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。怀孕向外刺激共同创造的母亲的各种变化 适应生长，营养交换和消除废物的解剖空间 发展胎儿。但是，考虑孕产妇与胎儿组织的亲密近似 是遗传上不一致的免疫学变化，可以防止母亲的免疫小球攻击和 拒绝外国胎儿组织同样重要。不幸的是，这些免疫学转变如何工作和 在怀孕期间刺激它们的原因仍然很差。在知识中的这些基本差距 关于繁殖的工作原理如何解决，妊娠并发症仍然不足为奇 婴儿和儿童死亡率的主要原因。我们对如何更全面地了解 迫切需要怀孕工作，将免疫学与其他身体变化整合到其他身体变化 这些知识差距，并揭示了缓解怀孕并发症的新的，更有效的策略。 我们的中心假设是孕酮，雌性复制性马酮对维持子宫必不可少的 静止（避免过早的子宫排空），还促进了母子免疫适应 维持健康期限怀孕所必需的。该假设基于越来越公认的免疫力 这种高度保守的生殖骑士的调节特性。我们的初步研究表明 孕激素将CD4+ T细胞分化为免疫抑制调节表型。 母体调节性T细胞的比例在循环系统和母亲界面上增加 健康怀孕，而各种并发症与胎儿耐受性中断相关（例如，早产， 先兆子痫，流产）与这些细胞的膨胀钝化有关。母体调节T细胞 通过核孕酮受体拮抗剂Ru-诱导的流产，膨胀也相似 486。我们还发现全身性淋巴组织中的各种母体免疫细胞和在母亲疫苗 界面表达规范的核孕酮受体。这包括材料调节T细胞，以及 特别是那些识别一般外国胎儿表达的抗原的人。相互选择性损失 母体调节性T细胞中的孕酮受体在怀孕期间钝化其膨胀，引起胎儿 浪费。基于这些令人兴奋的概念证明的初步发现，显示了受保护的好处 孕产妇免疫细胞的孕酮刺激，以下目的将更全面地研究 孕酮诱导了维持妊娠所需的全身和局部免疫学变化。目标1 将研究怀孕期间母体免疫细胞中孕激素反应的速度。 AIM 2将定义哪些物质免疫细胞子集需要孕激素的反应能力以维持 怀孕。 AIM 3将评估母体免疫元素孕酮反应能力如何影响 17 A-羟基酸蛋白酶在预防反复出生的过程中。