The long term goal of this project is to understand the cause of inflammatory bowel disease (IBD). This is a complex group of idiopathic chronic inflammatory disorders of which Crohn's disease (CD) and ulcerative colitis (UC) are the major forms. A simple explanation for the cause of IBD has yet to emerge. Several of the immunologic and pathological features of UC can, however, be explained as a consequence of persistent T lymphocyte (T cell) activation in the gut that results in the production of inflammatory cytokines that direct or indirectly promote chronic inflammation and tissue injury. Progress in understanding the pathogenesis of IBD is restricted by the lack of suitable animal models. Of the animal models of IBD that have been described, the causal factors, pathology and clinical spectrum of colitis that spontaneously occurs in interleukin-2-deficient (IL-2-/-) mice most closely resembles that of human UC. The IL-2-/- mouse is, therefore, one of the most promising animal model in which to investigate the immunopathogenesis of IBD. The purpose of the studies described in this proposal is, therefore, to determine the cause(s) of colitis in the IL-2-/- mouse which may provide new insights into the underlying causes of IBD in humans. The guiding hypothesis for these studies is that colitis is a consequence of the activity of abnormal mucosal T cell responses to normal enteric (gut bacteria) antigenic stimuli. Our studies to experimentally test this hypothesis have three specific aims. THE FIRST is to identify the T cell populations responsible for disease. This will be investigated by determining which populations of T cells present in IL-2-/- mice can, after adoptive transfer to otherwise normal healthy animals, cause disease.
THE SECOND AIM i s to determine if oral tolerance is intact in IL- 2-/- mice, and the nature of the antigenic stimuli that activates pathogenic T cells. Two approaches will be taken, (a) IL-2-/- mice will be crossed with T cell receptor (TCR) transgenic mice in which the majority of CD4 or CF8 T cells are specific for a defined antigen to determine if generation of the function gut T cell repertoire is normal, and if tolerance is maintained upon exposure to antigen in the gut in the absence of IL2 and, (b) germ free IL-2-/- mice will be conventionalized with members of the normal bacterial gut flora to determine if """"""""oral tolerance"""""""" is intact and, if not, which bacteria can prime mucosal immune responses that initiate an inflammatory immune responses that results in colitis.
THE THIRD AIM i s to investigate how T cells cause epithelial cell injury. The possibility that T cells from IL-2-/- mice can disrupt epithelial cell growth as a result of cell-mediated cytotoxicity or, through the production of toxic or inflammatory cytokines will be investigated.
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