Primate Endometrial Responses to Placental MHC Class I Molecules

描述(申请人提供)：灵长类滋养层细胞新表达的非经典MHC-I类分子被认为具有生物学意义，但在人类怀孕期间，母体生理和免疫系统对母胎界面上这些分子的体内反应很难研究。我们最近证明了灵长类动物胎盘MHC-I类分子的表达与恒河猴妊娠早期被动免疫的生物学相关性。恒河猴胎盘中表达的一种名为MAMU-AG的非多态MHC-I类分子的特异性单抗与人类胎盘中表达的HLA-G同源，治疗会导致胎盘发育和子宫内膜对植入的反应延迟或中断。然而，这些研究无法确定哪些方面是由于MAMU-AG的直接影响，哪些是由于可溶性MAMU-AG异构体，哪些可能是由于胎盘功能的其他继发性改变。我们推测，MAMU-AG与蜕膜NK细胞相互作用，促进早孕蜕膜的适当反应，包括巨噬细胞和T细胞的分化和分布，母体血管中平滑肌的修饰，以及功能子宫内膜的分化。为了解决这一假设，我们将评估可溶性MAMU-AG的表达，并确定其对恒河猴白细胞和子宫内膜分化的影响，具体有三个目的。具体目的1.明确重组可溶性MAMU-AG对非妊娠子宫内膜的影响。特定目的2.检测妊娠恒河猴和非妊娠恒河猴循环中的可溶性MAMU-AG。具体目的3.检测可溶性MAMU-AG对NK细胞、巨噬细胞和T细胞细胞因子分泌、激活、凋亡和增殖的影响。通过这些实验，我们将开始了解可溶性MHC-I类分子在调节母胎界面子宫内膜中白细胞亚群以及间质和血管元素的特定功能中的直接作用。胎盘和母体的免疫相互作用被认为是导致妊娠病理状况的原因，从不孕、自然流产到先兆子痫。然而，缺乏活体实验证据来支持这些假说。我们提出的研究不能在临床人体实验中进行，但人类和非人类灵长类妊娠之间的相似之处将使我们能够确定早期妊娠时子宫内膜对新的胎盘MHC表型的反应，并进行对人类怀孕具有直接意义的体内假说验证研究。公共卫生相关性：胎盘和母体的免疫相互作用被认为是导致妊娠病理状况的原因，从不孕和自然流产到先兆子痫。然而，缺乏活体实验证据来支持这些假说。我们建议的研究不能在临床人体实验中进行，但人类和非人类灵长类妊娠之间的相似之处将使我们能够确定早期恒河猴妊娠时子宫内膜对胎盘MHC的反应，并进行体内假设检验，对人类怀孕具有直接意义。由于目前人类白细胞抗原-G在移植和恶变方面的考虑，更好地了解妊娠的免疫反应不仅对先兆妊娠的治疗有重要意义，而且对移植物的接受和癌症免疫治疗也有重要意义。

DESCRIPTION (provided by applicant): The novel expression of nonclassical MHC class I molecules by the primate trophoblast is considered to be biologically significant, yet the in vivo responses of the maternal physiological and immunological systems to these molecules at the maternal-fetal interface is difficult to investigate in human pregnancy. We have recently demonstrated the biological relevance of primate placental MHC class I expression with passive immunization of rhesus monkeys during early pregnancy. Treatment with a specific monoclonal antibody to a nonpolymorphic MHC class I molecule designated Mamu-AG expressed in the rhesus placenta, homologous to HLA-G expressed in the human placenta, resulted in delay or disruption of placental development and endometrial responses to implantation. These studies, however, were unable to determine which aspects were due to direct effects of Mamu-AG, which were due to a soluble Mamu-AG isoform, and which may have been due to other secondary alterations in placental function. We hypothesize that Mamu-AG interacts with decidual NK cells to promote appropriate responses in the early pregnancy decidua, including the differentiation and distribution of macrophages and T cells, the modification of smooth muscle in maternal vessels, and differentiation in the functional endometrium. To begin to address this hypothesis, we will evaluate soluble Mamu-AG expression and define its effects on rhesus monkey leukocytes and endometrial differentiation with three specific aims. Specific Aim 1. To define the effects of recombinant soluble Mamu-AG on the nonpregnant endometrium. Specific Aim 2. To define circulating soluble Mamu-AG in pregnant and in nonpregnant rhesus monkeys. Specific Aim 3. To determine the effects of soluble Mamu-AG on cytokine secretion, activation, apoptosis, and proliferation in NK cells, macrophages and T cells. With these experiments we will begin to understand the direct role of soluble MHC class I molecules in regulating specific functions of leukocyte subsets as well as stromal and vascular elements in the endometrium at the maternal-fetal interface. Placental-maternal immune interactions are hypothesized to contribute to pathological conditions in pregnancy, ranging from infertility and spontaneous miscarriage to preeclampsia. Yet, there is a dearth of experimental evidence in vivo to support these hypotheses. Our proposed studies could not be carried out in clinical human experiments, but the close similarities between human and nonhuman primate pregnancy will allow us to define the endometrial response to the novel placental MHC phenotype in early pregnancy, and conduct hypothesis-testing in vivo research with direct significance for human pregnancy. PUBLIC HEALTH RELEVANCE: Placental-maternal immune interactions are hypothesized to contribute to pathological conditions in pregnancy, ranging from infertility and spontaneous miscarriage to preeclampsia. Yet, there is a dearth of experimental evidence in vivo to support these hypotheses. Our proposed studies could not be carried out in clinical human experiments, but the close similarities between human and nonhuman primate pregnancy will allow us to define the endometrial response to placental MHC in early rhesus gestation and conduct hypothesis-testing in vivo research with direct significance for human pregnancy. A better understanding of the immune response to the establishment of pregnancy may also have significance not only for therapy of threatened pregnancies, but for graft acceptance and cancer immunotherapy as well, owing to recent considerations of HLA-G in transplantation and malignant transformation.