or spontaneous models. Genetic factors regulate chronicity of experimental inflammation in the peptidoglycan, indomethacin and bacterial overgrowth models. With identical stimuli, inbred Lewis rats develop chronic, spontaneously relapsing granulomatous enterocolitis with extraintestinal inflammation, whereas Fischer F344 (MHC matched with Lewis) and Buffalo rats display only transient intestinal inflammation with no systemic response. Our hypothesis is that chronic intestinal and extraintestinal inflammation is the result of an inappropriately aggressive inflammatory response to ubiquitous luminal bacterial constituents, mediated by genetically determined defective downregulation of the immune response. The chronic phase of inflammation in Lewis rats is mediated by T lymphocytes. We will investigate this hypothesis with the following Specific Aims: 1. To determine the mechanisms by which normal luminal bacteria and bacterial components induce and perpetuate chronic experimental intestinal and systemic inflammation in genetically susceptible hosts. 2. To investigate the influence of normal luminal bacteria and bacterial cell wall polymers in initiating and perpetuating spontaneous intestinal and systemic inflammation in HLA-B27 transgenic rats. 3. To determine immunologic mechanisms of the genetically determined host susceptibility to bacteria and bacterial cell wall components. These investigations will be conducted in a unique environment by a team of investigators with diverse backgrounds who have effectively collaborated to generate data supporting the current application. The barrier-intact gnotobiotic rodent facility permits the investigators to study a spectrum of luminal bacterial concentrations ranging from absent (sterile) to increased (experimental small intestinal bacterial overgrowth). These studies will provide critical insights into the pathogenesis of Crohn's disease since they investigate mechanisms of genetic susceptibility to environmentally relevant antigens in models which uniquely develop chronic, spontaneously relapsing, granulomatous enterocolitis with associated extraintestinal inflammation.
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