The overall goal of this project is to understand the expression and function of major histocompatibility complex (MHC) class I and class II genes. Part of the study involves analysis of differentially expressed MHC epitopes and self peptide: MHC complexes utilizing monoclonal antibodies. These antibodies will be produced and used to 1) determine the cellular distribution of the complexes (immunofluorescence, immunoperoxidase staining), 2) isolate and characterize self peptides associated with the complexes (affinity chromatography, HPLC, sequencing; peptide synthesis), 3) determine intracellularly when and where the complexes form (electron microscopy), and 4) determine the influence of the complexes on function (alloreactivity, autoreactivity, antigen presentation) and on T cell repertoire development. Initial study will be conducted with a prototype monoclonal antibody which reacts with a differentially expressed epitope on a subset of class II molecules. Study of class I genes will also involve determining which Q and TL region genes encode cell surface proteins, and whether these products function as restriction elements for cytotoxic T lymphocytes (CTL). Expression of Q and TL region products will be analyzed by production of monoclonal antibodies and cloned alloreactive CTL. Cells transfected with novel or previously characterized class I genes will be utilized to facilitate this analysis. Functional study of Q and TL region class I products will be done by CTL analysis. Initial study will be conducted with a CTL clone which appears to recognize a novel K-end encoded self peptide associated with a Q region class I product. Transgenic mice and transfected cells will be utilized to identify and characterize the genes involved. Subsequent study will involve determining whether virus-specific or minor histocompatibility-specific CTL clones can be generated which recognize Q or TL region products. These studies will advance our understanding of the central role MHC genes play in controlling immune responses, and, hopefully, will permit the development of better therapeutic regimens for combatting infectious disease and immunological disorders.
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