NOVEL MHC CLASS II CONSTRUCTS FOR TREATMENTS OF CBD

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DESCRIPTION: Chronic Beryllium Disease (CBD) is a lung disease similar clinically to other granulomatous diseases such as sarcoidosis, schizomyosis and tuberculosis. Approximately 800,000 individuals are at risk for developing the disease, which is caused by metal and relatively insoluble compounds of beryllium. The disease begins as a sensitizing cell mediated immune response to beryllium antigen, which develops into a non-caseating granuloma. Evidence strongly suggests that CD4 plus T-cells and MHC class 2 allele HALDPB1*0201 are important in the immunopathogenesis of CBD. How the T-cell receptor (TCR) on the T-cells interacts with beryllium and the MHC and the mechanism that gives rises to the pathogenesis of CBD is unknown. To test critically the hypothesis that a specific MHC class 2 allele interacts with beryllium and induces T-cell responses that contribute directly to the pathogenesis of CBD, it is proposed to develop a family of novel recombinant HLA-DP constructs that will selectively eliminate inflammatory T-cell responses to beryllium. This will enable the testing of the role of such T-cell responses in CBD. Development and characterization of these novel constructs will provide the opportunity to identify unique points of intervention for controlling T-cells and in turn, the T-cell immune response and repertoire. These molecules may provide a template for engineering a novel treatment of CBD. The PI proposes to: 1) Characterize the recombinant HLA-DP constructs biochemically, 2) Characterize the binding interaction of beryllium with the recombinant HLA-DP constructs, 3) Identify high potency BE/antigen combinations responsible for proliferation of pathogenic T-cells and 4) To determine optimal conditions for tolerizing beryllium specific human T-cells.