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状况，在怀孕开始和怀孕期间，抗原特异性独特的组织特异性蛋白质首次被引入母体免疫系统。Aire基因编码一种转录调节因子，诱导胸腺组织特异性基因表达，从而确保胸腺细胞对这些抗原的耐受性。本文提出的研究探索了一种新的假设，即胸腺表达这些抗原，并且这种由Aire介导的表达对于胎儿的免疫耐受是必要的。本项目的具体目标是：1。确定Aire缺陷小鼠的胎儿和/或胎盘是否是母体免疫的目标。2. 研究人类和小鼠胸腺中妊娠相关抗原的发育调节。很少有研究直接涉及胸腺在母胎耐受中的作用——考虑到这个器官在对自身抗原的耐受中众所周知的作用，这是我们知识中的一个令人惊讶的空白。因此，本文概述的实验将对母胎耐受性和自身免疫性疾病的机制产生突破性的见解，反过来，对免疫介导性疾病的治疗干预也将产生新的影响。

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.