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）：可以说，怀孕是哺乳动物生物学中最有趣的免疫住宿的例子之一。胎盘在母亲和儿童之间提供障碍，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儿童的反应。胎盘的跨滋养细胞（EVT）细胞入侵了母体子宫组织，以建立与母体血液供应联系的生命。已经假设EVT细胞与母体免疫细胞之间的相互作用为植入和发育提供了控制影响。我们一直在研究HLA-E，F，G类分子的生物化学和免疫学，特别关注它们单独和互动的作用，以帮助适应其对她发展后代的产妇免疫反应。我们最近表明，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。实际上，侵入母体Decidua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。我们建议专注于HLA-E，F和G的特征，该特征最终与它们在孕产妇免疫环境中的功能有关。在以下特定目的中解决了有关修饰母体免疫反应的HLA-E，F，G的当前假设：1）检查HLA-F在外围免疫反应中的功能，在其中我们将解解HLA-F的DETIPHE肽或其他配体结合特性，并确定特定的受体与HLA-F相互作用。最终，这项工作旨在破译HLA-F在胎盘环境中的特定作用。 2）测试HLA-E与不同肽配体（包括HLA-GNAMER）结合的能力，通过在母体免疫细胞上结合激活受体来唤起特定的免疫反应。这项工作将检验以下假设：与HLA-E结合的HLA-G非剂量肽在胎盘免疫环境所必需的和特定的复合物上赋予了独特的功能。 3）研究可溶性和膜HLA-G的主要重点是确定其结构特征和与抑制受体的相互作用。这项工作旨在检验以下假设：HLA-G的主要功能是为HLA-E提供非鉴定肽，并直接用作与在dec骨免疫细胞上表达的抑制受体相互作用的经典I类替代物。我们还建议开发材料和试剂，以进一步了解Hla-e，F和G的结构，生物化学和功能。