The long-term objective of this research program is to understand at a molecular level how class I and class II molecules, encoded by the major histocompatibility complex of mouse are recognized by T-lymphocytes. This goal requires knowledge of the fundamental structural characteristics of these two families of proteins; the determination of these molecular characteristics and their relation to biological function constitute the principle focus of this proposal. The structure of """"""""novel"""""""" class I molecules, expressed on murine UV-induced fibrosarcomas and on other cell-lines, will be investigated using high-pressure liquid chromatography tryptic peptide mapping and protein sequencing. """"""""Novel"""""""" class I molecules will also be generated using molecular genetics to create new class I genes. Oligonucleotides will be sequentially excised from a normal class I gene and replaced by synthestic oligonucleotides encoding multiple amino acid differences. The recognitiion of these new class I gene products, by monoclonal antibodies and by cytotoxic T-lymphocytes, will also be investigated, in order to gain insights into the relationship between structure and function for these class I molecules. The topography of one class II molecule will be determined by examining the reactivity of specific antibodies using a cross-blocking radioimmune assay technique. The antibodies will be generated by using, as haptens, synthetic peptide fragments of this class II molecule. This basic approach should eventually lead to an understanding at a molecular level of the role which class I and class II molecules play in the control of the immune response. This is a prerequisite for the successful manipulation of the immune response and should result in rational molecular therapies for many varied diseases.
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