REGULATION OF HEMATOPOIESIS: ROLE OF HLA-DR ANTIGENS

本申请中提出假设是人类白细胞抗原-D区基因 产品在调节体内的扩散方面发挥作用 造血系统。最近支持这一理论的观察结果表明 建议如下：1)三是人类白细胞抗原DR受限的合作 调节红系爆裂产生的T细胞和单核细胞 (BFU-E)-刺激活性；2)未成熟的造血前体，如 BFU-E表达人类白细胞抗原-DR分子； 髓系细胞(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。这些加在一起， 数据表明，人类白细胞抗原-D区域编码的分子可能为 组织特异性识别信号，允许选择性地 DR相关功能的区划和调节。证明 这一理论需要证明细胞-细胞相互作用或细胞因子 由这些促进和遗传限制的相互作用 分子。针对这一目标的一个具体目标涉及确定 髓系细胞表达DR分子的分子变异基础 与淋巴样细胞相比。建议对这些物质进行生化分析 变种将极大地便利于最近开发的 DR阳性红系白血病细胞株和1例自体DR阳性 B淋巴母细胞系。这些线路还将用于生成新的 将区分DR分子的单抗。新开 随后，研制的单抗将被用于研究 DR分子在正常造血祖细胞上的表达及其改善 分离高度浓缩的这些细胞群体的技术。 丰富的前体细胞群体将被用于遗传学研究 在体外调节的限制性细胞-细胞和细胞因子相互作用 造血术。确定便利的和遗传的监管系统 受D区限制的基因产物可能为研究提供新的见解 与自身免疫现象相关的不典型增生以及与 我们对正常造血调控的理解。

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.