Induction of protective IL-10- producing B and T cells by defined subsets of resident intestinal bacteria

通过特定的肠道细菌亚群诱导产生保护性 IL-10 的 B 和 T 细胞

• 批准号: 10447742
• 负责人: Ryan B Sartor
• 金额: $ 33.04万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-19 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10447742
• 关键词: Address; Adult; Antigen-Presenting Cells; Archives; B-Lymphocytes; Bacteria; Bacterial Antigens; Bile Acids; Bioinformatics; Biopsy; CD4 Positive T Lymphocytes; Cell Communication; Cells; Chronic; Clinical; Clostridium; Colitis; Collection; Crohn' s disease; Data; Disease; Disease Progression; Enteral; Enterobacteriaceae; Epithelial; Equilibrium; Excision; FOXP3 gene; Feces; Fusobacteria; Gene Expression Profile; Genes; Genetic Transcription; Germ-Free; Gnotobiotic; Goals; Histamine; Homeostasis; Human; Immune; Immune response; Immunologics; Individual; Inflammation; Interferons; Interleukin-10; International; Intestines; Lamina Propria; Mediating; Metabolic; Metabolic Pathway; Microbiology; Modeling; Molecular; Mucous Membrane; Mus; Operative Surgical Procedures; Pathogenicity; Pathway interactions; Patients; Pediatric Crohn' s disease; Phenotype; Postoperative Period; Production; Proteobacteria; Recurrence; Regulatory T-Lymphocyte; Reporter; Resected; Resources; Risk; Signal Pathway; T cell response; T-Lymphocyte; TNFRSF11B gene; Testing; Tissues; Transplantation; Ulcerative Colitis; Volatile Fatty Acids; bacterial community; clinical predictors; clinically relevant; cohort; disorder risk; dysbiosis; genome sciences; germ free condition; host-microbe interactions; humanized mouse; in vivo; individualized medicine; innovation; insight; member; metabolomics; microbial; mouse model; novel; novel therapeutics; pathogenic bacteria; pediatric patients; predict clinical outcome; predictive signature; prevent; prospective; rRNA Genes; transcriptome sequencing

Dr. Sartor blends his internationally recognized expertise in host-microbial interactions and use of gnotobiotic mice with highly complementary cutting-edge experts in genome science (Shehzad Sheik, Terry Furey); molecular microbiology and bioinformatics (Anthony Fodor, Jeremiah Faith, Niels van der Lelie); metabolomics (Kun Lu); molecular predictors of clinical outcomes (Ted Denson, Rebekah Karns) and the considerable resources of Cores A and B to identify key members of protective resident bacterial species that preferentially induce IL-10-associated protective immune responses in novel gnotobiotic and humanized models of chronic experimental colitis and predict clinical outcomes in established cohorts of Crohn’s disease (CD) patients. Hypothesis: Subsets of resident intestinal bacteria activate protective IL10- associated immune responses in LP regulatory B and T lymphocytes and metabolites that mediate mucosal homeostasis and predict disease progression and complications in CD patients. We address this hypothesis through 3 complementary Aims: Aim 1: Identify resident bacterial species that selectively induce IL10- producing regulatory LP B and T cells and protect against experimental colitis (supported by Core A). Hypothesis: Subsets of resident bacteria selectively activate IL10-production by LP B and T cells and metabo- lites that mediate mucosal homeostasis. Identified bacterial strains will prevent and reverse chronic exp. colitis. Aim 2. Identify mechanisms of protection of bacterial species capable of reversing established colitis Hypothesis: Key protective bacterial species activate immunological and metabolic pathways that directly suppress TH1/17 immune responses and pathogenic bacterial subsets to prevent and reverse chronic colitis. 2A. Identify metabolite profiles of protective bacterial strains and test their protective function. 2B. Determine the ability of protective strains to normalize luminal and mucosal dysbiotic bacterial profiles. 2C. Identify protective immunologic pathways induced in IL10+ LP T and B cells by protective bacterial strains. Aim 3. Determine whether protective bacterial species and LP cell transcriptional signatures predict disease progression and post-operative recurrence in phenotyped adult and pediatric CD cohorts. Hypothesis: Protective bacterial species and IL10-associated transcriptional pathways identified in mice provide novel predictors of disease progression and complications in defined CD patient cohorts. This highly innovative and clinically relevant study will yield unique insights into immunologic, metabolic and microbial mechanisms by which resident bacterial subsets mediate mucosal and microbial homeostasis, predict clinical CD progression, complications and ultimately, characterize novel therapeutic bacterial species.

Sartor博士将他在宿主-微生物相互作用和使用gnotobiotic 小鼠与基因组科学的尖端专家（Shehzad Sheik，Terry Furey）高度互补; 分子微生物学和生物信息学（Anthony Fodor，Jeremiah Faith，Niels货车der Lelie）;代谢组学 (Kun Lu）;临床结果的分子预测因子（Ted Denson，Rebekah Karns）和相当大的 核心A和B的资源，以确定保护性常驻细菌物种的关键成员， 在新型非特异性和人源化慢性炎症模型中诱导IL-10相关保护性免疫应答 实验性结肠炎，并预测克罗恩病（CD）患者的临床结局。 假设：肠道常驻细菌亚群激活保护性IL 10相关免疫应答， 介导粘膜稳态和预测疾病的LP调节性B和T淋巴细胞及其代谢物 CD患者的进展和并发症。我们通过三个互补的目标来解决这个假设： 目的1：鉴定选择性诱导产生IL 10的调节性LP B和T的常驻细菌物种 细胞和保护免受实验性结肠炎（由核心A支持）。 假设：常驻细菌的亚群选择性地激活LP B和T细胞的IL 10产生，并代谢IL 10。 介导粘膜内环境稳定的炎症。确定的细菌菌株将预防和逆转慢性感染。结肠炎 目标二。确定能够逆转既定结肠炎的细菌菌种的保护机制 假设：关键的保护性细菌物种激活免疫和代谢途径， 抑制TH 1/17免疫应答和致病细菌亚群以预防和逆转慢性结肠炎。 2A.鉴定保护性菌株的代谢产物谱并测试其保护功能。 2B.确定保护性菌株使管腔和粘膜生态失调细菌谱正常化的能力。 2C.鉴定保护性细菌菌株在IL 10 + LP T和B细胞中诱导的保护性免疫途径。 目标3.确定保护性细菌物种和LP细胞转录特征是否预测 表型成人和儿童CD队列中的疾病进展和术后复发。 假设：在小鼠中鉴定出保护性细菌物种和IL 10相关转录途径 在确定的CD患者队列中提供疾病进展和并发症的新预测因子。 这项高度创新和临床相关的研究将产生独特的见解，免疫，代谢和 常驻细菌亚群介导粘膜和微生物稳态的微生物机制， 预测临床CD进展、并发症，并最终表征新型治疗细菌菌种。