Progesterone induced immune modulation during pregnancy

怀孕期间黄体酮诱导的免疫调节

• 批准号: 10653014
• 负责人: Sing Sing Way
• 金额: $ 84.22万
• 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/10653014
• 关键词: Allogenic; Anatomy; Animals; Antigens; Biological; Blood; CD4 Positive T Lymphocytes; Caproates; Cells; Child; Childhood; Circulation; Clinical; Defect; Effectiveness; Eligibility Determination; FOXP3 gene; Female; Fetal Development; Fetal Tissues; Growth; Human; Hydroxyprogesterone; Immune; Immunologics; In Vitro; Induced Abortion; Infant; Inflammation; Knowledge; Link; Lymphoid Tissue; Maternal-Fetal Exchange; Mechanics; Mifepristone; Modeling; Mothers; Nuclear; Nutrient; 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; cell type; cohort; design; fetal; fetal loss; healthy pregnancy; immunoregulation; mortality; pharmacologic; 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.

抽象的。怀孕在外部刺激了母亲的一系列变化，这些变化共同作用于创造 生长、营养交换和废物清除的解剖空间 发育中的胎儿。然而，考虑到母亲与胎儿组织的密切物理接近， 是遗传上不协调的，免疫变化，防止母亲的免疫细胞攻击和 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她们，目前还没有明确的答案。有了这些知识上的根本差距 关于生殖的工作原理尚未解决，怀孕并发症仍然存在也就不足为奇了 是导致婴儿和儿童死亡的主要原因。我们建议更全面地理解如何 孕期工作，结合免疫学和其他生理变化，是填充迫切需要的 这些知识差距和发现新的、更有效的减轻妊娠并发症的策略。 我们的中心假设是孕酮，女性生殖激素，对维持子宫至关重要 静止(避免子宫过早排空)也能促进母体的免疫适应 是维持健康足月妊娠所必需的。这一假说是基于日益公认的免疫-- 这种高度保守的生殖荷尔蒙的调节特性。我们的初步研究表明 黄体酮促使CD4+T细胞分化为免疫抑制调节表型。这个 母体调节性T细胞在血液循环和母胎界面的比例在 健康的妊娠，而与胎儿耐受性受损有关的各种并发症(如早产、 先兆子痫、流产)与这些细胞迟钝的扩张有关。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扩张。 486。我们还在全身淋巴组织和母胎组织中发现了各种母体免疫细胞 INTERFACE表达典型的核孕酮受体。这包括母体调节性T细胞，以及 尤其是那些识别基因外源胎儿表达的抗原的人。反过来，选择性的损失 母体调节性T细胞中的孕激素受体抑制其在怀孕期间的扩张，导致胎儿 浪费。基于这些令人兴奋的概念验证初步发现，显示了 孕酮对母体免疫细胞的刺激作用，将在以下几个方面进行较为全面的研究 孕酮引起维持妊娠所需的全身和局部免疫变化。目标1 将调查怀孕期间母体免疫细胞中孕酮反应的节奏。 目标2将定义哪些母体免疫细胞亚群需要孕酮应答才能维持 怀孕了。目标3将评估母体免疫细胞孕酮反应性如何影响 17α-羟孕酮己酸酯预防复发性早产。