IMPAIRED TUMOR IMMUNITY DURING H PYLORI INFECTION

幽门螺杆菌是一种重要的胃肠道致病菌， 涉及慢性胃炎、复发性消化性溃疡和胃溃疡 癌 由于腺癌和淋巴瘤是其他癌症的并发症， 胃肠道的慢性炎性疾病，包括 乳糜泻和溃疡性结肠炎，炎症过程本身 与肿瘤发展的发病机制有关。 有趣的是， 改变的T细胞功能可能在肿瘤发展中起作用， 或者先天性T细胞缺陷的实验动物 显著更多的肿瘤，通常与慢性 胃肠道炎症 有几种机制可以使T细胞 在H.幽门感染 首先，T细胞介导的免疫监视针对发育中的 如果某些T细胞反应被抑制， 抑制作为H的结果。幽门感染 第二，肿瘤 目标本身可以避免检测细菌，炎症介质 或细胞因子，减少表面分子的表达， 向T细胞发出信号以识别被破坏的转化细胞。 尽管很少 研究已经解决了胃病发病机制的这一方面 与H. pylori，患者外周血单核细胞 已经显示具有抑制的细胞毒活性 对抗肿瘤细胞。 我们自己的初步数据表明， 在感染过程中胃上皮细胞表面抗原的变化 螺杆菌幽门螺杆菌，这反过来又会导致不适当的T细胞激活 和不理想的肿瘤监测。 这些意见突出表明， 以确定在H.幽门 感染，并导致我们的假设，感染H。幽门 调节胃上皮细胞作为抗原呈递的作用 细胞导致T细胞活化改变，并减少对 胃肿瘤 为了验证这一假设，我们将解决以下问题 具体目标; 1)表征胃上皮细胞调节T 细胞功能 这一目标将定义胃肠道所需的元素， 上皮细胞被认为是抗原呈递细胞， 它们影响T细胞活化或效应子功能。 2)表征肽生成的机制，并与 胃上皮细胞中的II类MHC。 这一目标决定了H.幽门 抗原由胃上皮细胞处理， II类MHC-H的细胞内位点。幽门螺杆菌抗原的遭遇。 3)描述H.天然加工的幽门肽， 被选择用于由胃上皮细胞呈递。 这些研究将 鉴定显性H.与II类结合的幽门衍生肽 胃上皮细胞表达的MHC。 4)确定H. pylori感染对T细胞功能的影响 的 这方面的研究将考察H.幽门刺激抗原 呈现T细胞活化/抑制。 总之，这些研究将提高我们对控制 胃粘膜对H.幽门 感染和识别与感染相关的分子标志物， 胃癌的发病机制

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.