Maternal Microchimerism and Neonatal Tolerance

母体微嵌合和新生儿耐受性

• 批准号: 8070828
• 负责人: William J Burlingham
• 金额: $ 1.01万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2011-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8070828
• 关键词: Adult; Alloantigen; Anti-Inflammatory Agents; Anti-inflammatory; Antigens; Area; Autoantigens; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Back; Backcrossings; Blood; Breast Feeding; Breeding; Cardiac Myosins; Cell Lineage; Cells; Chronic; Dendritic Cells; Development; Effector Cell; Equilibrium; Exhibits; Exposure to; Fetal Development; Fetus; Goals; Graft Rejection; Haplotypes; Health; Heart Transplantation; Hematopoietic; Human Milk; IL2RA gene; Immune; Immune response; Immunity; Immunology; Individual; Inherited; Interleukin-10; Interleukin-2; Kinetics; Major Histocompatibility Complex; Maternal Exposure; Membrane; Microchimerism; Minor; Modeling; Mothers; Mouse Strains; Mus; NIMA; Neonatal; Nomads; Oral; Pathway interactions; Phase; Phenotype; Predisposition; Pregnancy; Pregnant Uterus; Regulatory T-Lymphocyte; Residual state; Resistance; Role; Site; Stem cells; T-Lymphocyte; Testing; Tissues; Transplantation; Work; fetal; fetus cell; heart allograft; insight; migration; neonate; offspring; peripheral tolerance; response

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.

描述（由申请人提供）：怀孕子宫是免疫特权部位。尽管主要的组织相容性复合体（MHC）和轻微的H差异，母体对胎儿的排斥是罕见的，而后代对迁移的母体细胞的接受是常见的。我们最近在小鼠中发现了母体抗原暴露的强烈新生儿耐受效应。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100天，无慢性排斥反应。本研究的目标是验证母体微嵌合的假设，即母体干细胞经胎盘迁移引起的母体微嵌合，并通过新生儿口服暴露于母体抗原而维持，诱导异体耐受性，同时增强自身抗原特异性耐受性。这一假设将通过三个特定目的来验证：1)我们将在F1回交育种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)我们将研究小鼠F1回交育种模型的品系差异，这些模型对携带非遗传性母源抗原的同种异体心脏移植物表现出耐受或排斥；特别是我们将分析母体造血微嵌合在维持新生儿诱导的耐受性或成人的致敏性中的作用，实质的程度！细胞微嵌合及其与后代树突状细胞相关的细胞膜转移的作用3)我们将通过验证母体微嵌合诱导T调节细胞抑制易感小鼠对心肌球蛋白自身免疫的假设，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。摘要：我们相信，如果成功，这一建议将推进我们对新生儿对母体抗原耐受机制的理解，这一领域对母婴健康具有重要意义，特别是对自身免疫性疾病易感个体。它还将为移植免疫学的“圣杯”——同种异体耐受性领域提供基本的新见解。