Solid organ and bone marrow transplantation has proven to be a feasible treatment for human afflictions, such as kidney, heart, liver, and lung disease, and cancer. The primary obstacle to success, however, is immunological rejection caused by alloantigenic between the donor and recipient. Minor (H) histocompatibility antigens, which are encoded by numerous loci scattered throughout the genome, figure prominently in this rejection process when individuals are matched for HLA. Since minor H genes are identified only by virtue of their alloantigens, major questions concerning the mechanisms by which such minor H loci produce their minor H antigens remain unresolved. Our overall goal is to elucidate these mechanisms. We propose to continue the molecular characterization of conceptually important mouse minor H genes encoded by the mouse Chromosome 2 locus, H3, and the Y-chromosome locus, Hya. H3 and Hya are both complex haplotypes, both at the functional and genetic level. We will first focus on H3, and analyze the H3a gene, which encodes (or controls) MHC class I-restricted H2Db determinants recognized by cytotoxic T cells (CTL). We will clone this gene, characterize it, and determine how it controls the H3a minor H antigen. This study will provide a detailed characterization of an autosomally- encoded minor H gene whose immunodominant antigen(s) stimulate CTL. We will then clone and characterize H3b, which encodes (or controls) MHC class II-restricted H2Ab determinants recognized by helper T cells (TH). This is a gene of particular interest in that acts as an immune response (IR) gene that controls cytotoxic T cell responses. This analysis will provide the first characterization of a minor H gene that acts by orchestrating immune response to other minor H antigens. Finally, we will analyze Hya, focusing the clarification of an intriguing form of genetic control in which Y encoded gene, Smcy, may control male-specific (HY) minor H peptides encoded by distinct gene(s). Overall, these studies should provide many new insights into the molecular basis of minor H antigens, and the genetic mechanisms by which they are controlled.
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