A Primate Model of Maternal Fetal Immune Tolerance

母胎免疫耐受的灵长类动物模型

• 批准号: 6883219
• 负责人: THADDEUS G GOLOS
• 金额: $ 47.6万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-08-03 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6883219
• 关键词: MHC class I antigen; Macaca mulatta; cell differentiation; cytokine; cytomegalovirus; developmental immunology; enzyme linked immunosorbent assay; flow cytometry; gene expression; immune tolerance /unresponsiveness; immunocytochemistry; in situ hybridization; messenger RNA; placental transfer; polymerase chain reaction; pregnancy immunology; protein localization; transfection; trophoblast; vertical transmission

The primate placenta is unique in its selective expression of nonclassical MHC class I molecules (in the human HLA-G and HLA- E). Recent work has strongly suggested that HLA-E may play an important role in its coexpression with HLA-G on human trophoblasts in establishing maternal-fetal immune tolerance. However, the functional relevance of the unusual expression of MHC molecules in the human placenta remains undefined. A lack of appropriate nonprimate animal models has significantly restrained progress in this area. Our central hypothesis is that nonclassical placental MHC class I molecules play a role in the modulation of the maternal response to pregnancy, both locally within the maternal endometrium as well as in the maternal peripheral serum. To functionally address the role(s) of MHC class I molecule expression in the placenta, we propose 4 specific aims, using a nonhuman primate model for maternal-fetal immune tolerance developed in the previous funding period. Specific Aim 1. To define the ontogeny of Mamu-E expression within the rhesus placenta and localize sites of mRNA and protein expression. Specific Aim 2. To evaluate maternal-fetal immune interactions and placental development in pregnancies with transgenic modification of rhesus placental MHC class I expression. Specific Aim 3. To determine MHC class I expression in rhesus monkey trophoblasts exposed to simian cytomegalovirus, with relevance for maternal-fetal viral transmission. Specific Aim 4. To define the expression of a soluble isoform of Mamu-AG. Although there has been remarkable progress in defining the biochemical and molecular characteristics of MHC class I molecules expressed in the human placenta, a significant gap remains in our appreciation of either the function of these molecules in normal pregnancy, or the role(s) they may play in pathological situations. With these 4 specific aims we proceed beyond defining placental nonclassical MHC class I expression in the nonhuman primate, to investigating function at the maternal-fetal interface. The successful implementation of our recent adaptation of transgenic technology to the primate placenta will provide unprecedented opportunity for novel models of primate placental biology.

灵长类动物胎盘在其非经典MHC I类分子（在人HLA-G和HLA-E中）的选择性表达中是独一无二的。最近的工作强烈表明，HLA-E在与HLA-G的共表达中可能在人类滋养细胞的共表达中发挥重要作用。但是，人胎盘中MHC分子异常表达的功能相关性仍然不确定。缺乏适当的非优势动物模型在该领域的进展显着限制。我们的中心假设是，非经典胎盘MHC I类分子在孕产妇对妊娠的反应的调节中发挥作用，均在母体子宫内膜内以及母体外周血清中。为了在功能上解决MHC I类分子在胎盘中的作用，我们使用非人类灵长类动物模型提出了4个特定目标，用于在上一个融资期间开发的母体及其免疫耐受性。具体目的1。定义恒河猴胎盘中Mamu-E表达的个体发育，并定位mRNA和蛋白质表达的位点。特定目的2。通过转基因修饰胎儿胎盘MHC I类表达，评估孕妇的免疫相互作用和胎盘发育。具体目的3。确定暴露于Simian巨细胞病毒的恒河猴滋养细胞中的MHC I类表达，与母亲 - 狂热病毒传播相关。特定目的4。定义mamu-ag的可溶同工型的表达。尽管在人类胎盘中表达的MHC I类分子的生化和分子特征取得了显着的进展，但我们对这些分子在正常妊娠中的功能或它们在病理情况下可能起的作用的显着差距仍然存在。通过这4个具体目标，我们将继续进行非人类灵长类动物中胎盘非经典MHC I类表达，以研究母亲 - 狂欢界面的功能。我们最近将转基因技术改编为灵长类动物胎盘的成功实施将为灵长类动物胎盘生物学的新型模型提供前所未有的机会。