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

基本信息

批准号：
10216241
负责人：
Ryan B Sartor
金额：
$ 35.56万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
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/10216241
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&apos 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&apos 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

项目摘要

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 博士融合了他在宿主-微生物相互作用和抗生素使用方面国际公认的专业知识与基因组科学领域的尖端专家高度互补的小鼠（Shehzad Sheik、Terry Furey）；分子微生物学和生物信息学（Anthony Fodor、Jeremiah Faith、Niels van der Lelie）；（Kun Lu）；临床结果的分子预测因素（Ted Denson，Rebekah Karns）以及相当大的影响核心 A 和 B 的资源，以确定优先保护性常驻细菌物种的关键成员在新型限生素和人源化慢性慢性病模型中诱导 IL-10 相关的保护性免疫反应实验性结肠炎并预测已建立的克罗恩病（CD）患者队列的临床结果。假设：常驻肠道细菌亚群可激活与 IL10 相关的保护性免疫反应 LP 调节 B 和 T 淋巴细胞以及介导粘膜稳态和预测疾病的代谢物我们通过 3 个互补的目标来解决这一假设：目标 1：识别选择性诱导产生 IL10 的调节性 LP B 和 T 的常驻细菌种类细胞并预防实验性结肠炎（由核心 A 支持）。假设：常驻细菌亚群选择性地激活 LP B 和 T 细胞及代谢产生 IL10 介导粘膜稳态的细菌菌株可以预防和逆转慢性结肠炎。目标 2. 确定能够逆转已形成的结肠炎的细菌物种的保护机制假设：关键的保护性细菌种类激活免疫和代谢途径，直接抑制 TH1/17 免疫反应和致病菌亚群，以预防和逆转慢性结肠炎。 2A. 鉴定保护性细菌菌株的代谢谱并测试其保护功能。 2B.确定保护性菌株使管腔和粘膜失调细菌谱正常化的能力。 2C. 鉴定保护性细菌菌株在 IL10+ LP T 和 B 细胞中诱导的保护性免疫途径。目标 3. 确定保护性细菌种类和 LP 细胞转录特征是否可以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种类和 IL10 相关转录途径为确定的 CD 患者群体提供疾病进展和并发症的新预测因子。这项高度创新且具有临床相关性的研究将对免疫学、代谢和免疫学产生独特的见解。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，并最终确定新的治疗细菌种类的特征。