Helicobacter pylori is an important gastrointestinal pathogen which is implicated in chronic gastritis, recurrent peptic ulceration and gastric cancer. As adenocarcinomas and lymphomas are a complication of other chronic inflammatory diseases of the gastrointestinal tract, including celiac disease and ulcerative colitis, the inflammatory process itself has been implicated in the pathogenesis of tumor development. Interestingly, altered T cell function may play a role in tumor development since patients or laboratory animals with congenital T cell deficiencies develop significantly more tumors, often in association with chronic gastrointestinal inflammation. Several mechanisms may allow T cell function to control the development of cancer during H. pylori infection. First of all, T cell-mediated immune surveillance against developing gastric neoplasms could be impaired if certain T cell responses are suppressed as a consequence of H. pylori infection. Secondly, the tumor targets themselves may avoid detection of bacteria, inflammatory mediators or cytokines, decrease the expression of surface molecules that normally signal T cells to recognize the destroy transformed cells. Although few studies have addressed this aspect of the pathogenesis of gastric disease associated with H. pylori, peripheral blood mononuclear cells from patients with gastric cancer have been shown to have suppressed cytotoxic activity against tumor cells. Our own preliminary data suggest that the expression of surface antigens by gastric epithelial cells is altered during infection with H. pylori which my, in turn, lead to inappropriate T cell activation and suboptimal tumor surveillance. These observations highlight the need to define how gastric T cell responses are regulated during H. pylori infection and lead to our hypothesis that infection with H. pylori modulates the role of the gastric epithelial cell as an antigen presenting cell leading to altered T cell activation and diminished surveillance for gastric neoplasms. To test this hypothesis we will address the following specific aims; 1) Characterize athe ability of gastric epithelial cells to modulate T cell function.
This aim will define the elements required for gastric epithelial cells to be considered antigen presenting cells thereby enabling them to influence T cell activation or effector function. 2) Characterize the mechanisms of peptide generation and association with class II MHC in gastric epithelial cells.
This aim determine how H. pylori antigens are handled by gastric epithelial cells an will identify the intracellular site of Class II MHC-H. pylori antigen encounter. 3) Characterize H. pylori peptides which are naturally processed and selected for presentation by gastric epithelial cells. These studies will identify dominant, H. pylori-derived peptides which are bound by Class II MHC expressed by gastric epithelial cells. 4) Determine the effects of H. pylori infection on T cell function. The studies in this aim will examine the impact of H. pylori stimulated antigen presentation of T cell activation/suppression. Together, these studies will enhance our understanding of the control of cell mediated immunity in the gastric mucosa in response to H. pylori infection and identify molecular markers which are associated with the pathogenesis of gastric cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK050669-01
Application #
2151710
Study Section
Special Emphasis Panel (SRC (24))
Project Start
1995-06-01
Project End
1998-05-31
Budget Start
1995-06-01
Budget End
1996-05-31
Support Year
1
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Pediatrics
Type
Schools of Medicine
DUNS #
041367053
City
Galveston
State
TX
Country
United States
Zip Code
77555
Beswick, Ellen J; Pinchuk, Iryna V; Earley, Rachel B et al. (2011) Role of gastric epithelial cell-derived transforming growth factor beta in reduced CD4+ T cell proliferation and development of regulatory T cells during Helicobacter pylori infection. Infect Immun 79:2737-45
Beswick, Ellen J; Reyes, Victor E (2009) CD74 in antigen presentation, inflammation, and cancers of the gastrointestinal tract. World J Gastroenterol 15:2855-61
Beswick, Ellen J; Reyes, Victor E (2008) Macrophage migration inhibitory factor and interleukin-8 produced by gastric epithelial cells during Helicobacter pylori exposure induce expression and activation of the epidermal growth factor receptor. Infect Immun 76:3233-40
Lu, Hong; Wu, Jeng Yih; Beswick, Ellen J et al. (2007) Functional and intracellular signaling differences associated with the Helicobacter pylori AlpAB adhesin from Western and East Asian strains. J Biol Chem 282:6242-54
Minohara, Yutaka; Boyd, David K; Hawkins, Hal K et al. (2007) The effect of the cag pathogenicity island on binding of Helicobacter pylori to gastric epithelial cells and the subsequent induction of apoptosis. Helicobacter 12:583-90
Beswick, Ellen J; Pinchuk, Irina V; Das, Soumita et al. (2007) Expression of the programmed death ligand 1, B7-H1, on gastric epithelial cells after Helicobacter pylori exposure promotes development of CD4+ CD25+ FoxP3+ regulatory T cells. Infect Immun 75:4334-41
Ding, Song-Ze; Minohara, Yutaka; Fan, Xue Jun et al. (2007) Helicobacter pylori infection induces oxidative stress and programmed cell death in human gastric epithelial cells. Infect Immun 75:4030-9
Bland, David A; Suarez, Giovanni; Beswick, Ellen J et al. (2006) H pylori receptor MHC class II contributes to the dynamic gastric epithelial apoptotic response. World J Gastroenterol 12:4689-93
Suarez, Giovanni; Reyes, Victor E; Beswick, Ellen J (2006) Immune response to H. pylori. World J Gastroenterol 12:5593-8
Beswick, Ellen J; Pinchuk, Irina V; Minch, Kyle et al. (2006) The Helicobacter pylori urease B subunit binds to CD74 on gastric epithelial cells and induces NF-kappaB activation and interleukin-8 production. Infect Immun 74:1148-55

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