UTERINE NK CELLS IN PRIMATE PREGNANCY

灵长类动物妊娠期的子宫 NK 细胞

• 批准号: 6521135
• 负责人: THADDEUS G GOLOS
• 金额: $ 25.52万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-02 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6521135
• 关键词: MHC class I antigen; Macaca mulatta; biological models; cell cell interaction; cell differentiation; cell growth regulation; female; immune tolerance /unresponsiveness; lectin; monoclonal antibody; natural killer cells; placenta; placental transfer; pregnancy; pregnancy immunology; trophoblast; uterus

Interactions of the placenta and the maternal immune system are likely to be critical in the establishment of pregnancy, and in particular the uterine immune environment may influence trophoblast differentiation, placental growth, and invasion of the maternal endometrium. Inappropriate development/regulation of these activities has enormous potential to contribute to placental dysfunction and maternal and fetal morbidity and mortality. We have recently demonstrated that the rhesus monkey placenta expresses a novel MHC class I locus, designated Mamu-AG, which has significant biochemical and molecular similarities to the human placental MHC class I molecular HLA-G. Although HLA-G is hypothesized to mediate maternal-fetal immune tolerance via interaction with maternal uterine natural killer (NK) cells, functional in vivo studies of the role(s) of placental MHC class I molecules in normal implantation and establishment and maintenance of pregnancy are not possible in a clinical setting. We hypothesize that Mamu-AG inhibits uterine and peripheral blood NK cell activity in the rhesus monkey via interactions with specific killer inhibitory receptors on NK cell membranes. In order to begin to test this hypothesis, we propose three specific aims: Specific Aim 1 is to generate Mamu-AG-specific monoclonal antibodies and to define the distribution of this MHC class I molecule in adult and fetal rhesus monkeys. Specific Aim 2 is to use anti-Mamu AG antibodies with both in vitro culture systems and in vivo passive immunization studies to explore the role of Mamu-AG in trophoblast-NK cell interactions and trophoblast differentiation. Specific Aim 3 is to clone natural killer inhibitory receptors (KIRs) of the trophoblast differentiation. Specific Aim 3 is to clone natural killer inhibitory receptors (KIRs) of the immunoglobulin (Ig) and C-type lectin superfamilies expressed in the rhesus monkey and characterize activity of the peripheral and decidual NK cells against trophoblast and non-trophoblast targets. These aims build on our previous studies which establish the rhesus monkey as a model for studying human maternal-fetal immune tolerance. The modulation of trophoblast-NK cell interactions in vivo will not only provide insights into maternal-fetal immune tolerance. The modulation of trophoblast-NK cell interactions in vivo will not only provide insights into maternal-fetal dialogue and placental biology, but will also advance the use of the primate model to study NK cell biology, relevant to the setting of infection as well as immune tolerance.

胎盘和母体免疫系统的相互作用在妊娠的建立中可能至关重要，尤其是子宫免疫环境可能会影响滋养细胞的分化，胎盘生长和侵袭母体子宫内膜。这些活动的不当发育/调节具有巨大的潜力，有助于胎盘功能障碍以及母体和胎儿的发病率和死亡率。我们最近证明，恒河猴胎盘表达了一个新型的MHC I类，该基因座指定为Mamu-AG，该基因座与人胎盘MHC I类HLA-G具有显着的生化和分子相似性。尽管假设HLA-G通过与母体子宫天然杀伤（NK）细胞相互作用来介导母体 - 易于免疫耐受性，但在临床环境中不可能在正常植入，妊娠正常植入和妊娠中的胎盘I类分子的作用中进行体内研究。我们假设Mamu-Ag通过与NK细胞膜上的特定杀伤抑制受体的相互作用来抑制恒河猴中的子宫和外周血NK细胞活性。为了开始检验这一假设，我们提出了三个特定的目的：具体目的1是生成Mamu-Ag特异性单克隆抗体，并定义该MHC I类分子在成人和胎儿恒河猴中的分布。具体目的2是将抗Mamu Ag抗体与体外培养系统和体内被动免疫研究一起使用，以探索MAMU-AG在滋养细胞-NK细胞相互作用和滋养细胞分化中的作用。具体目的3是克隆滋养细胞分化的自然杀伤受体（KIR）。具体目的3是在恒河猴中表达的免疫球蛋白（Ig）和C型凝集素超家族的克隆天然杀伤受体（KIR），并表征外周血和dec骨NK细胞对滋养细胞和非特性细胞靶标的活性。这些目标是基于我们以前的研究，该研究确立了恒河猴作为研究人类母亲免疫耐受性的模型。体内滋养细胞-NK细胞相互作用的调节不仅会提供对母亲 - 狂热耐受性的见解。体内滋养细胞-NK细胞相互作用的调节不仅将提供对母亲 - 狂欢对话和胎盘生物学的见解，而且还将推动使用灵长类动物模型研究NK细胞生物学，这与感染和免疫耐受性有关。