The spontaneous chronic colitis in T cell receptor (TCR) alpha mutant (knockout) mice provides an excellent experimental model of inflammatory bowel disease. The colitis shares many features with ulcerative colitis and is mediated by the T helper 2 pathway. Colonies of TCRalpha knockout mice deficient in cytokines and B cells have been developed at the Massachusetts General Hospital. The project will focus on the hypothesis that an unregulated immune response to enteric bacterial antigens at the mucosal site results in chronic colonic inflammation and autoantibody production. Certain enteric bacteria may play a protective role in the development of intestinal inflammation. The role of the appendix in the presentation of enteric bacterial antigens and in providing both pathogenic and regulatory cells in the pathogenesis of chronic colitis will be explored. A major focus of the project will be to examine the regulatory role of B cells in colitis. We have developed a new model of granulomatous colitis in B cell and lL-4 deficient TCRalpha knockout mice. Thus, the development of two distinct colitis models in mice that are of genetically of identical background and exposed to the same environment, provides an opportunity to analyze the mechanisms involved in T helper 2-mediated ulcerative colitis-like and T helper 1-mediated Crohn's disease-like colitis. Additional models of T helper 1-mediated colitis in IL-10 KO mice and CD45RB high transfer model will also be studied. Experiments will be designed to develop specific interventions, including B cell based therapies, to prevent and suppress chronic intestinal inflammation and contribute to the development of new therapeutic modalities for human inflammatory bowel disease. ? ? ? ?
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