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.

抽象的。怀孕在表面上会刺激母亲发生各种变化，这些变化共同努力创造 容纳生长、营养交换和废物消除的解剖空间 发育中的胎儿。然而，考虑到母体与胎儿组织在身体上的紧密接近， 是遗传上不一致的免疫变化，阻止母亲的免疫细胞攻击和 排斥外来胎儿组织同样重要。不幸的是，这些免疫学转变如何发挥作用以及 怀孕期间是什么刺激了它们，目前还不清楚。由于这些基本的知识差距 关于生殖如何进行的问题尚未得到解决，妊娠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 妊娠期的工作，将免疫学与其他生理变化相结合，迫切需要填充 这些知识差距并发现新的、更有效的减轻妊娠并发症的策略。 我们的中心假设是，黄体酮是维持子宫正常运转所必需的女性生殖激素。 静止（避免子宫过早排空），也促进母体免疫适应 维持健康足月妊娠所需的。这一假设是基于越来越多的人认识到免疫 这种高度保守的生殖激素的调节特性。我们的初步研究表明 黄体酮驱动 CD4+ T 细胞分化为免疫抑制调节表型。这 母体调节性 T 细胞在循环中和母胎界面处的比例增加 健康妊娠，而各种并发症与胎儿耐受性破坏有关（例如早产、 先兆子痫、流产）与这些细胞的增殖迟缓有关。母体调节性T细胞 核孕激素受体拮抗剂 RU- 诱导的流产也同样推翻了扩张。 486. 我们还在全身淋巴组织和母胎间发现了多种母体免疫细胞 界面表达典型的核孕酮受体。这包括母体调节性 T 细胞，以及 特别是那些识别遗传性外源胎儿表达的抗原的细胞。反过来，选择性丢失 母体调节性 T 细胞中的黄体酮受体在怀孕期间减弱其扩张，导致胎儿 浪费。基于这些令人兴奋的概念验证初步结果显示了 黄体酮对母体免疫细胞的刺激作用，以下目的将更全面地考察 黄体酮引起维持妊娠所需的全身和局部免疫变化。目标1 将研究怀孕期间母体免疫细胞中黄体酮反应的节奏。 目标 2 将确定哪些母体免疫细胞亚群需要黄体酮反应来维持 怀孕。目标 3 将评估母体免疫细胞孕酮反应如何影响功效 17α-羟基黄体酮己酸酯可预防复发性早产。