Our laboratory has recently shown that while cardiac allograft vasculopathy (CAV) requires histoincompatibility to develop, it can occur in tolerant recipients and even in immunodeficient recipients devoid of any adaptive immune response. Thus, additional mechanisms beyond conventional immune responsiveness on the part of the recipient to donor antigens appear to be present. We hypothesize that components of the innate immune system, particularly NK cells, contribute to the pathogenesis of CAV. This would represent a previously unidentified pathway toward CAV that might not be targeted by current chronic immunosuppressive therapy. To our knowledge a systematic and controlled study of the contribution of innate immunity to CAV has not been performed. In our first aim, we plan to fully characterize the role of NK cells and macrophages in the biological!y simple setting of parental to F1 transplants, and in combinations involving nonreactive (RAG1 -/-) mice incorporating vitro assays of NK cell function. In a second aim, we plan to investigate the most likely mechanisms further, including the involvement of IFN-gamma, perforin, and the fractalkine system. In a third aim we will explore in chimeric, tolerant recipients the importance of the factors established in Aims 1 and 2. In a fourth aim we will take these observations further by examining the efficacy of eliminating innate immune components from normal recipients undergoing various forms of immunosuppression of clinical relevance. This will afford an opportunity to evaluate the importance of innate reactivity as a causative component in a clinically relevant setting.
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