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（由申请人提供）：这项研究的总体目标是了解孕妇免疫耐受性在怀孕中的机制。母体免疫系统与胎儿同种异体移植之间的亲密关系是一种无与伦比的生理状况，其中首次将抗原独特的，组织特异性蛋白引入母亲免疫系统，并在妊娠期间。 AIRE基因编码转录调节剂，该调节剂在胸腺中诱导组织特异性基因的表达，从而确保对这些抗原的耐受性在发展胸腺细胞中。本文提出的研究探讨了胸腺表达这些抗原的新假设，而这种表达是由AIRE介导的，对于对胎儿的免疫耐受性是必要的。该项目的具体目的是：1。确定胎儿和/或胎盘是否是AIRE缺陷小鼠的产妇免疫的靶标。 2。检查人和鼠胸腺中与妊娠相关抗原的发育调控。很少有研究直接解决了胸腺在母亲宽容中的作用 - 考虑到该器官在耐受性抗原中的众所周知的作用，我们所知的一个令人惊讶的差距。因此，此处概述的实验将对产妇耐受性和自身免疫性疾病的机制产生突破性的见解，而反过来，将出现对免疫介导疾病的治疗干预的新含义。公共卫生相关性：许多医疗情况是由于对抗原的不当免疫耐受性，例如与癌细胞相关的免疫耐受性，或者是免疫不耐受的抗原，例如怀孕失败，自身免疫性疾病和对移植组织的抑制。怀孕代表了外国“移植物”与母体免疫系统之间共存的完美平衡，该系统适应促进胎儿的生长而不是拒绝胎儿的生长。了解围绕这种独特生理状况的事件将深入了解不育症，癌症和自身免疫性疾病。