The spontaneous development o chronic colonic inflammation in T cell receptor (TCR) mutant mice, in particular TCRalpha-mutant mice, provides an outstanding animal model of inflammatory bowel disease and a novel model to dissect mucosal immune regulatory mechanisms. The colonic disease in TCRalpha-mutant mice has many features of human ulcerative colitis. Colonies of mice mutant for TCRalpha, TCRbeta, TCRdelta and RAG-1 genes have been developed at the Massachusetts General Hospital. TCRalpha-mutant mice are being crossed with other mutant mice to develop TCRalpha-mutant mice deficient in B cells or a specific cytokine. The studies in these mice will involve characterization of the role of lymphocytes (T and B cell subsets, natural killer cells), antibodies and cytokines in the initiation and perpetuation of colonic inflammation. The studies include histological and immunohistological examination of tissues, flow cytometic and functional characterization of inflammatory cells in the colon, analysis of cytokines in the lymphoid tissues and the colon, detection of autoantibodies and antibacterial immune responses, and cell and serum transfer studies. The project will focus on the hypothesis that cytoline imbalance present at the mucosal site leads to unregulated immune responses to colonic luminal (bacterial) antigens resulting in chronic colonic inflammation. A major aim of the study will be to examine the role of the appendix and luminal bacteria in the development of inflammatory bowel disease. Experiments will also be designed to develop specific interventions in this model of inflammatory bowel disease, which will contribute to the development of new therapeutic modalities for human inflammatory bowel disease.
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