UTERINE NK CELLS IN PRIMATE PREGNANCY

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 目的：更好地了解自然流产背后的机制，开发先兆妊娠、移植接受和癌症免疫疗法的治疗方法。 对胎盘 MHC I 类表达的免疫反应被认为是重要的，但这种反应在人类或非人灵长类动物中的机制和意义尚不清楚。 Golos 博士的实验室最近表明，在对 Mamu-AG（恒河猴非经典滋养层 MHC I 类分子被认为是 HLA-G 同源物）被动免疫的怀孕恒河猴中，绒毛生长和胎盘血管化出现广泛的发育延迟，侵入性绒毛外滋养层对母体蜕膜血管的修饰被破坏，并且蜕膜白细胞对 Mamu-AG 的反应发生改变。植入。他们假设母体 NK 细胞对于胎盘 MHC 的识别至关重要，现在有试点数据证明 NK 细胞免疫耗竭对妊娠结局产生负面影响，导致抗 CD16 或抗 CD8 治疗后一周内自然流产。 有人提出，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，有两个具体目标： 具体目标 1. 确定蜕膜 NK 细胞的免疫耗竭对恒河猴着床、胎盘和蜕膜发育的影响。 具体目标 2. 确定胎盘/蜕膜对 NK 细胞免疫耗竭的敏感性窗口。 在这项研究中，实验室将重点关注抗 NK 细胞抗体的免疫耗竭，该抗体会耗竭 CD16 阳性或 CD8 阳性细胞或对照抗体。 目标 1 将明确外周 NK 细胞群在妊娠早期维持稳定植入部位的重要性。目标 2 将确定免疫耗竭对妊娠结局的影响是否仅限于着床后不久，并使我们能够开始识别对外周免疫耗竭不敏感的蜕膜 NK 细胞亚群。 与公众健康的相关性：据推测，胎盘-母体免疫相互作用会导致妊娠期的病理状况，包括不孕、自然流产和先兆子痫。了解这些相互作用对妊娠成功的重要性可能会指导胎盘 MHC 分子潜在治疗应用的临床前研究，或解决子宫内膜白细胞缺乏或不平衡在不孕或妊娠疾病中的重要性。非人类灵长类动物提供了一个模型，其中怀孕可以通过实验操作进行。更好地了解妊娠建立的免疫反应可能对于了解自然流产、开发针对先兆妊娠的疗法、移植物接受和癌症免疫疗法具有重要意义。

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.