The overall goal of this project is to define novel molecular interactions between lymphocytes and allogeneic endothelial cells (EC), and address the potential roles of such interactions in the development of accelerated transplant atherosclerosis (ATxA). The applicants' prior in vitro studies indicate that, of all mononuclear cell subsets tested, natural killer (NK) lymphocytes most effectively bind to and activate EC. Furthermore, human NK cell lines propagated in the presence of allogeneic EC lines lyse the stimulating EC line in an allospecific but MHC unrestricted fashion. This suggests that a novel antigen receptor on NK cells recognizes a non HLA polymorphic set of antigens expressed on vascular endothelial cells. Specific proposals now include to: (1) generate allospecific anti EC human NK clones; (2) produce anti NK clonotypic and anti EC murine monoclonal antibodies (mAbs) which inhibit NK mediated EC cytotoxicity; (3) biochemically characterize the molecules recognized by the inhibitory antibodies with standard immunochemical techniques and recombinant DNA technology, utilizing the mAbs or oligonucleotide probes derived from the immunochemical analyses to screen NK cell and EC cDNA libraries; and (4) correlate lymphocyte EC adhesion and activation with the development of ATxA, utilizing EC lines generated from transplanted donors and NK cell enriched lymphocytes from recipients as targets and effectors, respectively.
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