Human Decidual Leukocytes and Their Placental Ligands

描述（由申请人提供）：子宫内的胎儿携带父亲的抗原，应该作为外来移植物被母体免疫系统排斥，这是Peter Medawar在50多年前描述的一个免疫学之谜。填充子宫蜕膜的母体白细胞当然在耐受性中起重要作用。它们与附着并侵入蜕膜的胎盘外滋养细胞（EVT）相互作用。EVT表达一种不寻常的功能未知的I类MHC蛋白，HLA-G二聚体仅在孕妇和猿中发现。本研究的目的是描述母体白细胞和胎儿EVT的特征，并研究它们在妊娠各方面的相互作用，包括子宫螺旋动脉的重塑以增加发育中的胎儿的血流量，囊胚（16细胞期胚胎）植入子宫和母胎耐受性。蜕膜自然杀伤细胞（约占蜕膜白细胞的70%，在本项目的前5年被鉴定）通过几种方式促进母胎耐受。本研究旨在描述其余主要的蜕膜白细胞，巨噬细胞（约占白细胞的20%）和T细胞（5-20%），描述这些细胞之间发生的突触，并扩大我们对携带HLA-G二聚体的EVT与蜕膜白细胞相互作用的认识。微阵列分析将被用作表征人个体巨噬细胞的主要工具，以确定它们是否是M2调节性巨噬细胞以及它们可能分泌什么因子。它们可能在母胎耐受和子宫重塑中起重要作用。对包括调节性T细胞在内的蜕膜T细胞（白细胞的5-20%）的研究也将开始。侵入蜕膜并与蜕膜白细胞混合的EVT最近已被分离出来。它们将被进一步表征并用于研究它们与蜕膜自然杀伤细胞和巨噬细胞的相互作用。我们已经确定，这些相互作用导致几种细胞因子的分泌，并假设其他参与母胎耐受性和子宫重塑的蛋白质也被分泌。最后，我们将通过研究LIF对表达LIF受体的EVT的影响来探讨LIF促进着床的机制。敲除LIF的雌性小鼠是不育的，因为受孕后形成的囊胚不能植入子宫。该项目与女性生殖失败直接相关，即复发性自然流产（RSA），由于囊胚植入失败导致的某些形式的不孕症，子痫前期和由于血管重塑无法提供足够的血液供应而导致的胎儿生长限制。

DESCRIPTION (provided by applicant): The fetus in utero bears paternal antigens and should be rejected as a foreign graft by the maternal immune system, an immunological enigma described by Peter Medawar more than 50 years ago. Maternal leukocytes that populate the uterine decidua certainly play an important role in tolerance. They interact with placental extravillous trophoblasts (EVT) that attach to and invade the decidua. EVT express an unusual Class I MHC protein of unknown function, the HLA-G dimer that is found only in pregnant women and apes. The goal of this proposal is to characterize both maternal leukocytes and fetal EVT and to study their interactions that must contribute to various aspects of pregnancy, including remodeling of the uterine spiral arteries to increase blood flow to the developing fetus, implantation of the blastocyst (16 cell stage embryo) into the uterus and maternal- fetal tolerance. Decidual natural killer cells (~70% of leukocytes in the decidua that were characterized during the first 5 years of this project) contribute to maternal-fetal tolerance by several means. This proposal seeks to characterize the remaining major sets of decidual leukocytes, the macrophages (~20% of the leukocytes) and T cells (5-20%), to describe synapses that occur between these cells, and to expand our knowledge of the interaction of HLA-G dimer bearing EVT with decidual leukocytes. Microarray analysis will be used as a principal tool in characterizing human decidual macrophages in order to establish whether they are M2 regulatory macrophages and what factors they may secrete. They may have an important role in maternal-fetal tolerance and in uterine remodeling. Studies of decidual T cells (5-20% of the leukocytes) that include regulatory T cells will also be initiated. The EVT that invade the decidua and intermingle with the decidual leukocytes have been recently isolated. They will be characterized further and used to study their interaction with decidual natural killer cells and macrophages. We have already established that these interactions lead to the secretion of several cytokines and hypothesize that other proteins involved in maternal- fetal tolerance and in uterine remodeling are also secreted. Finally, the mechanism by which LIF contributes to implantation will be examined by studying its effects on EVT that express the LIF receptor. LIF knockout female mice are infertile because the blastocyst formed after conception cannot implant into the uterus. This project is directly related to reproductive failure in women, i.e. recurrent spontaneous abortion (RSA), some forms of infertility due to failure of implantation of the blastocyst, preeclampsia and fetal growth restriction due to the failure of vascular remodeling that provides an adequate blood supply.