The long-term research objectives of this laboratory is the definition of the structure of the murine Class I MHC transplantation antigens and the correlation of structural and genetic features to functional properties. Since, in the immune system, these molecules serve an essential role for cell-cell interaction our major goal is to understand the specificity and mechanism for this interaction at the molecular level. To gain insight on such features we intend to use structural techniques (radiochemical sequencing) for analysis of the H-2 protein product and DNA recombinant techniques. We will study H-2 MHC mutants in order to define and characterize precise structural determinants on the H-2 glycoprotein which form the """"""""sites"""""""" recognized by the cellular immune system (cytotoxic T-cells) both in allogeneic recognition and in H-2 restricted antigen specific recognition, as well as by the alloantibody system. This specific goal will be approached by analysis of a series of MHC mutant mouse strains which show histogenic reactivity to the parental strains. Analysis of these in vivo naturally occurring mutants will be supplemented by analysis of monoclonal antibody selected in vitro somatic cell mutants in order to compare specific structural alterations of the H-2 products with changes in biological specificity in tests such as tissue graft rejection, cell mediated lympholysis, and associated recognition of foreign antigens. While our major effort will at first be on the protein structure of the mutants, we also plan to use recombinant DNA techniques to analyze DNA segments containing selected parent and mutant genes in order to probe the mechanisms for generating diversity and polymorphism and to gain an understanding of the complex expression of the Class I molecules. We will also continue our structural analysis of the TL antigens, a molecularly similar family of antigens coded for by genes closely linked to the MHC. These antigens, however, are differentiation specific and such comparative structural studies with MHC antigens will help us gain insight into the structural and genetic differences responsible for the unique features of the TL system.
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