Endocrine regulation of maternal immunity in pregnancy

孕期母体免疫力的内分泌调节

• 批准号: 10116259
• 负责人: MARGARET G PETROFF
• 金额: $ 19.56万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10116259
• 关键词: Address; Adoptive Transfer; Aging; Allogenic; Antigens; Autoantigens; Autoimmune Diseases; Blood Circulation; Cells; Cessation of life; Data; Development; Drops; Endocrine; Ensure; Failure; Fetal Viability; Fetus; Foundations; Generations; Goals; Hormones; Human; Immune; Immune Tolerance; Immune response; Immune system; Immunity; Individual; Infiltration; Knowledge; Lead; Leukocytes; Location; Malignant Neoplasms; Maternal-Fetal Exchange; Maternally-Acquired Immunity; Mediating; Medicine; Modeling; Mus; Nurses; Operative Surgical Procedures; Organ Transplantation; Outcome; Output; Peripheral; Physiological; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Pregnant Women; Premature Birth; Prevention; Prevention strategy; Production; Progesterone; Progesterone Receptors; Regulation; Regulatory T-Lymphocyte; Reporter; Reproductive system; Research; Role; Site; Spontaneous abortion; Structure; T-Cell Development; T-Lymphocyte; Testing; Therapeutic; Thymic epithelial cell; Thymus Gland; Time; Transplantation; Woman; Work; adverse pregnancy outcome; base; cancer cell; early pregnancy; experimental study; fetal; fetal loss; healthy pregnancy; improved; in vivo; in vivo Model; insight; mouse model; novel; peripheral blood; pregnancy disorder; prevent; receptor expression; response; steroid hormone; success; therapeutic development

Elucidation of mechanisms whereby maternal immune tolerance to the semi-allogeneic fetus is established will yield important insight for development of novel preventative and therapeutic strategies to ensure healthy pregnancies. During pregnancy, progesterone has dramatic effects on the maternal thymus, the location wherein all T cells develop. Using a newly developed murine model, we have found that progesterone action in the thymus is required for optimal pregnancy outcome. Further, we found that the thymus responds early in pregnancy, during the time at which maternal tolerance to the fetus is established. Since the thymus is critical for generating regulatory T cells, which are key for successful pregnancy, our data lead us to hypothesize that pregnancy induces early changes to promote generation of thymus-derived regulatory T cells that in turn confer maternal-fetal tolerance. To address this postulate, we use our novel in vivo model to test the role of progesterone and pregnancy on thymic function and maternal-fetal tolerance in two Specific Aims: AIM 1. Determine the effects of pregnancy and PR in thymic epithelial cells on the dynamics of regulatory T cell production by the thymus. AIM 2. Determine the role of PR in thymic epithelial cells on fetal survival in allogeneic pregnancies and on functionality of TReg in pregnancy. The studies proposed here will overcome our limited understanding of a long-documented, but poorly understood phenomenon in pregnancy. Further, elucidation of the mechanisms of maternal-fetal tolerance, including the role of steroid hormones, have implications extending well beyond pregnancy, and will help to lay foundations for new ways to target and kill cancer cells, improve transplantation outcome, bolster the aging immune system, and prevent autoimmune disease.

阐明母体对半同种异体胎儿免疫耐受的机制将为开发新的预防和治疗策略以确保健康妊娠提供重要的见解。怀孕期间，黄体酮对母体胸腺（所有 T 细胞发育的场所）具有显着影响。使用新开发的小鼠模型，我们发现胸腺中的黄体酮作用是最佳妊娠结局所必需的。此外，我们发现胸腺在怀孕早期即母亲对胎儿的耐受性建立期间就会做出反应。由于胸腺对于生成调节性 T 细胞至关重要，而调节性 T 细胞是成功妊娠的关键，因此我们的数据使我们推测妊娠会诱导早期变化，促进胸腺衍生的调节性 T 细胞的生成，从而赋予母胎耐受性。为了解决这个假设，我们使用我们的新型体内模型来测试孕酮和妊娠对胸腺功能和母胎耐受性的作用，有两个具体目标：AIM 1.确定胸腺上皮细胞中妊娠和 PR 对胸腺产生调节性 T 细胞动态的影响。目的 2. 确定胸腺上皮细胞中 PR 对同种异体妊娠中胎儿存活和妊娠中 TReg 功能的作用。这里提出的研究将克服我们对怀孕中长期记录但知之甚少的现象的有限理解。此外，阐明母胎耐受机制，包括类固醇激素的作用，其影响远远超出怀孕范围，并将有助于为靶向和杀死癌细胞、改善移植结果、增强衰老免疫系统和预防自身免疫性疾病的新方法奠定基础。