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.

项目总结