The etiology of inflammatory bowel disease (IBD) is likely to be complex and multifactorial. Both genetic and environmental factors have been implicated although no definite disease susceptibility locus or pathogen has been identified. The final pathological endpoint of these diseases is immune destruction of the intestinal mucosa. It is generally felt that this immune destruction is driven by the presence of some abnormal intestinal antigen(s) (either due to an exogenous pathogen or the abnormal expression of an endogenous antigen) or that there is some basic defect in the regulation of the intestinal immune system. T lymphocytes play a central role in the immune system by specifically destroying abnormal cells and by regulating the activity of other immune cells. The intestine contains a distinct subpopulation of epithelium associated T cells, the intraepithelial lymphocytes (IELs). Very little is known about the antigens recognized by these cells or the role that they play in mucosal immunity. IELs are presumably derived from lymphocytes in the lamina propria (LPL) and are involved in immunological surveillance of the intestinal mucosa. They are, therefore, likely to play a significant role, either direct or indirect, in the pathogenesis of IBD. Recent evidence from our laboratory demonstrates that normal human intestinal IELs are clonally expanded and can recognize a major histocompatibility complex class I-like molecule, CD1. This indicates that human IELs are specific for a limited number of intestinal antigens with the CD1 molecules implicated as possible antigen presenting molecules. Similarly, if a characteristic set of T cell receptors (TCR) were to be identified in IBD, it would strongly suggest that specific antigens are recognized in this disease. Furthermore, it would provide a means for identifying these antigens. We therefore propose to fully characterize the TCR expression of normal and IBD intestinal IELs and LPLs, to isolate T cell clones expressing IBD associated TCRs and to determine whether CD1 plays a role in the pathogenesis of IBD.
The specific aims are: (1) To characterize the TCR alpha-beta heterodimers expressed by normal intestinal IELs and LPLs using polymerase chain reaction amplification and molecular cloning; (2) To similarly determine whether a restricted subset of TCR alpha and beta chains are expressed by IELs and LPLs in IBD; (3) To establish IEL and LPL T cell clones which express dominant TCRs associated with IBD; and (4) To determine whether CD1 serves as a recognition molecule for human intestinal IELs and LPLs in IBD.
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