A consequence of the extraordinary MHC polymorphism in human populations is that individuality is seen in the immune response to all antigens. For HLA class I genes the polymorphism determines antigen specificity of cytolytic lymphocyte responses to tumors, intracellular infections and allogeneic tissue transplants. Whereas model studies in mice can selectively focus on the small number of MHC types represented by the inbred strains, the medical importance of an individual patients HLA type necessitates an inclusive approach to the study of humans, particularly in a society consisting of racially mixed populations of diverse geographical origin. Research supported by this project in the last 10 years has worked towards defining the structural diversity of HLA class I polymorphism in human populations, its functional import and the insight it can provide regarding the history of the human immune system. The success of the endeavor has revealed inadequacies in clinical tissue typing and catalyzed development of more accurate and precise DNA-based methods. In turn the application of such methods has revealed a previously undiscovered type of HLA-A allele which though genotypically present is not expressed. Identification of such """"""""null"""""""" alleles and distinguishing them from their functional counterparts will be important in matching donors and recipients for transplantation. Analogous loss of HLA-A expression is a common feature of human tumors, a phenomenon believed to result from selection of variants by immune pressure from cytolytic lymphocytes. The proposed research will determine the cause of HLA class I down regulation in inherited HLA class I null alleles (Aim l) and their somatically altered counterparts in tumors (Aim 2), and test the hypothesis that similar processes are at work, which result from pressures of immunity. Also under test will be the hypothesis that HLA-A is paru~cularly prone to inactivation, perhaps as a consequence of its age and infiexibility compared to HLA-B. Preliminary study of HLA-A null alleles and analysis of the low expression of HLA-C both point to the importance of post transcriptional regulation of mRNA in controlling the expression and function of HLA class I genes. Of potential importance are the divergent spice sites flanking exon 3. The experiments of Aim 3 will focus on understanding the mechanisms controlling HLA class I mRNA splicing and the levels of cytoplasmic mRNA. The hypothesis that exon 3 contains an enhancer of mRNA splicing will be tested.
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