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 results in an early gastric infiltration of neutrophils, macrophages, CD4+ T cells, and B cells. These gastric infiltrates are accompanied by increased levels of gastric IFN-y, TNF- 0_,and IL-1 and by loss of gastric parietal cells, zymogenic cells, and dysplasia of gastric mucosal cells. Very little is known about the mechanisms by which this gastric infiltrate induces subsequent gastric epithelial pathology. A small animal model of Helicobacter infection, the H. felis mouse model, closely mimics the human disease in that severe gastric atrophy and gastric adenocarcinoma develops after infection. This model has allowed a careful analysis of the adaptive immune response to Helicobacter infection. Using a novel adoptive transfer model of disease, we have shown that it is the host CD4+ T cell response which is crucial for the development of H. felis-associated gastric pathology. This has directed our attention to the role of the CD4+ T cell, and its potential effector mechanisms, in the development of Helicobacter-associated gastric epithelial cell destruction and pathology. This grant application focuses on the hypothesis that recruitment and activation of CD4+ T cells in the stomach results in secondary non-antigen specific gastric epithelial cell alterations. These changes in epithelial cell proliferation and differentiation lead to gastric dysplasia and cancer formation. In order to elucidate this immune / epithelial cell relationship and its sequelae, we propose to: 1) characterize the antigen recognition requirements of the CD4+ T cell critical for the development of Helicobacter-associated gastric pathology; and 2) determine the role of secreted or cell-surface products in the generation of Helicobacter-associated gastric epithelial pathology. These studies will utilize both in vivo models of disease, as well as a novel primary gastric epithelial cell cul_tre system. 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 _ERFORMANCE SITE(S) (organization, city, state) Washington University 660 South Euclid Avenue St. Louis, MO 63110 KEY PERSONNEL. See instructions. Use continuation pages as needed to provide the required information in Start with Principal Investigator. List all other key personnel in alphabetical order, last name first. Name Organization Lorenz, Robinna G. Washington University Chaplin, David D. University of Alabama at Birmingham McCracken, Vance J. Washington University Schreiber, Robert D. Washington University the format shown below. Role on Project Principal Investigator Collaborator Research Associate Collaborator Disclosure Permission Statement. Applicable to SBIR/STTR Only, See instructions. [] Yes [] No _ PHS 398 (Rev. 05101) Page 2 Form Page 2 _ Principal Investigator/Program Director (Last, first, middle): Lorenz, Robinna G. The name of the principal investigator/program director must be provided at the top of each printed page and each continuation page. RESEARCH GRANT TABLE OF CONTENTS Page Numbers Face Page ......................................................................................................................................................... 1 Description,
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