Primate Endometrial Responses to Placental MHC Class I Molecules

灵长类动物子宫内膜对胎盘 MHC I 类分子的反应

• 批准号: 7530139
• 负责人: THADDEUS G GOLOS
• 金额: $ 19.1万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7530139
• 关键词: Address; Apoptosis; Biological; Blood Vessels; Clinical; Condition; Decidua; Disruption; Endometrial; Endometrium; HLA G antigen; Histocompatibility Antigens Class I; Human; Immune; Immune response; Indium; Infertility; Leukocytes; MHC Class I Genes; Macaca mulatta; Malignant - descriptor; Maternal-Fetal Exchange; Modification; Monoclonal Antibodies; Natural Killer Cells; Passive Immunization; Patient currently pregnant; Phenotype; Physiological; Placenta; Placentation; Pre-Eclampsia; Pregnancy; Primates; Protein Isoforms; Public Health; Range; Recombinants; Research; Role; Smooth Muscle; Spontaneous abortion; Surface; System; T-Lymphocyte; Testing; Transplantation; cancer immunotherapy; cytokine; implantation; in vivo; macrophage; nonhuman primate; novel; research study; response; trophoblast

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.

描述（由申请人提供）：灵长类动物滋养细胞的非经典MHC I类分子的新表达被认为具有生物学意义，但在母体fetal界面上，母体生理和免疫系统对这些分子的体内反应是很困难的在人类怀孕中进行调查。我们最近证明了灵长类动物胎盘MHC I类表达的生物学相关性，并在怀孕初期对恒河猴的被动免疫进行了免疫。用特异性的单克隆抗体对指定在恒河猴胎盘中表达的MAMU-AG的非晶型MHC I类分子进行治疗，该分子与人类胎盘中表达的HLA-G同源，导致胎盘发育的延迟或破坏胎盘发育和对植入的胎盘发育反应。但是，这些研究无法确定哪些方面是由于Mamu-AG的直接影响，这是由于可溶性Mamu-Ag同工型引起的，这可能是由于胎盘功能的其他次要变化所致。我们假设MAMU-AG与决定的NK细胞相互作用，以促进妊娠早期的适当反应，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性子宫内膜的分化。为了开始解决这一假设，我们将评估可溶性MAMU-AG表达，并定义其对恒河猴白细胞和子宫内膜分化的影响，并具有三个特定的目标。具体目的1。定义重组可溶性Mamu-AG对非妊娠子宫内膜的影响。具体目的2。定义孕妇和未怀孕的恒河猴的循环可溶性mamu-ag。具体目的3。确定可溶性Mamu-AG对NK细胞，巨噬细胞和T细胞中细胞因子分泌，激活，凋亡和增殖的影响。通过这些实验，我们将开始理解可溶性MHC I类分子在调节白细胞亚群的特定功能以及子宫内膜中的基质和血管元素中的直接作用。假设胎盘母亲的免疫相互作用有助于怀孕的病理状况，从不育症和自发流产到先兆子痫。然而，在体内缺乏实验证据来支持这些假设。我们提出的研究不能在人类临床实验中进行，但是人类和非人类灵长类动物怀孕之间的紧密相似性将使我们能够在早期怀孕中定义对新型胎盘MHC表型的子宫内膜反应，并在体内进行假设检测，并在体内进行假设检测。人类怀孕的直接意义。公共卫生相关性：假设胎盘女性免疫相互作用有助于怀孕的病理状况，从不育症和自发流产到先兆子痫。然而，在体内缺乏实验证据来支持这些假设。我们提出的研究不能在临床人类实验中进行，但是人类和非人类灵长类动物怀孕之间的紧密相似性将使我们能够在早期的恒河猴妊娠中定义对胎盘MHC的子宫内膜反应，并在体内进行假设检测，具有直接的意义。人类怀孕。更好地理解对妊娠的免疫反应的理解也可能不仅具有威胁性妊娠治疗的意义，而且还具有GRAFT接受​​和癌症免疫疗法的意义，这也是由于最近考虑了HLA-G在移植和恶性转化方面的考虑。