REGULATION OF HEMATOPOIESIS: ROLE OF HLA-DR ANTIGENS

本申请提出的假设是HLA-D区基因 产品的功能是调节 造血系统 支持这一理论的最新观察结果 建议如下：1）三是HLA-DR限制性合作， 调节红系爆发产生的T细胞和单核细胞 （BFU-E）-刺激活性; 2）不成熟造血前体，如 BFU-E表达HLA-DR分子;和3）HLA-DR抗原表达于 骨髓细胞（即BFU-E、CFU-GM、单核细胞）不同于DR抗原 在同一个体的淋巴细胞上表达。 综上所述各项 数据表明，HLA-D区域编码的分子可能为 组织特异性识别信号，允许选择性 DR相关功能的区室化和调节。 证明 这一理论需要证明细胞-细胞相互作用或细胞-因子 相互作用的促进和遗传限制， 分子。 针对这一目标的一个具体目标是确定 骨髓细胞表达DR分子的分子变异基础 与淋巴细胞相比。 对这些样品的生化分析 最近的发展将大大促进变体， DR阳性红系白血病细胞系和自体DR阳性 B淋巴母细胞样细胞系。 这些线路还将用于生成新的 这些单克隆抗体将区分DR分子。 新 开发的单克隆抗体将用于研究 DR分子在正常造血前体细胞上表达， 用于分离这些细胞的高度富集群体的技术。 富集的前体细胞群体将用于遗传学研究， 限制性细胞-细胞和细胞-因子相互作用， 造血 确定一个监管系统， D区基因产物的限制性可能为研究 与自身免疫现象相关的发育不良， 我们对正常造血调节的理解

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.