Colitis induced by immune responses to luminal bacteria

对腔内细菌的免疫反应诱发结肠炎

基本信息

批准号：
7163032
负责人：
Ryan B Sartor
金额：
$ 27.42万
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：
1998
资助国家：
美国
起止时间：
1998-08-01 至 2008-09-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7163032
关键词：
Address Adjuvant Adoptive Transfer Antibiotics Antibodies Antigen Presentation Pathway Antigen-Presenting Cells Antigens Bacteria Bacterial Antigens Bacteroides Biology Bone Marrow Transplantation CD4 Positive T Lymphocytes Cell physiology Chronic Coculture Techniques Colitis Collaborations Contracts Crohn&apos s disease Data Dendritic Cells Development Disease Doctor of Medicine Down-Regulation Engineering Enteral Enterobacteriaceae Enterococcus faecalis Environment Environmental Risk Factor Etiology Exhibits Funding Genetic Genetic Predisposition to Disease Germ-Free Gnotobiotic Grant Helicobacter hepaticus Human Immune Tolerance Immune response Immunologics In Vitro Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Inflammatory disease of the intestine Interferons Interleukin-10 Interleukin-12 Interleukin-18 Interleukin-2 Kinetics Lactobacillus plantarum Left Lymphocyte Lymphocyte Activation Major Histocompatibility Complex Mediating Mediator of activation protein Mesentery Modeling Molecular Mus New Zealand North Carolina Organism Pathogenesis Phase Physiologic pulse Physiological Population Pulse taking Rattus Recombinants Relative (related person)Research Personnel Resistance Resources Rodent Rodent Model Role Side Specificity Sterility Stimulus T-Lymphocyte T-Lymphocyte Subsets Therapeutic Intervention Tin Toll-like receptors Transforming Growth Factors Transgenic Organisms Ulcerative Colitis Universities Veterinary Medicine Week Wild Type Mouse bacterial lysate cell mediated immune response clinically relevant college commensal microbes cytokine experience gallium alloy GF gastrointestinal germ free condition in vivo innovation insight lymph nodes macrophage microbial novel novel therapeutics prevent progesterone 11-hemisuccinate-(2-iodohistamine)research study response therapy design

项目摘要

This proposal is to renew a collaborative grant which includes Dr. Sartor at the University of North Carolina at Chapel Hill and Dr. Sue Tonkonogy at the College of Veterinary Medicine, North Carolina State University. The etiology of the inflammatory bowel diseases (1BD) is unknown, but both genetic and environmental factors are involved. In the current funding period of this grant we have used genetically engineered murine models to provide convincing evidence that the normal endogenous enteric bacterial flora are essential to the development of chronic colitis, in genetically susceptible rodents. Very importantly, we have demonstrated that all resident enteric bacteria are not equal in their capacities to induce inflammation: some are aggressive (Enterococcusfaecalis in IL-10 KO mice), some are neutral (H. hepaticus in IL-10 4- mice) and some are protective (Lactobacillus plantarum in IL-l0 "t-mice). Chronic intestinal inflammation in these models is mediated by activated Tm lymphocytes which are induced by normal cecal bacteria. We have demonstrated an important role for endogenous IL-l 0 in downregulating pathogenic responses of antigen presenting cells (APC) and T lymphocyte to normal bacterial components. Our data support the hypothesis that chronic intestinal inflammation in genetically susceptible hosts is the result of an' overly aggressive cellular immune response to a subset of ubiquitous luminal bacterial constituents. Genetic susceptibility is determined by defective downregulation of inflammatory responses or defective mucosal barrier function. This clinically relevant hypothesis will be addressed by the following Specific Aims: 1. Determine the mechanisms by which endogenous IL-10 regulates responses of APC to environmentally relevant bacterial constituents and inflammatory mediators; 2) Determine the role of endogenous IL-10 produced by APC in regulating responses of naive and activated T cells to environmentally relevant bacterial antigens; 3) Identify the bacterial species preferentially inducing colitis and pathogenic immune responses in IL-10 deficient mice and protective responses in normal mice. The NiH-funded Core Center for Gastrointestinal Biology and Disease at UNC supports a barrier-intact gnotobiotic rodent facility, allowing the investigators a unique environment to selectively colonize germ-free mice with defined luminal bacterial species. These studies will provide novel insights into the pathogenesis of IBD and open new opportunities for novel therapeutic interventions designed to block induction of the antigen-specific immune response to luminal bacteria.

该提案旨在续签一项合作资助，其中包括北卡罗来纳大学的 Sartor 博士（位于 Chapel Hill 和北卡罗来纳州立大学兽医学院的 Sue Tonkonogy 博士。炎症性肠病（1BD）的病因尚不清楚，但遗传和环境因素都受到影响。涉及。在本次资助的当前资助期内，我们使用基因工程小鼠模型来提供令人信服的证据表明，正常的内源性肠道细菌菌群对于慢性疾病的发展至关重要结肠炎，存在于遗传易感的啮齿动物中。非常重要的是，我们已经证明所有常驻肠道细菌都是它们诱发炎症的能力并不相同：有些具有攻击性（IL-10 KO 小鼠中的粪肠球菌），有些是中性的（IL-10 4-小鼠中的肝螺杆菌），有些是保护性的（IL-10“t-小鼠中的植物乳杆菌”）。这些模型中的慢性肠道炎症是由激活的 Tm 淋巴细胞介导的，而这些淋巴细胞是由正常细胞诱导的。盲肠细菌。我们已经证明了内源性 IL-1 0 在下调致病反应中的重要作用抗原呈递细胞 (APC) 和 T 淋巴细胞转化为正常细菌成分。我们的数据支持这样的假设：遗传易感宿主的慢性肠道炎症是由于对普遍存在的腔内细菌成分子集的过度侵略性细胞免疫反应。遗传易感性由炎症反应下调缺陷或粘膜屏障缺陷决定功能。这一临床相关假设将通过以下具体目标来解决： 1. 确定内源性 IL-10 调节 APC 对环境相关细菌反应的机制成分和炎症介质； 2) 确定APC产生的内源性IL-10在细胞因子中的作用调节初始和活化 T 细胞对环境相关细菌抗原的反应； 3) 识别在 IL-10 缺陷小鼠中优先诱导结肠炎和致病性免疫反应的细菌种类正常小鼠的保护反应。美国国立卫生研究院 (NiH) 资助的北卡罗来纳大学胃肠生物学和疾病核心中心支持屏障完好的抗生素啮齿动物设施，为研究人员提供了一个独特的环境，可以选择性地定植具有明确定义的无菌小鼠管腔细菌种类。这些研究将为 IBD 的发病机制提供新的见解，并开辟新的领域。旨在阻止抗原特异性免疫反应诱导的新型治疗干预措施的机会到管腔细菌。