This program Project proposes an integrated investigation of molecular genetic, biochemical, serological and functional aspects of the human major histocompatibility complex (HLA). This includes the analysis of the genetic composition of the HLA complex, the molecular genetic basis for HLA polymorphism for both HLA Class I and HLA Class II determinants, regulation of HLA gene expression and functional aspects of HLA region gene products particularly as they relate to T-lymphocyte activation and generation of cytotoxic effector molecules. The program consists of FIVE projects and a CORE Components: (1) Structural characterization of HLA Class I genes and gene products. We will in this project study the HLA-A and B genes, the poorly defined HLA-C genes and non-classical Class I genes. (2) Production of monoclonal anti-MHC (HLA) antibodies by human and murine hybridomas. This will include the construction of HLA-transgenic mice followed by immunization with HLA antigens. The immunogeneity of discrete allelic differences between HLA determinants will be accessed in this system. (3) Structural polymorphism of HLA Class II antigens. A new standardized two dimensional gel system designed for analysis of Class II molecules following immunoprecipitation should provide a powerful typing for HLA Class II antigens and should be useful in family studies for the analysis of genetic recombination within the HLA-D region. (4) Gene regulation of HLA Class II expression in lymphocytes will be investigated focusing on determining the genetic defect in the Bare Lymphocyte Syndrome. (5) T- lymphocyte recognition of HLA Class I and Class II epitopes will be investigated and molecular cloning of cytotoxic effector molecules will be undertaken. This program aims at gaining basic information about allograft reactions and to obtain a better understanding of some of the underlying mechanisms for the relationship between the HLA system and disease-causing genes.
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