Leveraging early-life events to promote tolerance to autoimmunity

利用生命早期事件促进对自身免疫的耐受

• 批准号: 10853727
• 负责人: Michael A Silverman
• 金额: $ 5.51万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10853727
• 关键词: Adult; Affect; Alleles; Anatomy; Antigen Presentation; Antigens; Autoantigens; Autoimmune Diabetes; Autoimmune Diseases; Autoimmunity; Bacteria; Birth; CD4 Positive T Lymphocytes; Cells; Child; Childhood; Communities; Complement; Complex; Data; Development; Diabetes Mellitus; Disease; Environmental Risk Factor; Event; Exposure to; Genetic; Genetic Models; Germ-Free; Gnotobiotic; Goals; Growth; HLA Antigens; Haplotypes; Histocompatibility Antigens Class II; Human; Immune; Immune response; Immune system; Immunization; In Vitro; Inbred NOD Mice; Incidence; Insulin-Dependent Diabetes Mellitus; Intestines; Investigation; Knowledge; Life; Major Histocompatibility Complex; Maps; Mediating; Metabolic; Microbe; Modeling; Mucous Membrane; Mus; Pathway interactions; Peptides; Peripheral; Persons; Phylogenetic Analysis; Predisposition; Property; Proteins; Publishing; Regulatory T-Lymphocyte; Research; Risk; Role; Shapes; Site; System; Systems Development; T cell receptor repertoire sequencing; T cell response; T-Lymphocyte; Testing; Therapeutic; Time; Transgenic Mice; Transgenic Organisms; Weaning; Work; diabetes pathogenesis; early life exposure; effective therapy; genetic linkage; gut microbiome; gut microbiota; host microbiota; immunoregulation; in vivo; innovation; insight; intestinal homeostasis; islet autoimmunity; mass spectrometric imaging; member; metabolomics; microbial; microbial community; microbial products; microbiome; microbiota; microorganism antigen; microorganism interaction; mouse model; prevent; protective effect; rational design; response; restraint; tool; transmission process; validation studies

PROJECT SUMMARY Type 1 diabetes (T1D) is an autoimmune disease that affects millions of people worldwide. The incidence of T1D is rising, especially in young children. Although significant progress has been made to predict who is at risk for developing T1D, there are no effective therapies to prevent this disease. Both genetic and environmental factors contribute to the risk of developing T1D. Certain major histocompatibility complex/human leukocyte antigen (MHC/HLA) class II haplotypes dominantly protect against the development of T1D, and we recently discovered that protective MHCII molecules shape early-life microbial communities which in turn impact immune system development to prevent T1D. Modeling microbial protection from T1D in NOD mice may provide critical insights to support our long-term goal of developing microbiota-based therapies to prevent T1D in humans. Due to the complexity and high levels of variability of the intestinal microbiome, determining the specific microbial strains that drive immune system development and function is problematic. The development of gnotobiotic mice with defined adult microbial communities has been an important advance in the field because they simplify the complexity and variability of the system and allow for well-controlled, mechanistic studies. However, a gnotobiotic mouse model to study pediatric disease is lacking. We developed a new gnotobiotic mouse model of the early- life microbiome which we call Pediatric Community or “PedsCom”. PedsCom is a consortium of 9 bacterial strains isolated from the intestine of pre-weaning diabetes-protected Eα16/NOD mice. Remarkably, this 9- microbe community robustly induces regulatory T cells (Tregs) and confers protection from T1D to diabetes- susceptible NOD mice. We hypothesize that specific PedsCom microbes work in concert to prevent T1D by providing microbial antigens and metabolites that induce peripheral regulatory T cells (pTregs) during a critical early life window of immune system development. Aim 1 examines the timing, localization, and metabolites produced by specific PedsCom members which drive pTreg cell development and prevent autoimmunity. Aim 2 examines the mechanisms by which pTregs are induced by PedsCom microbes and their protein antigens and whether pTregs whose TCRs recognize specific microbial antigens mediate protection from T1D. Successful completion of these aims will provide critical information on which early-life microbes induce pTregs, and the degree to which microbial antigens and metabolites work together to generate a diabetes- protective immune system. In addition, PedsCom mice are an innovative tool for investigating early-life host- microbiota interactions.

项目概要 1 型糖尿病 (T1D) 是一种影响全球数百万人的自身免疫性疾病。 尽管在预测哪些人面临风险方面已经取得了重大进展，但 T1D 的发病率正在上升，尤其是在幼儿中。 对于 T1D 的发生，目前尚无有效的疗法来预防这种疾病的遗传和环境因素。 某些主要组织相容性复合体/人类白细胞会导致发生 T1D 的风险。 抗原 (MHC/HLA) II 类单倍型主要预防 T1D 的发展，我们最近 发现保护性 MHCII 分子塑造了生命早期的微生物群落，进而影响免疫 预防 T1D 的系统开发对 NOD 小鼠的 T1D 微生物保护模型可能提供关键作用。 支持我们开发基于微生物群的疗法来预防人类 T1D 的长期目标。 根据肠道微生物组的复杂性和高度变异性，确定特定的微生物 驱动免疫系统发育和功能的菌株是有问题的。 确定成体微生物群落是该领域的一个重要进步，因为它们简化了 系统的复杂性和可变性，并允许进行良好控制的机械研究。 缺乏研究儿科疾病的小鼠模型，我们开发了一种新的早期无菌小鼠模型。 我们称之为儿科社区或“PedsCom”的生命微生物组是 9 种细菌的联合体。 值得注意的是，从断奶前糖尿病保护的 Eα16/NOD 小鼠的肠道中分离出的菌株。 微生物群落强有力地诱导调节性 T 细胞 (Treg) 并提供从 T1D 到糖尿病的保护 NOD 小鼠。我们勇敢地说，特定的 PedsCom 微生物可以协同作用来预防易感 T1D。 通过提供微生物抗原和代谢物来诱导外周调节性 T 细胞 (pTreg) 目标 1 检查免疫系统发育的关键早期生命窗口。 由特定 PedsCom 成员产生的代谢物可驱动 pTreg 细胞发育并预防 目标 2 检查 PedsCom 微生物及其诱导的 pTreg 的机制。 蛋白质抗原以及 TCR 识别特定微生物抗原的 pTreg 是否介导免受感染的保护 T1D 的成功完成将提供早期微生物诱导的关键信息。 pTregs，以及微生物抗原和代谢物共同作用产生糖尿病的程度- 此外，PedsCom 小鼠是研究早期宿主的创新工具。 微生物群相互作用。