HLA -A, and -B class I proteins are cell-surface-expressed peptide- binding proteins responsible for immune control of viral infections in human tissues, and for immune surveillance of certain types of cancers. They are also powerful stimulators of allospecific antibody responses in mammalian pregnancy and in recipients of HLA-A, -B mismatched organ and tissue transplants. HLA-A, -B antigens and associated 'minor H' antigenic peptides, when expressed on costimulatory donor antigen-presenting cells, can activate specific CD8 + precursor T cells for recruitment to the graft from the lymph nodes and spleen via the blood. There the A,B antigens, expressed on virtually all cell types, can serve as targets for the diffuse tissue infiltration and damage commonly found in episodes of acute cellular rejection. However, little is known about the precise role of the donor HLA-A, -B antigens in the graft-host relationship that develops during chronic rejection, particularly in light of the focal nature of the infiltrates, the bias toward CD4+ T cells in perivascular lesions, the importance of humoral antibody in some cases, and in most cases, the absence of interstitial inflammation characteristic of acute rejection. This proposal will test a hypothesis that the local and systemic release of soluble forms of donor-cell-derived HLA-A, -B antigens stimulates a host CD4+ T cell response to reprocessed HLA-A, -B alloantigen, that is the principal driving force for eventual humoral and cell-mediated chronic rejection of organ transplantation. This award will enhance my career development by allowing me to devote my primary research effort to new basic science approaches to the related problems of HLA class i-specific acute and chronic rejection in clinical transplantation. It will also provide entry into a new area of research, namely the use of a DNA vaccine approach for analysis of in vitro and in vivo immune response to reprocessed HLA-class I allo(peptide) antigen, which will directly compliment my previous training in mouse skin transplantation and enhance my career interest in learning new ways of preventing HLA-class I-specific sensitization and inducing HLA-class I-specific tolerance in human clinical organ transplantation.
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