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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

基本信息

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
项目类别：
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

项目摘要

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.