HLA-E, F, G interactions & the immunology of pregnancy

HLA-E、F、G 相互作用

基本信息

批准号：
7410014
负责人：
DANIEL E. GERAGHTY
金额：
$ 36.17万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-06-01 至 2010-03-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Pregnancy is arguably one of the most interesting examples of immune accommodation seen in mammalian biology. The placenta provides a barrier between the mother and child, regulating the reaction of maternal immune cells towards the allogeneic child at a time when its own immune system is immature or absent. Extravillous trophoblast (EVT) cells of the placenta invade deep into the maternal uterine tissue to establish a life giving connection with the maternal blood supply. It has been hypothesized that the interaction between EVT cells and maternal immune cells provides a controlling influence for implantation and development. We have been studying the biochemistry and immunology of the HLA-E, F, G class I molecules with a special focus on how they act individually and interactively, to help accommodate the maternal immune response to her developing offspring. We have recently shown that all placental cells that express HLA-G also express HLA-E and a subset of these also express HLA-F. Indeed, EVT cells that have invaded the maternal decidua are thus far the only normal cells known to simultaneously express all three nonclassical antigens. We propose to focus on features of HLA-E, F, and G that relate ultimately to their functions in the maternal-placental immune environment. Our current hypotheses concerning HLA-E, F, G in modifying a maternal immune response are being addressed in the following specific aims: 1) To examine the function of HLA-F in the peripheral immune response where we will decipher peptide or other ligand binding properties of HLA-F and identify a specific receptor interacting with HLA-F. This work is ultimately aimed at deciphering a specific role for HLA-F in the placental environment. 2) To test the ability of HLA-E bound to different peptide ligands, including the HLA-G nonamer, to evoke a specific immune response through binding an activatory receptor on maternal immune cells. This work will test the hypothesis that the HLA-G nonamer peptide bound to HLA-E confers a unique function on the complex necessary and specific for the placental immune environment. 3) To study soluble and membrane HLA-G with a major focus on determining their structural characteristics and interactions with inhibitory receptors. This work is aimed at testing the hypothesis that the primary function of HLA-G is to provide nonamer peptide to HLA-E and to otherwise act directly as a surrogate to classical class I interacting with inhibitory receptors expressed on decidual immune cells. We also propose to develop materials and reagents useful towards the further understanding of the structure, biochemistry, and function of HLA- E, F, and G.

描述（由申请人提供）：怀孕可以说是哺乳动物生物学中最有趣的免疫调节例子之一。胎盘在母亲和孩子之间提供了一道屏障，在其自身免疫系统不成熟或不存在时调节母体免疫细胞对同种异体孩子的反应。胎盘的绒毛外滋养层（EVT）细胞深入母体子宫组织，与母体血液供应建立生命联系。据推测，EVT 细胞和母体免疫细胞之间的相互作用为植入和发育提供控制影响。我们一直在研究 HLA-E、F、G I 类分子的生物化学和免疫学，特别关注它们如何单独和相互作用地发挥作用，以帮助适应母体对其发育中的后代的免疫反应。我们最近发现，所有表达 HLA-G 的胎盘细胞也表达 HLA-E，其中一部分也表达 HLA-F。事实上，侵入母体蜕膜的 EVT 细胞是迄今为止唯一已知同时表达所有三种非经典抗原的正常细胞。我们建议重点关注 HLA-E、F 和 G 的特征，这些特征最终与其在母体胎盘免疫环境中的功能相关。我们目前关于 HLA-E、F、G 在改变母体免疫反应中的假设正在以下具体目标中得到解决：1) 检查 HLA-F 在外周免疫反应中的功能，我们将破译肽或其他配体结合HLA-F 的特性并鉴定与 HLA-F 相互作用的特定受体。这项工作的最终目的是破译 HLA-F 在胎盘环境中的具体作用。 2) 测试 HLA-E 与不同肽配体（包括 HLA-G 九聚体）结合的能力，通过与母体免疫细胞上的激活受体结合而引发特异性免疫反应。这项工作将检验以下假设：与 HLA-E 结合的 HLA-G 九聚肽赋予胎盘免疫环境必需且特异的复合物独特的功能。 3) 研究可溶性和膜性 HLA-G，重点确定其结构特征以及与抑制性受体的相互作用。这项工作旨在检验以下假设：HLA-G 的主要功能是向 HLA-E 提供九聚物肽，并直接作为与蜕膜免疫细胞上表达的抑制性受体相互作用的经典 I 类肽的替代物。我们还建议开发有助于进一步了解 HLA-E、F 和 G 的结构、生物化学和功能的材料和试剂。