The role of T cell derived cytokines in Helicobacter pylori

T细胞源性细胞因子在幽门螺杆菌中的作用

• 批准号: 9236072
• 负责人: HOLLY Marie Scott ALGOOD
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9236072
• 关键词: Affect; Antigens; Automobile Driving; Award; Bacteria; Biopsy; CCL20 gene; CD4 Positive T Lymphocytes; Carcinogens; Cell Communication; Cell Count; Cell physiology; Cells; Chronic; Chronic Gastritis; Data; Dendritic Cells; Dendritic cell activation; Development; Disease; Disease Outcome; Epithelial Cells; Exhibits; Gastric mucosa; Gastritis; General Population; Goals; Helicobacter Infections; Helicobacter pylori; Human; Immune; Immune response; Immunologics; Immunotherapy; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Interferon Type II; Interleukin-1; Interleukin-17; Intervention; Intestinal Metaplasia; Lead; Lymphocyte; MMP2 gene; MMP9 gene; Maintenance; Malignant Neoplasms; Mediating; Mesentery; Metalloproteases; Modeling; Modification; Mus; Natural Killer Cells; Organoids; Outcome; Pathogenicity; Pathology; Pathway interactions; Peptic Ulcer; Pharmacologic Substance; Play; Population; Premalignant; Production; Publishing; Recruitment Activity; Regulatory T-Lymphocyte; Research; Risk; Role; Site; Smoking; Stomach; Stress; Structure of aggregated lymphoid follicle of small intestine; Systems Biology; T cell response; T-Lymphocyte; Testing; Tissues; Up-Regulation; Veterans; Virulence Factors; Work; World Health Organization; adverse outcome; allergic airway disease; antimicrobial; cell type; cellular targeting; chemokine; cytokine; design; high salt diet; improved; insight; interleukin-21; lymph nodes; malignant stomach neoplasm; member; microbiota; mouse model; pre-clinical; prevent; public health relevance; receptor; response

 DESCRIPTION (provided by applicant): Helicobacter pylori is the dominant member of the gastric microbiota in a majority of the world's population. H. pylori colonization can lead to protection from some pro-inflammatory diseases such as allergic airway disease, but also can lead to significant detrimental outcomes, including gastritis, peptic ulcers and gastric cancer. Infection with H. pylori is the single most common ris factor of gastric cancer; for this reason, H. pylori was defined by the World Health Organization as a Class I carcinogen. Current data suggest that, in addition to bacterial virulence factors, the magnitude and types of immune responses influence the outcome of colonization. The long-term chronic pro-inflammatory response to H. pylori is believed to drive or initiate the pathways which lead to the adverse outcomes of colonization including chronic gastritis, intestinal metaplasia, and gastric cancer. We have accumulated preliminary data that strongly implicate interleukin-21 (IL-21), a cytokine produced by many subsets of activated CD4+ T cells, as a critical driver of adverse consequences of H. pylori colonization and infection. There is a fundamental gap in our understanding of how many pro-inflammatory molecules lead to these detrimental outcomes. The major goal of this application is to investigate the mechanisms by which IL-21 regulates the immune response to H. pylori, by primarily utilizing mouse models that focus on the primary detrimental outcome of infection, gastritis. A second goal is to determine the impact of IL-17 and IL-21 immunotherapies on gastritis. Moreover, organoids and human biopsies will be used to investigate IL-21 activated pathways at various steps along the gastric precancerous cascade. In this proposal, the specific aims are designed to elucidate the mechanism by which IL-21 modulates both immune and non- immune cell responses. Our central hypothesis is that IL-21 is a master regulator of the inflammatory response during H. pylori infection, thereby driving detrimental outcomes (such as gastritis). The Specific Aims are: 1. To investigate the mechanisms by which IL-21 regulates pro-inflammatory T cell priming and activation during H. pylori infection. 2. To determine the contributions of IL-21 in dendritic cell function during H. pylori infection. 3. To elucidate the contribution of IL-21-mediated epithelial cell responses to control of gastritis and H. pylori colonization. This research will also inform myriad of other infectious and chronic inflammatory disorders for which IL-21 is increasingly recognized to play a central role. Defining mechanisms through which H. pylori induces gastric cancer may provide important insights into other malignancies that arise from inflammatory foci. Moreover, the proposed studies will generate new insights into the fundamental mechanisms involved in the development of chronic inflammation.

 描述（由申请人提供）： 幽门螺杆菌是世界上大多数人口中胃菌群的主要成员。幽门螺杆菌定植可导致免受某些促炎性疾病（例如过敏性气道疾病）的保护，但也可能导致巨大的有害结果，包括胃炎，消化性溃疡和胃癌。幽门螺杆菌感染是胃癌的最常见RIS因子。因此，幽门螺杆菌由世界卫生组织定义为I类致癌。当前数据表明，除了细菌病毒因素外， 免疫反应的大小和类型会影响定殖的结果。据信，对幽门螺杆菌的长期慢性促炎反应可以驱动或启动途径，从而导致定植的不良后果，包括慢性胃炎，肠道化生和胃癌。我们累积了初步数据，这些数据强烈暗示了白介素21（IL-21），这是由活化的CD4+ T细胞的许多亚群产生的细胞因子，因为至关重要的是，我们对有多少促炎分子有多少促炎性分子有基本的差距。该应用的主要目的是研究IL-21通过主要利用小鼠模型来调节对幽门螺杆菌的免疫响应的机制，该模型侧重于感染的主要有害结果，胃炎。第二个目标是确定IL-17和IL-21免疫疗法对胃炎的影响。此外，可以使用类器官和人类活检来研究沿胃癌前级联的各个步骤的IL-21活化途径。在此提案中，具体目的旨在阐明IL-21调节免疫和非免疫细胞反应的机制。我们的中心假设是IL-21是幽门螺杆菌感染期间炎症反应的主要调节剂，从而推动确定结果（例如胃炎）。具体目的是：1。研究IL-21在幽门螺杆菌感染期间调节促炎的T细胞启动和激活的机制。 2。确定IL-21在树突状细胞中的贡献 幽门螺杆菌感染期间的功能。 3。阐明IL-21介导的上皮细胞反应对胃炎和幽门螺杆菌定植的控制。这项研究还将告知众多其他感染性和慢性炎症性疾病，IL-21越来越被认为发挥着核心作用。幽门螺杆菌诱导胃癌的定义机制可以为炎症灶引起的其他恶性肿瘤提供重要的见解。此外，拟议的研究将产生有关涉及慢性炎症发展的基本机制的新见解。