Progesterone induced immune modulation during pregnancy

怀孕期间黄体酮诱导的免疫调节

• 批准号: 10625933
• 负责人: Sing Sing Way
• 金额: $ 3.98万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10625933
• 关键词: Allogenic; Anatomy; Animals; Antigens; Biological; Blood; Blood Circulation; CD4 Positive T Lymphocytes; Caproates; Cells; Child; Childhood; Clinical; Defect; Effectiveness; FOXP3 gene; Female; Fetal Development; Fetal Tissues; Growth; Human; Hydroxyprogesterone; Immune; Immunologics; In Vitro; Induced Abortion; Infant; Inflammation; Knowledge; Lead; Link; Lymphoid Tissue; Maternal-Fetal Exchange; Mechanics; Mifepristone; Modeling; Mothers; Nuclear; Nutrient; Pharmacology; Phenotype; Physiological; Pre-Eclampsia; Predisposition; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Pregnant Women; Premature Birth; Progesterone; Progesterone Receptors; Property; Prospective cohort; Recurrence; Regulatory T-Lymphocyte; Reproduction; Specificity; Spontaneous abortion; T-Lymphocyte; Testing; Tissues; Uterus; Waste Products; Woman; Work; antagonist; base; cell type; cohort; design; fetal; fetal loss; healthy pregnancy; immunoregulation; mortality; premature; prevent; protective efficacy; public health relevance; receptor expression; recruit; reproductive hormone; shift work

Abstract. Pregnancy outwardly stimulates an assortment of changes in mothers that work together for creating the anatomical space that accommodates growth, nutrient exchange and elimination of waste products for the developing fetus. However, considering intimate physical approximation of maternal with fetal tissues which are genetically discordant, immunological changes that prevent mother’s immune cells from attacking and rejecting foreign fetal tissues are equally important. Unfortunately, how these immunological shifts work and what stimulates them during pregnancy remain poorly undefined. With these fundamental gaps in knowledge pertaining to how reproduction works unresolved, it should be no surprise that pregnancy complications remain the leading cause of infant and childhood mortality. We propose a more comprehensive understanding of how pregnancy works, integrating immunological with other physiological changes, is urgently needed for filling these knowledge gaps and uncovering new, more effective strategies for mitigating pregnancy complications. Our central hypothesis is that progesterone, the female reproductive hormone essential for maintaining uterine quiescence (averting premature uterine emptying), also promotes maternal immunological adaptations required for sustaining healthy term pregnancy. This hypothesis is based on increasingly recognized immune- modulatory properties for this highly conserved reproductive hormone. Our preliminary studies show progesterone drives differentiation of CD4+ T cells into an immune suppressive regulatory phenotype. The proportion of maternal regulatory T cells increase in the circulation and at the maternal-fetal interface during healthy pregnancy, whereas a variety of complications linked with disrupted fetal tolerance (e.g. prematurity, preeclampsia, miscarriage) are associated with blunted expansion of these cells. Maternal regulatory T cells expansion is similarly overturned with abortion induced by the nuclear progesterone receptor antagonist, RU- 486. We also find a variety of maternal immune cells in systemic lymphoid tissues and at the maternal-fetal interface express the canonical nuclear progesterone receptor. This includes maternal regulatory T cells, and in particular those recognizing genetically foreign fetal-expressed antigens. Reciprocally, selective loss of progesterone receptor in maternal regulatory T cells blunts their expansion during pregnancy causing fetal wastage. Based on these exciting proof-of-concept preliminary findings showing the protective benefits of progesterone stimulation of maternal immune cells, the following aims will more comprehensively investigate progesterone induced systemic and local immunological changes required for maintaining pregnancy. Aim 1 will investigate the tempo of progesterone responsiveness amongst maternal immune cells during pregnancy. Aim 2 will define which maternal immune cell subsets require progesterone responsiveness for maintaining pregnancy. Aim 3 will evaluate how maternal immune cell progesterone responsiveness impacts the efficacy of 17 a-hydroxyprogesterone caproate in protecting against recurrent preterm birth.

抽象。怀孕在外表上刺激了母亲们的各种各样的变化， 解剖空间，容纳生长，营养交换和废物的消除， 发育中的胎儿然而，考虑到母体与胎儿组织的密切物理接近， 是遗传上不一致的免疫学变化，阻止母亲的免疫细胞攻击， 排斥外来胎儿组织也同样重要。不幸的是，这些免疫变化是如何起作用的， 在怀孕期间是什么刺激了它们仍然不太清楚。这些基本的知识缺口 关于生殖如何工作的问题尚未解决，怀孕并发症仍然存在也就不足为奇了。 婴儿和儿童死亡的主要原因。我们建议更全面地了解如何 怀孕工作，整合免疫与其他生理变化，是迫切需要填补 这些知识差距和发现新的，更有效的战略，以减轻怀孕并发症。 我们的中心假设是，孕酮，女性生殖激素维持子宫 静止（避免子宫过早排空），也促进母体免疫适应 维持健康的足月妊娠所需的。这一假设是基于越来越多的公认的免疫- 这种高度保守的生殖激素的调节特性。我们的初步研究显示 孕酮驱动CD 4 + T细胞分化为免疫抑制调节表型。的 母体调节性T细胞的比例增加，在循环和母胎界面期间， 健康妊娠，而与胎儿耐受性破坏相关的各种并发症（例如早产， 先兆子痫、流产）与这些细胞的钝性扩增有关。母体调节性T细胞 核孕酮受体拮抗剂RU-1诱导的流产也同样逆转了这种扩张。 486.我们还发现，在全身淋巴组织和母胎 界面表达典型的核孕酮受体。这包括母体调节性T细胞， 特别是识别遗传上外源胎儿表达的抗原的那些。相反，选择性丧失 孕激素受体在母体调节性T细胞减弱其在妊娠期间的扩张， 浪费基于这些令人兴奋的概念验证初步发现， 孕激素对母体免疫细胞的刺激作用，下面将进行更全面的探讨 孕酮诱导维持妊娠所需的全身和局部免疫学变化。要求1 将研究妊娠期间母体免疫细胞对孕酮反应的克里思。 目的2将确定哪些母体免疫细胞亚群需要孕酮反应性来维持 怀孕目的3将评估母体免疫细胞孕酮反应性如何影响 17 α-羟基孕酮己酸预防复发性早产。