UTERINE NK CELLS IN PRIMATE PREGNANCY

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 目的：为了更好地了解自然流产背后的机制，开发先兆妊娠，移植物接受和癌症免疫治疗的疗法。 胎盘MHC I类表达的免疫反应被认为是重要的，但无论是在人类或非人灵长类动物的这种反应的机制和意义是很好地理解。 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的同源物）被动免疫的怀孕恒河猴中，胎盘的绒毛生长和血管化存在广泛的发育延迟，侵入性绒毛外滋养层对母体蜕膜血管的修饰被破坏，以及蜕膜白细胞对着床的反应改变。假设母体NK细胞在识别胎盘MHC中至关重要，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CD 16或抗CD 8治疗后一周内引起自然流产。 这表明胎盘MHC I类分子在灵长类动物妊娠的母体免疫应答中具有重要作用，并将进一步研究这些应答的机制和意义，具体目标有两个： 具体目标1。确定恒河猴蜕膜NK细胞免疫耗竭对着床、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，这些抗体消耗CD 16阳性或CD 8阳性细胞或对照抗体。 目的1将明确外周血NK细胞群在维持妊娠早期稳定着床部位中的重要性。目的2将确定免疫耗竭对妊娠结局的影响是否仅限于着床后即刻，并允许我们开始鉴定对外周免疫耗竭不敏感的蜕膜NK细胞亚群。 与公共卫生的关系：胎盘-母体免疫相互作用被假设为导致妊娠中的病理状况，从不孕症和自发流产到先兆子痫。了解这些相互作用在妊娠成功中的重要性可能会指导胎盘MHC分子潜在治疗应用的临床前研究，或解决不孕症或妊娠障碍中子宫内膜白细胞缺陷或失衡的重要性。非人类灵长类动物提供了一个怀孕可以进行实验操作的模型。更好地了解建立妊娠的免疫反应可能对理解自发性流产、开发先兆妊娠的治疗方法、移植物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.