IMPAIRED TUMOR IMMUNITY DURING H PYLORI INFECTION

幽门螺杆菌是一种重要的胃肠道病原体。 与慢性胃炎、复发性消化性溃疡和胃病有关 癌症。因为腺癌和淋巴瘤是其他疾病的并发症 胃肠道慢性炎症性疾病，包括 乳糜泻和溃疡性结肠炎，炎症过程本身就有 被认为与肿瘤的发生发展密切相关。有趣的是， T细胞功能改变可能在患者的肿瘤发展中发挥作用 或者是患有先天性T细胞缺陷的实验室动物 明显更多的肿瘤，通常与慢性 胃肠道发炎。几种机制可能允许T细胞 在幽门螺杆菌感染期间控制癌症发展的作用。 首先，T细胞介导的免疫监视不利于发育 如果某些T细胞反应是 由于幽门螺杆菌感染而被抑制。第二，肿瘤 目标本身可能会避免检测到细菌、炎症介质 或细胞因子，减少正常情况下表面分子的表达 向T细胞发出信号，识别被破坏的转化细胞。虽然为数不多 研究已经解决了胃病发病机制的这一方面。 与幽门螺杆菌相关的患者外周血单个核细胞 已经被证明具有抑制细胞毒活性的作用 抗肿瘤细胞。我们自己的初步数据表明， 胃上皮细胞表面抗原在感染过程中发生改变 幽门螺杆菌，这可能导致不适当的T细胞激活 以及次优的肿瘤监测。这些观察结果突显了 幽门螺杆菌感染过程中胃T细胞反应的调控 感染并导致我们的假设是感染幽门螺杆菌 调节胃上皮细胞作为抗原提呈物的作用 导致T细胞活化改变和监测减少的细胞 胃肿瘤。为了验证这一假设，我们将解决以下问题 目标明确； 1)表征胃上皮细胞调节T细胞的能力 细胞功能。这一目标将定义胃所需的元素 上皮细胞被认为是抗原提呈细胞，从而使 从而影响T细胞的激活或效应器功能。 2)描述多肽的产生和结合的机制 胃上皮细胞中的II类MHC。这一目的决定了幽门螺杆菌如何 抗原由胃上皮细胞处理，并将识别 II类MHC-H的胞内结合部位。幽门螺杆菌抗原相遇。 3)鉴定自然加工的幽门螺杆菌多肽和 经选择由胃上皮细胞呈递。这些研究将 确定与第II类结合的优势幽门螺杆菌衍生多肽 胃上皮细胞表达MHC。 4)确定幽门螺杆菌感染对T细胞功能的影响。这个 这一目标的研究将检验幽门螺杆菌刺激抗原的影响。 T细胞激活/抑制的表现。 总而言之，这些研究将加强我们对控制 幽门螺杆菌对胃粘膜细胞免疫的影响 感染并确定与病毒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.