Maternal Microchimerism and Neonatal Tolerance

描述（由申请人提供）：妊娠子宫是免疫豁免部位。尽管主要组织相容性复合体（MHC）和微小的H差异，胎儿排斥母亲是罕见的，并接受移民母体细胞的后代是常见的。我们最近在小鼠中显示了母体抗原暴露的强新生儿耐受效应。这种效应需要妊娠期和哺乳期暴露，导致40-50%的受体接受母体抗原+心脏移植物超过100天，没有慢性排斥反应。拟议的工作的目标将是测试的假设，母体微嵌合体所产生的经胎盘迁移的母体干细胞和持续的口服暴露于母体抗原的新生儿，诱导同种异体耐受，同时加强自身抗原特异性耐受。1）我们将确定母体暴露对F1回交育种模型中母体抗原特异性T调节细胞和T效应细胞的发育和表型的影响，该模型导致对母体抗原的移植耐受; 2）我们将研究小鼠F1回交育种模型中的品系差异，这些模型表现出对携带非遗传性母体抗原的心脏同种异体移植物的耐受或排斥;特别地，我们将分析母体造血微嵌合体在维持成人中母体诱导的耐受性或致敏性中的作用，实质的程度！细胞微嵌合体，以及与后代树突状细胞相关的细胞间膜转移的作用;和3）我们将通过测试母体微嵌合体诱导T调节细胞的假设来研究长期存活的母体抗原+心脏同种异体移植物对慢性排斥反应的特殊抗性，所述T调节细胞可以抑制易感小鼠品系中对心脏肌球蛋白的自身免疫。总结：我们相信，如果成功的话，这一提议将促进我们对新生儿对母体抗原耐受机制的理解，这是一个对母亲和婴儿健康具有重要意义的领域，特别是在自身免疫性疾病易感个体中。它还将在同种异体耐受性领域提供基本的新见解，这是移植免疫学的“圣杯”。

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.