T CELL ACTIVATION AND CRYPT CELL APOPTOSIS

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Increased levels of crypt cell apoptosis are observed in inflammatory bowel disease (IBD), graft versus host disease (GVHD), AIDS colitis and small bowel allograft rejection whereas colon cancer is associated with the failure of normal pathways of epthithelial cell apoptosis. In the past, models have utilized total body irradiation or administered cytotoxic drugs to induce and study crypt cell apoptosis. In the current proposal we utilize T cell activation to induce crypt cell apoptosis. Results of TUNEL staining (specific for apoptosis) have revealed that T cell activation induced crypt cell apoptosis which was present in small and large intestine segments but most notable in the terminal ileum. Crypt cell apoptosis was induced after T cell activation in DO11.10 T cell receptor transgenic mice with OVA antigen and in normal C57/BL6(B6 and BALB/c mice with anti-CD3 (2C11) mAb. Pretreatment of mice with anti-tumor necrosis factor-alpha (TNF-alpha) or anti- interferon-gamma (IFN-gamma) mAbs reduced effects of T cell activation on crypt cell apoptosis by 40 and 70 percent respectively. Compared to anti-CD3-treated B6 controls, crypt cell apoptosis were reduced by approximately 70 percent in CD95 (Fas) (lpr/lpr)-deficient mice compared to B6 controls and by more than 95 percent in lpr/lpr mice pretreated with anti-TNF-alpha mAb. Thus, our hypothesis is that intestinal T cell activation induced crypt cell apoptosis through a combination of CD95 and TNF receptor (TNFR-1)-mediated pathways. In this proposal we will utilize bone marrow (BM) chimera mice to 1) address the requirement for CD95L expression by nonhematopoietic (e.g. epithelial) or BM-derived (e.g. T and B cells, monocytes, etc.) cells, 2) adress the requirement for CD95 expression by episthelial cells, and 3) addresss the role of TNF-alpha in crypt cell apoptosis by activating T cells in double (p55/p75-/-) TNFR-1 knockout mice alone and in combination with lpr/lpr mice. In summary, we have presented a novel model for inducing epithelial cell apoptosis by T cell activation. It is expected that a thorough assessment of the mechanisms involved in these pathways will yield new information applicable to IBVD, GVHD, and AIDA enteropathy as well as cancer pathogenesis where a failure in crypt cell apoptosis is involved in early malignant transformation.