The hypothesis put forth in this application is that HLA-D region gene products function in the regulation of proliferation within the hematopoietic system. Recent observations in support of this theory have suggested the following: 1) Three is HLA-DR-restricted cooperation between T cells and monocytes that regulates the production of erythroid burst (BFU-E)-stimulating activities; 2) immature hematopoietic precursors like the BFU-E express HLA-DR molecules; and 3) HLA-DR antigens expressed on myeloid cells (i.e. BFU-E, CFU-GM, monocytes) differ from DR antigens expressed on lymphocytes from the same individual. Taken together, these data suggest that HLA-D region-encoded molecules may provide the basis for tissue-specific recognition signals, allowing for selective compartmentalization and regulation of DR-associated function. Proof of this theory requires demonstrating cell-cell interactions or cell-factor interactions that are facilitated and genetically limited by these molecules.
One specific aim directed at this goal involves identifying the basis of the molecular variation in DR molecules expressed by myeloid cells as compared to lymphoid cells. The proposed biochemical analysis of these variants will be greatly facilitated by the recent development of a DR-positive erythroid leukemia cell line and an autologous DR-positive B-lymphoblastoid line. These lines will also be used to generate new monoclonal antibodies that will distinguish between DR molecules. Newly developed monoclonal antibodies will then be used to study the structure of DR molecules expressed on normal hematopoietic precursors and to improve techniques for isolating highly enriched populations of these cells. Enriched populations of precursor cells will be used to study genetically restricted cell-cell and cell-factor interactions that regulate in vitro hematopoiesis. Identifying a regulatory system facilitated and genetically restricted by D-region gene products may provide new insights for studying dysplasias associated with autoimmune phenomenon as well as contribute to our understanding of the regulation of normal hematopoiesis.
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