UTERINE NK CELLS IN PREGNANCY

妊娠期子宫 NK 细胞

• 批准号: 2902283
• 负责人: THADDEUS G GOLOS
• 金额: $ 25.14万
• 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/2902283
• 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可能在妊娠的建立中至关重要，特别是子宫免疫环境可能影响滋养层分化、胎盘生长和母体子宫内膜的侵袭。这些活动的不适当发展/调节有巨大的潜力，有助于胎盘功能障碍和母亲和胎儿的发病率和死亡率。我们最近已经证明，恒河猴胎盘表达一种新的MHC I类基因座，命名为Mamu-AG，它具有显着的生物化学和分子相似性的人胎盘MHC I类分子HLA-G。尽管HLA-G被假设为通过与母体子宫自然杀伤（NK）细胞的相互作用介导母胎免疫耐受，但在临床环境中不可能进行胎盘MHC I类分子在正常着床以及妊娠的建立和维持中的作用的功能性体内研究。我们推测，Mamu-AG通过与NK细胞膜上的特异性杀伤抑制受体相互作用抑制恒河猴子宫和外周血NK细胞活性。为了开始测试这一假设，我们提出了三个具体的目标：具体目标1是产生Mamu-AG特异性单克隆抗体，并确定该MHC I类分子在成年和胎儿恒河猴中的分布。具体目标2是将抗Mamu AG抗体用于体外培养系统和体内被动免疫研究，以探索Mamu-AG在滋养层-NK细胞相互作用和滋养层分化中的作用。具体目标3是克隆滋养层分化的自然杀伤抑制性受体（KIR）。具体目标3是克隆恒河猴中表达的免疫球蛋白（IG）和C型凝集素超家族的自然杀伤抑制受体（KIR），并表征外周和蜕膜NK细胞对滋养层和非滋养层靶标的活性。这些目标建立在我们以前的研究，建立恒河猴作为研究人类母胎免疫耐受的模型。滋养层细胞-NK细胞相互作用在体内的调制不仅提供了对母胎免疫耐受的见解。滋养层-NK细胞相互作用在体内的调制不仅将提供对母胎对话和胎盘生物学的见解，而且还将推进灵长类动物模型的使用，以研究NK细胞生物学，与感染的设置以及免疫耐受性有关。