The role of T cell derived cytokines in Helicobacter pylori

 描述(由申请人提供)： 在世界大多数人口中，幽门螺杆菌是胃微生物区系中的主要成员。幽门螺杆菌的定植可以预防一些促炎性疾病，如过敏性呼吸道疾病，但也可能导致严重的有害后果，包括胃炎、消化性溃疡和胃癌。幽门螺杆菌感染是胃癌最常见的RIS因素；因此，世界卫生组织将幽门螺杆菌定义为I类致癌物质。目前的数据表明，除了细菌的毒性因素外， 免疫反应的大小和类型影响殖民的结果。幽门螺杆菌的长期慢性促炎反应被认为是导致慢性胃炎、肠化生和胃癌等定植不良后果的驱动或启动途径。我们已经积累的初步数据强烈暗示白介素21(IL-21)，一种由许多激活的CD4+T细胞亚群产生的细胞因子，是幽门螺杆菌定植和感染不良后果的关键驱动因素。对于有多少促炎分子导致这些有害结果，我们的理解存在一个根本性的差距。这项应用的主要目的是通过主要利用关注感染的主要有害结果-胃炎的小鼠模型来研究IL-21调节对幽门螺杆菌的免疫反应的机制。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，器官和人体活检将被用来研究沿着胃癌前病变级联的不同步骤中IL-21激活的途径。在这项提案中，特定的目的旨在阐明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，在幽门螺杆菌感染过程中，IL-21是炎症反应的主要调节因子，从而推动不良后果(如胃炎)。其具体目的是：1.探讨IL-21在幽门螺杆菌感染过程中调节促炎性T细胞启动和激活的机制。2.检测IL-21在树突状细胞中的作用 在幽门螺杆菌感染过程中发挥作用。3.探讨IL-21介导的上皮细胞反应在控制胃炎和幽门螺杆菌定植中的作用。这项研究还将为无数其他感染性和慢性炎症性疾病提供信息，IL-21在这些疾病中发挥着核心作用。确定幽门螺杆菌诱发胃癌的机制可能会为研究其他由炎症性病灶引起的恶性肿瘤提供重要的见解。此外，拟议的研究将对慢性炎症发生的基本机制产生新的见解。

 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.