Endocrine regulation of maternal immunity in pregnancy

阐明母体对半同种异体胎儿的免疫耐受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。在怀孕期间，孕酮对母体胸腺有显著的影响，胸腺是所有T细胞发育的地方。使用新开发的小鼠模型，我们发现胸腺中的黄体酮作用是获得最佳妊娠结果所必需的。此外，我们还发现胸腺在妊娠早期即母体对胎儿耐受性建立期间有反应。由于胸腺对于产生调节性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假设妊娠诱导早期变化以促进胸腺衍生的调节性T细胞的产生，从而赋予母胎耐受性。为了解决这一假设，我们使用我们的新的体内模型来测试孕激素和妊娠对胸腺功能和母胎耐受的作用，在两个特定的目的：AIM 1。确定妊娠和胸腺上皮细胞PR对胸腺产生调节性T细胞动力学的影响。AIM 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长期记录但知之甚少的怀孕现象的有限理解。此外，对母胎耐受机制的阐明，包括类固醇激素的作用，具有远远超出妊娠的影响，并将有助于为靶向和杀死癌细胞的新方法奠定基础，改善移植结果，支持衰老的免疫系统，并预防自身免疫性疾病。

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.