HLA-G AND NK RECEPTOR INTERACTIONS IN TROPHOBLAST

滋养层中 HLA-G 和 NK 受体的相互作用

• 批准号: 2775414
• 负责人: JONATHAN E BOYSON
• 金额: $ 3.17万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-06-15 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2775414
• 关键词: MHC class I antigen; antigen receptors; cell line; cytolysis; gene targeting; natural killer cells; pregnancy immunology; receptor binding; trophoblast

The fetus expresses paternally-derived as well as maternally- derived molecules and thus can be considered a semi-allogeneic graft with respect to the mother. In the human placenta, most classical MHC class I molecules are not expressed. However, a nonclassical MHC class I molecule, HLA-G, is highly expressed on fetal cells invading the maternal decidua. Although its function remains unclear, these data suggest that HLA-G plays a role in fetal-maternal interactions. Accumulating data suggest that HLA- G serves to protect the otherwise MHC class I-deficient fetal trophoblasts from lysis by maternal decidual natural killer (NK) cells by binding to inhibitory receptors expressed on these cells. Elucidation of the nature of HLA-G/NK cell interactions will be crucial in determining its importance in gestational disease. Aberrant HLA-G expression may lead to gestational complications such as pre-eclampsia, in which there is poor placentation, or spontaneous abortion. To test the hypothesis that HLA-G protects trophoblasts from NK cell lysis, we will generate HLA deletion mutants of the HLA-G-expressing choriocarcinoma (trophoblast) cell line JEG-3 using gene targeting techniques to knock out MHC class I genes. We will then determine whether these mutants are susceptible to lysis by NK cells. Furthermore, we will construct novel multivalent HLA-G tetramers for use as reagents so that we can systematically identify HLA-G receptors and the cells on which they are expressed.

胎儿表现出来自父方和母方的- 衍生的分子，因此可以被认为是半同种异体 对母亲的嫁接。在人类胎盘中，大多数 经典的MHC I类分子没有表达。然而，a 非经典的MHC-I类分子，人类白细胞抗原-G在 胎儿细胞侵入母体蜕膜。虽然它的功能 目前尚不清楚，这些数据表明，人类白细胞抗原-G在 胎儿与母体的相互作用。越来越多的数据表明，人类白细胞抗原- G用来保护原本MHC I类缺陷的胎儿 母体蜕膜自然杀伤(NK)裂解的滋养层细胞 通过与表达在这些细胞上的抑制性受体结合 细胞。人类白细胞抗原-G/自然杀伤细胞相互作用本质的阐明 将是决定其在妊娠中的重要性的关键 疾病。人类白细胞抗原-G表达异常可能导致妊娠 先兆子痫等并发症，其中有较差的 胎盘形成，或自然流产。来检验这一假设 人类白细胞抗原G保护滋养层细胞免受NK细胞溶解，我们将 构建表达人类白细胞抗原G的人类白细胞抗原缺失突变体 绒毛膜癌(滋养层)细胞系JEG-3的基因治疗 敲除MHC I类基因的靶向技术。我们会 然后通过以下方法确定这些突变体是否对裂解敏感 NK细胞。此外，我们还将构建新的多价人类白细胞抗原G 作为试剂使用的四聚体，这样我们就可以系统地 识别人类白细胞抗原G受体及其所在的细胞 表达。