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,

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK059911-05
Application #
7163038
Study Section
Special Emphasis Panel (ZRG1-SSS-F (01))
Program Officer
Carrington, Jill L
Project Start
2003-01-10
Project End
2009-12-31
Budget Start
2007-01-01
Budget End
2009-12-31
Support Year
5
Fiscal Year
2007
Total Cost
$261,224
Indirect Cost
Name
University of Alabama Birmingham
Department
Pathology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Tanner, Scott M; Daft, Joseph G; Hill, Stephanie A et al. (2016) Altered T-Cell Balance in Lymphoid Organs of a Mouse Model of Colorectal Cancer. J Histochem Cytochem 64:753-767
Daft, Joseph G; Lorenz, Robin G (2015) Role of the gastrointestinal ecosystem in the development of type 1 diabetes. Pediatr Diabetes 16:407-18
Tanner, S M; Staley, E M; Lorenz, R G (2013) Altered generation of induced regulatory T cells in the FVB.mdr1a-/- mouse model of colitis. Mucosal Immunol 6:309-23
Durham, Carolyn G; Schwiebert, Lisa M; Lorenz, Robin G (2013) Use of the cockroach antigen model of acute asthma to determine the immunomodulatory role of early exposure to gastrointestinal infection. Methods Mol Biol 1032:271-86
Staley, Elizabeth M; Tanner, Scott M; Daft, Joseph G et al. (2013) Maintenance of host leukocytes in peripheral immune compartments following lethal irradiation and bone marrow reconstitution: implications for graft versus host disease. Transpl Immunol 28:112-9
Staley, Elizabeth M; Yarbrough, Vanisha R; Schoeb, Trenton R et al. (2012) Murine P-glycoprotein deficiency alters intestinal injury repair and blunts lipopolysaccharide-induced radioprotection. Radiat Res 178:207-16
Schmitz, Julia M; Durham, Carolyn G; Schoeb, Trenton R et al. (2011) Helicobacter felis--associated gastric disease in microbiota-restricted mice. J Histochem Cytochem 59:826-41
Staley, Elizabeth M; Dimmitt, Reed A; Schoeb, Trenton R et al. (2011) Critical role for P-glycoprotein expression in hematopoietic cells in the FVB.Mdr1a(-/-) model of colitis. J Pediatr Gastroenterol Nutr 53:666-73
Dimmitt, Reed A; Staley, Elizabeth M; Chuang, Gin et al. (2010) Role of postnatal acquisition of the intestinal microbiome in the early development of immune function. J Pediatr Gastroenterol Nutr 51:262-73
Tatum Jr, Philip M; Harmon, Carroll M; Lorenz, Robin G et al. (2010) Toll-like receptor 4 is protective against neonatal murine ischemia-reperfusion intestinal injury. J Pediatr Surg 45:1246-55

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