Maternal Central Immune Tolerance to the Fetal-Placental Unit

描述（由申请人提供）：本研究的总体目标是了解妊娠期母体对胎儿免疫耐受的机制。母体免疫系统和胎儿同种异体移植物之间的亲密关系是一种无与伦比的生理情况，其中抗原性独特的组织特异性蛋白质在妊娠开始时和妊娠期间首次引入母体免疫系统。Aire基因编码转录调节因子，其诱导胸腺中的组织特异性基因表达，从而确保发育中的胸腺细胞对这些抗原的耐受性。本文提出的研究探讨了新的假设，即胸腺表达这些抗原，这种表达，作为Aire介导的，是必要的免疫耐受胎儿。该项目的具体目标是：1。确定胎儿和/或胎盘是否是Aire缺陷小鼠母体免疫的靶点。2.检查人类和小鼠胸腺中妊娠相关抗原的发育调节。很少有研究直接讨论了胸腺在母胎耐受中的作用-考虑到该器官在对自身抗原耐受中的众所周知的作用，这在我们的知识中是一个令人惊讶的空白。因此，本文概述的实验将产生对母体-胎儿耐受性以及自身免疫性疾病的机制的突破性见解，并且反过来，将产生对免疫介导的疾病的治疗性干预的新含义。 公共卫生相关性：许多医疗情况产生于对抗原的不适当的免疫耐受，如与癌细胞相关的抗原，或不适当的免疫不耐受，如妊娠失败，自身免疫性疾病和移植组织排斥。怀孕代表着外来“移植物”和母体免疫系统之间完美的共存平衡，母体免疫系统会适应以促进胎儿的生长，而不是排斥胎儿。了解围绕这一独特生理情况的事件将有助于了解如何缓解不孕症、癌症和自身免疫性疾病。

DESCRIPTION (provided by applicant): The overall goal of this research is to understand the mechanisms of maternal immune tolerance to the fetus in pregnancy. The intimacy between the maternal immune system and the fetal allograft is an unparalleled physiological situation in which antigenically unique, tissue-specific proteins are introduced to the mothers immune system for the first time at the commencement and for the duration of pregnancy. The Aire gene encodes a transcriptional regulator that induces tissue-specific gene expression in the thymus, such that tolerance to these antigens is ensured in developing thymocytes. The studies proposed herein explore the novel hypothesis that the thymus expresses these antigens, and that this expression, as mediated by Aire, is necessary for immune tolerance to the fetus. The Specific Aims of this project are: 1. Determine whether the fetus and/or placenta are targets of maternal immunity in Aire- deficient mice. 2. Examine the developmental regulation of gestation-associated antigens in the human and murine thymus. Few studies have directly addressed the role of the thymus in maternal-fetal tolerance - a surprising gap in our knowledge, considering the well known role of this organ in tolerance to self antigens. The experiments outlined here will thus yield ground-breaking insights into the mechanisms of maternal- fetal tolerance as well as autoimmune disease, and in turn, new implications for therapeutic intervention of immune-mediated disease will arise. PUBLIC HEALTH RELEVANCE: Numerous medical situations arise from either inappropriate immune tolerance to antigens, such as those associated with cancer cells, or inappropriate immune intolerance, such as that of failed pregnancy, autoimmune disease, and rejection of transplanted tissue. Pregnancy represents a perfect balance of coexistence between a foreign "graft" and the maternal immune system, which adapts to promote the growth of the fetus rather than reject it. Understanding the events surrounding this unique physiological situation will yield insight on how infertility, cancer and autoimmune disease may be alleviated.