UTERINE NK CELLS IN PRIMATE PREGNANCY

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 目的：为了更好地了解自然流产背后的机制，开发治疗先兆妊娠、移植物接受和癌症免疫治疗的方法。 对胎盘MHC I类分子表达的免疫反应被认为是重要的，然而这种反应在人类或非人类灵长类动物中的机制和意义都不是很清楚。Golos博士的实验室最近发现，被动免疫Mamu-AG的怀孕恒河猴，胎盘绒毛生长和血管形成的广泛延迟，侵袭性绒毛外滋养层细胞对母体蜕膜血管的修改，以及蜕膜白细胞对植入的反应都发生了改变。假设母体NK细胞在识别胎盘MHC中起关键作用，他们现在有初步数据表明，NK细胞免疫耗竭对妊娠结局有负面影响，在抗CD16或抗CD8治疗后一周内导致自然流产。这是胎盘MHC-I类分子在灵长类动物妊娠母体免疫反应中发挥重要作用的证据，并将进一步研究这些反应的机制和意义，有两个特定的目的： 具体目的1.探讨蜕膜NK细胞免疫耗竭对猕猴着床、胎盘和蜕膜发育的影响。 明确胎盘/蜕膜对NK细胞免疫耗竭的敏感性窗口。 在这项研究中，实验室将专注于抗NK细胞抗体的免疫耗竭，即耗尽CD16阳性或CD8阳性细胞，或对照抗体。目的1明确外周血自然杀伤细胞在早期妊娠中维持稳定着床部位的重要性。目的2确定免疫耗竭对妊娠结局的影响是否仅限于植入后即刻，并使我们能够开始鉴定对外周免疫耗竭不敏感的蜕膜NK细胞亚群。 与公共卫生的相关性：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因素，从不孕、自然流产到先兆子痫。了解这些相互作用在妊娠成功中的重要性可能会指导临床前研究胎盘MHC分子的潜在治疗应用，或者解决子宫内膜白细胞缺乏或失衡在不孕症或妊娠障碍中的重要性。非人灵长类动物提供了一个模型，在这个模型中，怀孕是可以进行实验操作的。更好地了解妊娠的免疫反应可能对了解自然流产、开发治疗先兆妊娠、移植物的接受和癌症免疫治疗具有重要意义。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Objective: To better understand the mechanisms behind spontaneous miscarriage, to develop therapies for threatened pregnancies, graft acceptance, and cancer immunotherapy. The immunological response to placental MHC class I expression is considered to be important, yet neither the mechanisms nor the significance of this response in humans or nonhuman primates is well understood. Dr. Golos' lab has recently shown that in pregnant rhesus monkeys passively immunized against Mamu-AG, the rhesus nonclassical trophoblast MHC class I molecule thought to be a homolog of HLA-G, there is a broad developmental delay in villous growth and vascularization of the placenta, a disruption of the modification of maternal decidual vessels by invasive extravillous trophoblasts, and altered decidual leukocyte responses to implantation. Hypothesizing that maternal NK cells are critical in the recognition of placental MHC, they now have pilot data demonstrating that NK cell immunodepletion has a negative impact on pregnancy outcome, causing spontaneous abortion within a week after anti-CD16 or anti-CD8 treatment. It is proposed that this is evidence for an important role of placental MHC class I molecules in the maternal immunological response to pregnancy in primates, and will further study the mechanisms and significance of these responses with two specific aims: Specific Aim 1. To determine the effect of immunodepletion of decidual NK cells on implantation, and placental and decidual development in rhesus monkeys. Specific Aim 2. To define the window of placental/decidual sensitivity to NK cell immunodepletion. For this study, the lab will focus on immunodepletion with anti-NK cell antibodies, which deplete CD16-positive or CD8-positive cells, or control antibodies. Aim 1 will define the importance of peripheral NK cell populations in maintaining a stable implantation site in early gestation. Aim 2 will determine if the effects of immunodepletion on pregnancy outcome are restricted to the immediate post-implantation period, and allow us to begin to identify the subpopulation of decidual NK cells not sensitive to peripheral immunodepletion. RELEVANCE TO PUBLIC HEALTH: Placental-maternal immune interactions are hypothesized to contribute to pathological conditions in pregnancy, ranging from infertility and spontaneous miscarriage to preeclampsia. Understanding the importance of these interactions in pregnancy success may guide preclinical studies in potential therapeutic applications of placental MHC molecules, or address the importance of deficiencies or imbalances of endometrial leukocytes in infertility or pregnancy disorders. The nonhuman primate provides a model in which pregnancy is amenable to experimental manipulation. A better understanding of the immune response to the establishment of pregnancy may have significance for understanding spontaneous miscarriage, developing therapies for threatened pregnancies, graft acceptance, and cancer immunotherapy.