We seek to extend the observations made during the past granting period relating to the mechanism of the dysregulated mucosal immune responses seen in IBD. We have identified and partially cloned a molecule expressed by normal intestinal epithelial cells which appears to be involved in the activation of CD8+ suppressor T cells in T cell:epithelial cell co-cultures. This molecule is a 180kd glycoprotein which is capable of binding to CD8 and activating CD8 associated p56lck. During the past granting period, we demonstrated that IEC derived from patients with IBD fail to express gp180 normally (either absent or expressed in an altered form) which may account for the failure of these cells to activate CD8+ T cells in co-cultures. The activation of CD4+ cytokine producing T cells may account for the active inflammation seen in IBD. The failure to activate CD8+ T cells may account for its perpetuation. In the current granting period we propose to extend these studies looking at the genetic basis of the defect in gp180 expression, assessing the molecular nature of the defect and whether the defect exists in family members as one of the predisposing factors in the development of IBD. In addition these studies will analyze the functional consequence of the absence of gp180 expression looking at the ability of patients and their families to develop oral tolerance to soluble protein antigens. These studies will be linked to analyses of intestinal permeability where defects have been described in both patients and their first degree relatives. The outcome of theses studies will be the correlation of immunologic, environmental and genetic factors in the development of IBD.
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