Maternal Microchimerism and Neonatal Tolerance

描述(由申请人提供)：怀孕的子宫是一个免疫特权部位。尽管主要组织相容性复合体(MHC)和微小的H差异，母亲对胎儿的排斥是罕见的，而后代接受迁移的母体细胞是常见的。我们最近在小鼠身上显示了母体抗原暴露对新生儿的强烈耐受作用。这种需要孕期和哺乳期暴露的效果，导致40%-50%的受者接受母体抗原+同种异体心脏移植100天，没有慢性排斥反应。这项拟议工作的目标将是检验一种假设，即母体干细胞通过胎盘迁移并通过新生儿口服母体抗原维持的母体微嵌合，在增强自身抗原特异性耐受的同时，诱导同种异体耐受。这一假说将通过三个具体目标来验证：1)我们将在F1回交模型中确定母体暴露对母体抗原特异性T调节细胞和T效应细胞的发育和表型的影响，从而导致对母体抗原的移植耐受；2)我们将检查携带非遗传母体抗原的同种异体心脏移植耐受或排斥的小鼠回交模型中的品系差异；特别是我们将分析母体造血微嵌合在维持新生儿诱导的成人耐受或致敏中的作用，实质组织的程度！细胞微嵌合，以及与子代树突状细胞相关的细胞间膜转移的作用；以及3)我们将通过检验母体微嵌合诱导T调节细胞抑制对心肌肌球蛋白自身免疫的易感小鼠品系的假设，来研究长期存活的母体抗原+同种异体心脏移植对慢性排斥反应的特殊抵抗力。摘要：我们相信，如果成功，这一建议将促进我们对新生儿对母体抗原的耐受机制(S)的理解，这一领域对母婴健康，特别是对自身免疫性疾病易感人群具有重要意义。它还将在移植免疫学的“圣杯”--同种异体耐受领域提供基本的新见解。

DESCRIPTION (provided by applicant): The pregnant uterus is an immunologically privileged site. Despite major histocompatibility complex (MHC) and minor H differences, rejection of the fetus by mother is rare and acceptance of migrant maternal cells by the offspring is common. We recently showed a strong neonatal tolerance effect of maternal antigen exposure in mice. This effect, which required both gestation and lactation-phase exposure, resulted in acceptance of maternal antigen + heart allograft for >100 days in 40-50% of recipients, without chronic rejection. The goal of the proposed work will be to test the hypothesis that maternal microchimerism arising by transplacental migration of maternal stem cells and sustained by oral exposure to maternal antigens in the neonate, induces allotolerance while reinforcing self antigen-specific tolerance. This hypothesis will be tested by means of three specific aims: 1) We will determine the influence of maternal exposure upon the development and phenotype of maternal antigen specific T regulatory and T effector cells in an F1 backcross breeding model that results in transplant tolerance to maternal antigens; 2) We will examine the strain differences in mouse F1 back-cross breeding models that exhibit either tolerance or rejection of heart allografts carrying the non-inherited maternal antigens; in particular we will analyze the role of maternal hematopoeitic microchimerism in sustaining neonatally induced tolerance or sensitization in the adult, the extent of parenchyma! cell microchimerism, and the role of intercellular membrane transfer associated with dendritic cells of the offspring; and 3) We will investigate the peculiar resistance of the long-term surviving, maternal antigen + heart allograft to chronic rejection by testing the hypothesis that maternal microchimerism induces T regulatory cells that can suppress autoimmunity to cardiac myosin in susceptible mouse strains. SUMMARY: We believe that if successful, this proposal will advance our understanding of the mechanism(s) of neonatal tolerance to maternal antigens, an area of great significance for the health of mother and baby, especially in autoimmune disease-susceptible individuals. It will also provide fundamental new insights in the field of allo-tolerance, the "holy grail" of transplant immunology.