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。在概念结构中，相互关联的免疫学学科，包括 自身免疫，移植，肿瘤免疫学和疫苗学目前被认为是经典的原则， 二元“自身”与“非自身”抗原的区别。然而，依赖于基因同质的近亲繁殖动物， 在建立这些免疫学原理时，排除了它们对自然远系繁殖的个体的适用性。 在发育和繁殖过程中普遍遇到遗传外源抗原的群体。为 例如，在人类中，从子宫内开始暴露于遗传学上的外来母体组织， 后代对免疫学上不一致的非遗传性母体抗原的耐受性。互惠互利，持久 对表达不一致父本抗原的遗传外源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结果突出了强有力的免疫调节途径， 在哺乳动物生殖中，当发育和遗传遗传时， 多样性被人为地消除了。因此，恢复同源基因之间的遗传和抗原异质性， 个体内和个体间的染色体进行交配， 关于自身免疫发病机制的基本新见解，以及治疗精细化的新策略， 调节免疫刺激和抑制之间的平衡。我研究的长期目标是 改善过度遭受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发病，我的实验室有独特的重新， 集中了许多前沿工具来研究母胎免疫耐受和免疫- 产前感染引发妊娠并发症的发病机制。我们方法的核心是 发展创新的生殖模式，概括个体之间的遗传异质性， 和人类中自然遇到的个体内同源染色体之间的异质性 和其他远系繁殖的种群通过探测在细胞内遇到的遗传性外来抗原的仓库， 持续的双向免疫耐受所需的母胎妊娠二联体，我们最近 确定了遗传外源微嵌合细胞在维持每种免疫耐受性中的显着必要性。 发展背景。这些新建立的生殖优势表明了大自然的意图， 在怀孕期间保持母胎之间的细胞双向转移，并长期保留 在母体和后代中，这些基因外源的微嵌合细胞， 从一个奇怪的科学现象到阐明免疫耐受性如何自然发生的宝贵工具， 工程.因此，NIH先锋奖的支持将用于在新的环境中启动我的实验室。 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。