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: 10392103
• 负责人: Amitinder Kaur
• 金额: $ 75.43万
• 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/10392103
• 关键词: Affect; Amniotic Fluid; Animals; Antibodies; Blood; Blood Cells; CD4 Positive T Lymphocytes; Cell physiology; 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; Natural Killer Cells; Neurologic; Neurologic Deficit; Peripheral; Physiology; Placenta; Play; Population; Pregnancy; Pregnancy Complications; Pregnancy Maintenance; Pregnancy Outcome; Pregnancy loss; Premature Birth; Premature Labor; Prevention; Regulation; Rhesus; Role; Sampling; Second Pregnancy Trimester; Testing; Third Pregnancy Trimester; Tissues; Umbilical Cord Blood; adverse pregnancy outcome; base; 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.

摘要 母体/胎儿界面的免疫细胞发挥着双重作用，协调免疫耐受， 妊娠维持，同时还保护免受胎盘病原体，如巨细胞病毒（CMV）。 专门的抑制性免疫细胞，称为自然杀伤（NK）细胞，是主要的和动态的免疫细胞。 在整个妊娠期间，细胞在蜕膜中繁殖。然而，在我们理解的作用， NK细胞在保护胎儿免受免疫排斥和病原体入侵中的作用。NK细胞的作用， 包括最近发现的巨细胞病毒（CMV）特异性记忆NK细胞，在胎儿 对先天性CMV传播的耐受性和保护性定义不明确。本研究旨在定义 母体NK细胞群在调节胎儿耐受和保护胎盘免受CMV感染中的作用 在慢性母体CMV感染的情况下传播。我们的团队有着独特的能力来解剖 母胎界面的免疫功能，在非人灵长类动物中具有丰富的专业知识 (NHP)妊娠和胎盘CMV传播的模型，以及免疫细胞的调查， 人胎盘和脐带血中的母胎界面。NHP模型提供了研究 通过选择性胎儿收获， 接触母胎界面的免疫细胞，以及外周和 体内效应NK细胞的组织消耗。我们假设母体NK细胞对两者都至关重要 妊娠维持和预防妊娠早期CMV再激活。理解这一 维持免疫耐受与保护免受胎盘病原体侵害之间的交叉点对于 制定以免疫为基础的战略，以减少不良妊娠造成的发病率和死亡率; 结果。