Maternal Central Immune Tolerance to the Fetal-Placental Unit

母体对胎儿胎盘单位的中枢免疫耐受

基本信息

批准号：
8038448
负责人：
MARGARET G PETROFF
金额：
$ 18万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-05 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8038448
关键词：
Address Allografting Antibodies Antigens Apoptotic Autoantigens Autoimmune Diseases Autoimmune Process Cessation of life Child Development Discrimination Disease Ensure Equilibrium Event Exhibits Failure Female Fetal Viability Fetus Gene Expression Generations Genes Genetic Transcription Goals Growth Human Immune Immune Tolerance Immune response Immune system Immunity Immunocompetence Immunofluorescence Immunologic Infertility Knowledge Leukocytes Lymphocyte Malignant Neoplasms Mediating Medical Medicine Mothers Mus Mutation Organ Ovary Personal Satisfaction Physiological Placenta Pregnancy Process Proteins Regulation Regulator Genes Reporting Research Role Symptoms Syndrome T-Lymphocyte Therapeutic Intervention Thymic epithelial cell Thymus Gland Time Tissue-Specific Gene Expression Tissues Translating Transplanted tissue Uterus Woman cancer cell central tolerance congenic design fetal insight intimate behavior novel prevent public health relevance reproductive research study sex stem thymocyte

项目摘要

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.

描述（申请人提供）：本研究的总体目标是了解妊娠期母体对胎儿的免疫耐受机制。母体免疫系统和胎儿同种异体移植物之间的密切关系是一种无与伦比的生理状况，在这种情况下，抗原独特的组织特异性蛋白质在妊娠开始时和妊娠期间首次被引入母体免疫系统。 Aire 基因编码一种转录调节因子，可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。本文提出的研究探索了一个新的假设，即胸腺表达这些抗原，并且这种由艾尔介导的表达对于胎儿的免疫耐受是必需的。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目标。 2. 检查人类和小鼠胸腺中妊娠相关抗原的发育调节。很少有研究直接探讨胸腺在母胎耐受中的作用——考虑到胸腺在自身抗原耐受中的众所周知的作用，我们的知识存在令人惊讶的差距。因此，这里概述的实验将对母胎耐受和自身免疫性疾病的机制产生突破性的见解，反过来，也会对免疫介导疾病的治疗干预产生新的影响。公共卫生相关性：许多医疗状况都是由于对抗原的不适当的免疫耐受（例如与癌细胞相关的抗原）或不适当的免疫不耐受（例如妊娠失败、自身免疫性疾病和移植组织排斥）引起的。怀孕代表了外来“移植物”和母体免疫系统之间共存的完美平衡，母体免疫系统会适应促进胎儿的生长而不是排斥胎儿。了解围绕这种独特生理状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。