Primate Endometrial Responses to Placental MHC Class I Molecules

描述（由申请人提供）：灵长类动物滋养细胞非经典MHC I类分子的新表达被认为具有生物学意义，然而母体生理和免疫系统在母体-胎儿界面对这些分子的体内反应很难在人类妊娠中进行研究。我们最近证明了灵长类动物胎盘MHC I类表达与妊娠早期恒河猴被动免疫的生物学相关性。针对恒河猴胎盘中表达的MHC I类非多态性分子Mamu-AG（与人胎盘中表达的HLA-G同源）的特异性单克隆抗体，可延迟或破坏胎盘发育和子宫内膜对着床的反应。然而，这些研究无法确定哪些方面是由于Mamu-AG的直接影响，哪些方面是由于可溶性Mamu-AG异构体，哪些方面可能是由于胎盘功能的其他继发性改变。我们假设Mamu-AG与蜕膜NK细胞相互作用，促进妊娠早期蜕膜的适当反应，包括巨噬细胞和T细胞的分化和分布，母体血管平滑肌的修饰，以及功能性子宫内膜的分化。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。具体目标目的探讨重组可溶性Mamu-AG对非妊娠子宫内膜的影响。具体目标2。目的：明确妊娠恒河猴和非妊娠恒河猴循环可溶性Mamu-AG。具体目标3。探讨可溶性Mamu-AG对NK细胞、巨噬细胞和T细胞中细胞因子分泌、活化、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类分子在调节白细胞亚群以及母胎界面子宫内膜基质和血管成分的特定功能中的直接作用。胎盘-母体免疫相互作用被假设有助于妊娠病理状况，从不孕症和自然流产到先兆子痫。然而，缺乏体内实验证据来支持这些假设。我们提出的研究不能在临床人体实验中进行，但人类和非人灵长类动物妊娠的相似之处将使我们能够确定子宫内膜对妊娠早期胎盘MHC新表型的反应，并进行对人类妊娠有直接意义的体内研究假设检验。公共卫生相关性：假设胎盘-母体免疫相互作用有助于妊娠病理状况，从不孕症和自然流产到先兆子痫。然而，缺乏体内实验证据来支持这些假设。我们提出的研究不能在临床人体实验中进行，但人类和非人灵长类动物妊娠的相似之处将使我们能够确定恒河猴妊娠早期子宫内膜对胎盘MHC的反应，并进行对人类妊娠有直接意义的体内假设检验研究。由于最近考虑到HLA-G在移植和恶性转化中的作用，更好地了解妊娠建立时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.