Recent advances have both confirmed and refined the working hypothesis of this Program Project. Since the last submission of this Program Project in September 1991, evidence of altered T-cell responses in inflammatory bowel disease (IBD) has increased. This competitive continuation proposal of the Program Project Grant, IBD: Genetic and Immunopathologic Mechanisms is based on the hypothesis that all forms of inflammatory bowel diseases are the result of genetic traits that affect normal regulation of mucosal T-cell responses. The genetic susceptibility results either in altered T- cell activation and differentiation to specific antigens (including bacterial, mucosal, or other environmental antigens), or antigen independent stimuli which in turn, disturb the profile of proinflammatory and regulatory T-cell cytokines crucial for maintenance of normal mucosal inflammation. """"""""Ulcerative Colitis Specific ANCA: Role in Disease Pathogenesis"""""""" (Targan) and """"""""Marker B Lymphocytes in Inflammatory Bowel Disease"""""""" (Braun) take advantage of disease-specific marker antibodies to identify antigenic targets in ulcerative colitis and Crohn's disease. Mucosal T-cell and B-cell immune responses will be characterized as part of the validation strategy for antigen candidates. """"""""Immunogenetic Linkage of IBD and Its Subclinical Markers"""""""" (Rotter) applies formal human genetic strategies to test the association and gene identify of chromosome 6 loci with IBD. """"""""Specificity and Homing of Pathogenic T-cells in Mouse Colitis"""""""" (Kronenberg) exploits a mouse model of IBD (CD45RB/HIGH T-cell transfer to scid/scid mice) to directly test the roles of antigen-specific recognition, subsets of T-cells, T-cell differentiation, and enteric bacteria in disease expression. Thus, the proposed hypothesis for IBD pathogenesis will be tested through an integrated set of human and murine experimental investigations in a highly interactive Program Project.
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