The bacteria, Helicobacter pylori, is a major pathogen which, in addition to infecting over half of the world's population, is linked to gastric and duodenal ulcer disease, mucosal-associated lymphomas, and adenocarcinoma. Infection with H.pylori initially leads to recruitment and activation of the non-specific innate immune response. These mononuclear cells secrete proinflammatory cytokines that directly affect the gastric epithelium, as well as recruit lymphocytes into the inflammatory focus. Very little is known about the characteristics of this immune infiltrate, its antigen specificity, or its role in subsequent development of gastric diseases; however, it has now been shown that infection with H.pylori can lead to the production of anti- parietal cell antibodies. This has led to the hypothesis that Helicobacter infection induces an autoimmune response that causes subsequent gastric epithelial cell destruction and pathology. A small animal model of Helicobacter infection, the H.felis mouse model, closely mimics the human disease and allows a careful analysis of the adaptive immune response to Helicobacter infection. The investigator has shown that it is the host T cell response that is crucial for the development of H.felis-associated gastric pathology. This has directed attention to the role of the cellular immune response, and its potential autoimmune nature, in the development of Helicobacter-associated gastric epithelial cell destruction and pathology. This grant application focuses on understanding the relationship between the cellular immune response to Helicobacter infection, and the development of subsequent gastric epithelial alterations. These changes in epithelial proliferation, differentiation, and cell death lead to clinical ulcer disease and increased metaplasia. In order to elucidate this immune/epithelial cell relationship and its sequelae, the investigators propose to identify the immune T lymphocyte subset critical for the development of Helicobacter- associated gastric pathology and to determine the mechanism by which Helicobacter-induced immune responses generate gastric epithelial pathology. The understanding of the basic mechanisms by which the host immune response to Helicobacter induces gastric epithelial pathology will lay the foundation for further studies on the regulation of the inflammatory response and the design of immunotherapies for Helicobacter infection and associated digestive diseases.
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