FUNCTION/REGULATION OF HLA ANTIGENS ON CULTURED CELLS

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This project involves studies of the comparative functional and biochemical properties and the regulation of expression of Class II histocompatibility (HLA) determinants on different types of cultured human cells. The Principal Investigator has extensive experience with the technical aspects of serological and cellular HLA allotyping of cultured human cells, with conducting functional studies of their HLA antigens, and with inducing the expression of Class II antigens on cultured cells that do not already express them. These studies already helped establish that human tumor cell lines express genetically appropriate HLA A,B,C and, in some cases, DR antigens; that induction of Class II antigens can occur with differential expression of different Class II antigen types on some normal and tumor cell lines; and, that the Class II alloantigens expressed on some cell lines fail to act as strong stimulators of primary allogeneic proliferative or cytolytic responses but can act as secondary stimulators and as targets of cytolytic responses. The proposed studies will continue and expand the previous studies in order to determine the basis and the significance of these and other functional differences between the histocompatibility antigens on different cell types. The studies will use naive allogeneic responder T-cells and cloned responder T-cells with known specificity for particular allogeneic HLA antigens or hapten-modified self-HLA antigens; monoclonal antibodies to T-cell differentiation antigens and particular Class II (DR, DQ or DP) determinants; cytofluorograph and cell sorting techniques to select subpopulations of stimulator cells with particularly disparate Class II antigen pattern differences; biochemical techniques; and soluble leukocyte response mediators to determine whether differences in functional activities can be attributed to differences in quantitative, qualitative, or biochemical characteristics of the stimulatory cells' native or induced Class II HLA determinants. These studies will collectively improve our understanding of the role that histocompatibility determinants may play in the induction of auto immune disease responses, in the induction of graft vs. host responses and graft rejection, in the immune response of tumor patients to their own tumors, and our understanding of the regulation and function of different HLA antigens in normal cell-cell interactions.