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.

项目摘要 1型糖尿病（T1 D）是一种自身免疫性疾病，影响全球数百万人。的发生率 T1 D正在上升，特别是在幼儿中。尽管在预测谁有风险方面已经取得了重大进展 对于发展T1 D，没有有效的治疗方法来预防这种疾病。遗传和环境 这些因素会增加T1 D的风险。某些主要组织相容性复合体/人白细胞 抗原（MHC/HLA）II类单倍型主要防止T1 D的发展，最近我们 发现保护性MHCII分子塑造了早期生命的微生物群落，反过来又影响了免疫系统。 预防T1 D的系统开发。在NOD小鼠中模拟T1 D的微生物保护可能提供关键的 这些见解支持我们开发基于微生物群的疗法以预防人类T1 D的长期目标。由于 肠道微生物组的复杂性和高度变异性，决定了特定的微生物 驱动免疫系统发育和功能的菌株是有问题的。无菌小鼠的研究进展 已经是该领域的一个重要进展，因为它们简化了 系统的复杂性和可变性，并允许良好控制的机制研究。然而，一种 缺乏研究儿科疾病的小鼠模型。我们开发了一种新的早期- 我们称之为儿科社区或“PedsCom”。PedsCom是一个由9种细菌组成的财团， 从断奶前糖尿病保护的Eα16/NOD小鼠的肠道中分离的菌株。值得注意的是，这9- 微生物群落强烈诱导调节性T细胞（TlD），并保护糖尿病患者免受T1 D的影响。 易感NOD小鼠。我们假设特定的PedsCom微生物协同工作以预防T1 D 通过提供微生物抗原和代谢物诱导外周调节性T细胞（pT细胞）， 免疫系统发育的关键早期窗口。目标1检查了时间、定位和 由特定PedsCom成员产生的代谢物，驱动pTreg细胞发育并防止 自身免疫目的2：研究PedsCom微生物诱导pTbR的机制及其对pTbR的影响。 蛋白质抗原以及TCR识别特异性微生物抗原的pTCRs是否介导了对 T1 D。这些目标的成功完成将提供关于早期微生物诱导的关键信息。 pT 3，以及微生物抗原和代谢物共同作用产生糖尿病的程度- 保护性免疫系统此外，PedsCom小鼠是研究早期生命宿主的创新工具， 微生物群的相互作用