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：
10642799
负责人：
Ryan B Sartor
金额：
$ 30.33万
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/10642799
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 Colon Crohn&apos s disease Data Disease Progression Enteral Enterobacteriaceae Epithelium Excision FOXP3 gene Faith Feces Fusobacteria Gene Expression Profile Genes Genetic Transcription Germ-Free Gnotobiotic Goals Histamine Homeostasis Human Immune Immune response Immunologics Individual Inflammation 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 Recurrent disease 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 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博士融合了他的国际认可的宿主互动中的专业知识和使用Gnotobiotic 具有高度完善的基因组科学专家（Shehzad Sheik，Terry Furey）的老鼠；分子微生物学和生物信息学（Anthony Fodor，Jeremiah Faith，Niels van der Lelie）；代谢组学（kun lu）;临床结局的分子预测指标（Ted Denson，Rebekah Karns）和考虑因素核心A和B的资源，以识别受保护居民细菌的主要成员，优先在新型的gnotobiotic和人性化模型中诱导IL-10相关的受保护免疫反应实验性结肠炎并预测既定的克罗恩病（CD）患者的临床结果。假设：居民肠道细菌的子集激活受保护的IL10-相关免疫复杂 LP调节B和T淋巴细胞和T淋巴细胞和代谢物，可介导粘膜稳态并预测疾病 CD患者的进展和并发症。我们通过3个完整的目标解决了这一假设： AIM 1：确定居民的细菌种类，有选择地影响IL10-产生调节性LP B和T 细胞并预防实验性结肠炎（由核心A支持）。假设：居民细菌的子集选择性地激活LP B和T细胞的IL10生产以及代谢介导粘膜稳态的精英。鉴定的细菌菌株将预防和反向慢性exp。结肠炎。目标2。确定能够逆转已建立结肠炎的细菌物种保护的机制假设：关键保护细菌种类激活直接的免疫学和代谢途径抑制TH1/17免疫反应和致病细菌亚群，以预防和逆转慢性结肠炎。 2a。鉴定受保护细菌菌株的代谢产物特征并测试其受保护功能。 2b。确定保护菌株使腔和粘膜失调细菌概况归一化的能力。 2C。通过保护性细菌菌株鉴定在IL10+ LP T和B细胞中诱导的受保护的免疫途径。目标3。确定受保护的细菌物种和LP细胞转录特征是否预测表型成人和小儿CD同龄人的疾病进展和术后复发。假设：在小鼠中鉴定出的保护性细菌和IL10相关的转录途径提供了定义的CD患者队列中疾病进展和并发症的新预测指标。这项高度创新和临床相关的研究将产生对免疫，代谢和居民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的进展，并发症和最终表征了新型治疗细菌。