TRANSGENIC RAT MODEL OF INFLAMMATORY BOWEL DISEASE

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The human class I major histocompatibility antigen HLA-B27 is strongly associated with a group of rheumatic disorders termed spondyloarthropathies. These disorders show a clinically well documented relationship to inflammatory bowel disease (IBD), although the basis for this relationship is not well understood. We have produced transgenic rats expressing HLA-B27, and have observed that they develop a multisystem disease that bears strong resemblance to the spectrum of disease encountered in humans with HLA-B27. The most striking aspect of this disease in the transgenic rats is chronic gastrointestinal inflammation, particularly in the colon but also involving the small intestine and stomach. This process shares a number of significant features with human IBD, and as a result, the B27 transgenic rats need to be considered as a potentially important animal model for IBD, understanding of which has been hampered in the past for lack of a faithful and convenient animal model. This project will examine the role of T lymphocytes in the pathogenesis of the inflammatory bowel disease of the B27 transgenic rats. Preliminary data indicates that T cells are critical for the initiation of the disease. These experiments, will be directed toward identifying the phenotype, ontogeny, and antigenic specificity of the disease-inducing T cells. The results should be specific information regarding the immune response leading to intestinal inflammation, and this would be expected to lead directly to a fundamentally improved understanding of the pathogenesis of IBD.