Immunological identity redefined by genetically foreign microchimeric cells

外源微嵌合细胞重新定义免疫学特性

• 批准号: 9756134
• 负责人: Sing Sing Way
• 金额: $ 109.2万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9756134
• 关键词: Animal Model; Animals; Antigens; Autoimmunity; Automobile Driving; Award; Cells; Cellular biology; Cessation of life; Child; Chromosomes; Data; Development; Discipline; Equilibrium; Exposure to; Fetus; Genetic; Genetic Heterogeneity; Genetic Variation; Goals; Heterogeneity; Human; Immune; Immune System Diseases; Immune Tolerance; Immunization; Immunologics; Immunology; Immunosuppression; Inbreeding; Individual; Infant Health; Infection; Inherited; Laboratories; Masks; Modeling; Molecular; Morbidity - disease rate; Mothers; Nature; Partner in relationship; Pathogenesis; Plant Roots; Population; Pregnancy; Pregnancy Complications; Premature Infant; Regulatory Pathway; Reproduction; Research; Textiles; Tissues; Transplantation; Tumor Immunity; United States National Institutes of Health; Work; exposed human population; fetal; improved; in utero; individual variation; innovation; insight; novel therapeutic intervention; offspring; prenatal; preservation; public health relevance; reproductive; tool; tumor immunology; vaccinology

Abstract. Engrained in the conceptual fabric of how interrelated immunological disciplines including autoimmunity, transplantation, tumor immunology and vaccinology are currently viewed is the classical tenet of binary “self” versus “non-self” antigen distinction. However, reliance on genetically homogenous inbred animals in establishing these immunological principles precludes their applicability to individuals in natural outbred populations that ubiquitously encounter genetically foreign antigens during development and reproduction. For example in humans, exposure to genetically foreign maternal tissue beginning in utero consistently primes in offspring tolerance to immunologically discordant non-inherited maternal antigens. Reciprocally, long-lasting tolerance to genetically foreign fetal chimeric cells that express discordant paternal antigens is retained in mothers after pregnancy. These human observations highlight potent immune regulatory pathways engrained within mammalian reproduction that are efficiently masked when developmental and hereditary genetic diversity is artificially eliminated. Therefore, restoring genetic and antigen heterogeneity amongst homologous chromosomes within individuals, and between individuals for mating has exciting potential to unveil fundamental new insights on the pathogenesis of autoimmunity, and new strategies for therapeutically fine- tuning the balance between immune stimulation and suppression. The long-term goal of my research is improved health for infants and children that suffer unduly from communicable infection. Considering infants born prematurely are especially vulnerable to death or long-term morbidity, my laboratory has uniquely re- focused many leading edge tools to investigate maternal-fetal immunological tolerance and the immune- pathogenesis of pregnancy complications triggered by prenatal infection. Central to our approach has been development of innovative reproductive models that recapitulate genetic heterogeneity between individuals, and heterogeneity amongst homologous chromosomes within individuals, naturally encountered in humans and other outbred populations. By probing depots of genetically foreign antigen encountered within the maternal-fetal gestational dyad needed for persistent bi-directional immunological tolerance, we recently identified the remarkable necessity for genetically foreign microchimeric cells in maintaining tolerance in each developmental context. These newly established reproductive benefits demonstrating nature's intent in preserving bi-directional transfer of cells between mother and fetus during pregnancy, and long-term retention of these genetically foreign microchimeric cells in both mother and offspring, pivotally transforms chimeric cells from a curious scientific phenomena to invaluable tools for illuminating how immunological tolerance naturally works. Accordingly, support from the NIH Pioneer Award would be used to launch my laboratory in the new scientific direction investigating the fundamental immunology and molecular cell biology of microchimeric cells.

抽象的。根植于相互关联的免疫学学科的概念结构，包括 自身免疫、移植、肿瘤免疫学和疫苗学目前被认为是 二元“自我”与“非我”抗原的区别。然而，对基因同源近亲交配动物的依赖 在建立这些免疫学原理时，排除了它们对自然近交种个体的适用性 在发育和繁殖过程中普遍遇到外来基因抗原的种群。为 例如，在人类中，从子宫开始接触遗传外来母体组织的情况一直是 子代对免疫不一致的非遗传母体抗原的耐受性。互惠，持久 对表达不一致父系抗原的外来胎儿嵌合细胞的耐受性保留在 怀孕后的母亲。这些人类观察突显了强大的免疫调节途径 在哺乳动物的繁殖中，当发育和遗传遗传时被有效地掩盖 多样性被人为地消除了。因此，恢复同源基因和抗原的异质性 个体内部和个体之间的染色体交配具有令人兴奋的潜力来揭开 对自身免疫发病机制的基本新见解，以及治疗精细的新策略- 调整免疫刺激和免疫抑制之间的平衡。我研究的长期目标是 改善患有过度传染性感染的婴儿和儿童的健康。考虑到婴儿 早产儿特别容易死亡或长期患病，我的实验室有独一无二的 集中了许多前沿工具来研究母婴免疫耐受和免疫- 产前感染引发妊娠并发症的发病机制。我们方法的核心是 开发创新的生殖模式，概括个体之间的遗传异质性， 以及个体内同源染色体之间的异质性，这在人类中是自然存在的 和其他异种繁殖的种群。通过探测在日本境内遇到的外来基因抗原库 持续双向免疫耐受所需的母婴妊娠二联体，我们最近 明确了基因外源微嵌合体细胞在维持每个细胞的耐受性方面的显著必要性 发展背景。这些新确立的生殖益处表明了大自然在 妊娠期母婴间细胞双向移植的保存和长期保留 在母亲和子代中这些遗传上外来的微嵌合体细胞中，关键是转化嵌合细胞 从一种奇特的科学现象到无价的工具，用来阐明免疫耐受是如何自然地 行得通。因此，NIH先锋奖的支持将用于在新的 研究微嵌合细胞的基础免疫学和分子细胞生物学的科学方向。