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: 9339521
• 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/9339521
• 关键词: Alpha Cell; 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; innovation; insight; novel therapeutic intervention; offspring; prenatal; 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.

摘要：免疫学学科如何相互关联的概念结构根深蒂固，包括 自身免疫学、移植学、肿瘤免疫学和疫苗学目前被认为是经典的原则 然而，“自身”与“非自身”抗原的二元区别依赖于遗传同质的近交动物。 在建立这些免疫学原理时，排除了它们对自然近交个体的适用性 在发育和繁殖过程中普遍遇到遗传外来抗原的群体。 例如，在人类中，从子宫初期就开始接触遗传性外源母体组织 后代对免疫不一致的非遗传性母体抗原的耐受性是相互的、持久的。 对表达不一致父本抗原的遗传外来胎儿嵌合细胞的耐受性保留在 这些人类观察结果凸显了怀孕后的母亲们根深蒂固的有效免疫调节途径。 在哺乳动物的生殖过程中，当发育和遗传遗传时，它们被有效地掩盖 因此，多样性被人为消除，从而在同源性中恢复遗传和抗原异质性。 个体内部和个体之间用于交配的染色体具有令人兴奋的潜力 关于自身免疫发病机制的基本新见解，以及精细治疗的新策略 调整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。 早产儿特别容易死亡或长期发病，我的实验室有独特的研究 集中了许多前沿工具来研究母胎免疫耐受和免疫- 产前感染引发的妊娠并发症的发病机制是我们方法的核心。 开发创新的生殖模型，概括个体之间的遗传异质性， 以及人类自然遇到的个体内同源染色体之间的异质性 和其他近亲繁殖群体中通过探测基因外来抗原的库。 持续双向免疫耐受所需的母胎妊娠二元体，我们最近 确定了遗传外源微嵌合细胞在维持每种细胞的耐受性方面的显着必要性 这些新确立的生殖益处表明了自然的意图。 保留妊娠期间母体和胎儿之间细胞的双向转移并长期保留 这些遗传外源微嵌合细胞在母亲和后代中的作用，关键性地转化了嵌合细胞 从一种奇怪的科学现象到阐明免疫耐受如何自然发生的宝贵工具 因此，美国国立卫生研究院先锋奖的支持将用于在新的实验室中启动我的实验室。 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。