The pathogenesis of inflammatory bowel disease (ulcerative colitis and Crohn's disease) has not been resolved despite numerous studies. A major drawback has been the lack of suitable animal models. Recently mice mutant for T cell receptor (TCR) and RAG-1 genes have been created by gene targeting in embryonic stem cells. We have determined that mice mutant for TCRalpha or TCRbeta genes but not for TCRdelta or the RAG-1 genes, develop an inflammatory bowel disease, which is restricted to the rectum and colon and resembles ulcerative colitis. We propose to develop colonies of mice mutant for TCRalpha, beta or delta, and RAG-1 genes, using the animal facilities at the Massachusetts General Hospital. Studies performed on colonies of these mutant mice will permit evaluation of the role of various T and B cell subsets and natural killer cells in the development of inflammatory bowel disease. We will document the incidence and progression of the disease and identify factors associated with the disease process. The studies will include histological and immunohistological examination of tissues, flow cytometric and functional characterization of inflammatory cells in the colon and rectum and detection of autoantibodies in the sera of the diseased animals. This project will focus on the hypothesis that an abnormality of immunoregulatory T cells at the mucosal sites leads to altered immune response to luminal antigens resulting in mucosal injury, possibly due to autoimmune mechanisms.
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