IMPAIRED TUMOR IMMUNITY DURING H PYLORI INFECTION

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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.