Using an immunologically versatile herd of MHC inbred miniature swine, we have developed and validated the only large animal model of heart and lung transplantation in which vascular and bronchial lesions reproduce with fidelity and consistency those lesions seen in human heart and lung transplant recipients suffering from chronic rejection. The current proposal is designed to elucidate the cellular and molecular mechanisms underlying the pathogenesis of chronic rejection in this clinically relevant large animal model and then to corroborate these finding in human heart transplant recipients. Our hypotheses, based on emerging rodent and human studies, are 1) that chronic rejection is mediated by an immune process initiated by CD4+ T cells that recognize donor allopeptides via the indirect pathway of allorecognition, 2) that recognition of non l MHC peptides derived from either viral antigens (e.g., CMV) or self proteins (e.g., cardiac myosin) can interact with the immune response to MHC peptides, and 3) that these immune responses can ignite, amplify or recruit one another, thus augmenting the chronic rejection response. To establish whether chronic rejection in large animals and humans is the end-result of the immune recognition of allopeptides, and to determine if the recognition of non-MHC peptides contribute to this process, we will use synthetic MHC allopeptides, MHC-linked viral tetramer analyses, and cardiac myosin to interrogate indirect alloimmununity, anti-viral immunity, and organ-specific autoimmunity, respectively. We plan to 1) examine and compare the roles of MHC allopeptides and organ-specific autoimmunity to cardiac myosin and antiviral immunity in the pathogenesis of CHR in miniature swine, 2) examine and compare the roles of MHC allopeptides and anti-viral immunity in the development of CLR in miniature swine, and 3) determine the role of autoimmune responses to cardiac myosin and anti-viral immunity to CMV in development of chronic rejection in human heart recipients. These mechanistic studies are critical to the development of successful therapeutic strategies aimed at extinguishing the chronic rejection response at its inception. A strategy of early intervention (at the immune recognition phase) would have the best chance of avoiding the programmed sequela of tissue injury and inflammation.
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