Role of maternal-fetal interface NK cells in pregnancy maintenance and congenital CMV transmission

母胎界面 NK 细胞在妊娠维持和先天性 CMV 传播中的作用

• 批准号: 10586146
• 负责人: Amitinder Kaur
• 金额: $ 71.19万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-07 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586146
• 关键词: Acceleration; Affect; Amniotic Fluid; Animals; Antibodies; Blood; Blood Cells; CD4 Positive T Lymphocytes; Cells; Chronic; Congenital Abnormality; Cytomegalovirus; Cytomegalovirus Infections; Decidua; Decidual Cell; Development; Endometrium; Equilibrium; Event; Fetal Development; Fetal Tissues; Fetus; Fracture; Frequencies; Gestational Age; Harvest; Health; Human; Immune; Immune System Diseases; Immune Tolerance; Immunity; Immunocompetent; Immunologic Surveillance; Immunologics; Immunology; Impairment; Inflammation; Inflammatory; Invaded; Investigation; Late pregnancy; Leukocytes; Macaca; Macaca mulatta; Maternal-Fetal Exchange; Mediating; Memory; Methods; Modeling; Monitor; Morbidity - disease rate; NK Cell Activation; Natural Killer Cells; Neurologic; Neurologic Deficit; Peripheral; Physiology; Placenta; Play; Population; Pregnancy; Pregnancy Complications; Pregnancy Maintenance; Pregnancy Outcome; Pregnancy Trimesters; Pregnancy loss; Premature Labor; Prevention; Regulation; Rhesus; Role; Sampling; Second Pregnancy Trimester; Testing; Third Pregnancy Trimester; Tissues; Umbilical Cord Blood; adverse pregnancy outcome; congenital cytomegalovirus; congenital infection; design; early pregnancy; effective therapy; embryo/fetus antigen; fetal; fetal immunity; hearing loss risk; immune function; immunogenic; in utero; in vivo; mortality; nonhuman primate; novel therapeutics; pathogen; pregnancy prevention; pregnant; premature; prevent; receptor; seropositive; tool; transmission process; trophoblast

Abstract Immune cells at the maternal/fetal interface play dual roles of orchestrating immune tolerance required for pregnancy maintenance, while also protecting against placental pathogens, such as cytomegalovirus (CMV). Specialized inhibitory immune cells, known as natural killer (NK) cells, are predominant and dynamic immune cells populating the decidua throughout gestation. Yet, there is a major gap in our understanding of the role of NK cells in protection of the fetus against immune rejection and pathogen invasion. The role of NK cells, including recently identified cytomegalovirus (CMV)-specific memory NK cells, in the interplay between fetal tolerance and protection against congenital CMV transmission is poorly defined. This study aims to define the role of maternal NK cell populations in regulation of fetal tolerance and protection against placental CMV transmission in the setting of chronic maternal CMV infection. Our group is uniquely equipped to dissect the immunologic functions at the maternal-fetal interface with significant expertise in both a nonhuman primate (NHP) model of pregnancy and placental CMV transmission as well as investigations of immune cells at the maternal-fetal interface in human placenta and cord blood. The NHP model affords the opportunity to study the immunology and physiology of pregnancy across the gestational stages through elective fetal harvest and access to the immune cells at the maternal-fetal interface, as well as validated strategies for peripheral and tissue depletion of effector NK cells in vivo. We hypothesize that maternal NK cells are critical to both pregnancy maintenance and prevention of CMV reactivation in early pregnancy. Understanding this intersection between maintaining immune tolerance while protecting against placental pathogens is critical to developing immune-based strategies to reduce the morbidity and mortality resulting from adverse pregnancy outcomes.

抽象的 母体/胎儿界面处的免疫细胞起着策划免疫耐受性的双重作用 维持妊娠，同时还可以防止胎盘病原体，例如巨细胞病毒（CMV）。 专门的抑制性免疫细胞，称为天然杀伤（NK）细胞，主要是主导和动态免疫 整个妊娠的细胞填充了deciDua。然而，我们的理解是一个重大差距 NK细胞可保护胎儿免疫排斥和病原体侵袭。 NK细胞的作用， 在胎儿之间的相互作用中，包括最近确定的巨细胞病毒（CMV）特异性记忆NK细胞 对先天性CMV传播的耐受性和保护范围很差。这项研究旨在定义 母体NK细胞种群在调节胎儿耐受性和针对胎盘CMV的保护中的作用 在慢性母体CMV感染的情况下传播。我们的小组具有独特的能力来剖析 在母亲界面的免疫功能在非人类灵长类动物中具有重要专业知识 （NHP）妊娠和胎盘CMV传播模型以及对免疫细胞的研究 人胎盘和脐带血的母亲界面。 NHP模型提供了研究 通过选举胎儿收获和 访问母亲界面处的免疫细胞，以及经过验证的外围策略和 在体内效应nk细胞的组织耗竭。我们假设母体NK细胞对两者都至关重要 怀孕和预防怀孕早期CMV重新激活。了解这一点 维持免疫耐受性的同时保护胎盘病原体之间的交集对 制定基于免疫的策略来降低不良怀孕导致的发病率和死亡率 结果。