IMPAIRED TUMOR IMMUNITY DURING H PYLORI INFECTION

幽门螺杆菌是一种重要的致病菌，在 在慢性胃炎、胃和十二指肠溃疡以及胃部 癌症。尽管胃上皮细胞的幽门螺杆菌感染 引发免疫反应，洞察调节 这些回应的发展是有限的。最近的研究表明 粘膜上皮细胞是免疫的积极参与者 对粘膜病原体的反应。胃窦部上皮 结构性地表达第二类MHC分子，我们的细胞 显示这些上皮细胞表达其他重要的标志物 是抗原提呈细胞所必需的。我们注意到胃部 体内外上皮细胞表达CD86共刺激分子 分子和这种表达增加与上升的同时 局部CD4T细胞数量与上皮II类MHC的表达 与当地CD 4 T细胞数量的增加同步增加 幽门螺杆菌感染过程中上皮c；ass II MHC的表达。我们的 最近的研究表明，幽门螺杆菌抗原是由 胃上皮细胞，并被运输到含有 人类白细胞抗原-DM，在第二类MHC介导的抗原中必不可少的分子 呈现和对病原体的免疫力。因此，胃上皮细胞 拥有抗原提呈细胞的关键功能要素。自.以来 抗原的处理和递呈是 一种免疫反应的发展，我们的观察使我们 假设胃上皮细胞是胃电活动的中枢调节细胞 幽门螺杆菌感染过程中的炎症和免疫反应 这些反应的性质受到细菌的影响。至 检验这一假设，我们将解决以下具体目标，如下所示 在#年初期进行的研究的自然延伸 资金问题。 1)描述胃抗原内化的机制 上皮细胞。在这个目标中，我们将(A)描述幽门螺杆菌 人胃上皮细胞选择性内化的抗原 细胞及其促进摄取的机制；(B)确定如何 幽门螺杆菌内化抗原可能改变正常的多个步骤 抗原处理(步骤)和(C)识别能够 有选择性地由胃上皮细胞提呈给T细胞。 2)描述允许胃上皮细胞 影响CD4T细胞功能。在这个目标中，我们将(A)界定 第II类MHC在极化的胃上皮细胞中的分布 (B)表征II-CS的表达和功能，这是一种重要的辅助性- T细胞表面CD44受体，人胃上皮细胞。 这些研究的总体目标是更好地理解 幽门螺杆菌与胃上皮细胞和免疫细胞的相互作用 这决定了感染的结果。这些研究可能会有所帮助 解释为什么幽门螺杆菌感染持续存在，以及这种机制 允许幽门螺杆菌逃避免疫防御也可能允许相关的 肿瘤可以逃避免疫监视。理解分子 调节局部对天然免疫反应的基础 感染也会促进治疗性或 针对这种临床重要病原体的预防性疫苗。

Helicobacter pylori is an important pathogen which plays the major role in chronic gastritis, gastric and duodenal ulcers and gastric carcinomas. Although H pylori infection of the gastric epithelium elicits immune responses, insight into the mechanisms that regulate the development of those responses is limited. Recent studies have suggested that mucosal epithelial cells are active participants in immune responses to mucosal pathogens. The antral gastric epithelium constitutively expresses class II MHC molecules, and our cells have shown that these epithelial cells express other important markers which are required by antigen presenting cells. We noted that gastric epithelial cells in vitro and in vivo expressed the CD86 co-stimulatory molecule and this expression increased in parallel with the rise of local CD4+ T cell numbers and epithelial class II MHC expression increased in parallel with the rise of local CD4+ T cell numbers and epithelial c;ass II MHC expression during infection with H. pylori. Our most recent studies suggest that H pylori antigens are endocytosed by gastric epithelial cells and transported into endosomes that contain HLA-DM, a molecule which is essential in class II MHC-mediated antigen presentation and immunity to pathogens. Thus, gastric epithelial cells possess key functional elements of antigen presenting cells. Since antigen processing and presentation are pivotal events in the development of an immune response, our observations have led us to hypothesize that gastric epithelial cells are central regulators of the inflammatory and immunologic responses during H. pylori infection and that the nature of those responses is influenced by the bacteria. To examine this hypothesis we will address the following specific aims, as natural extensions of the studies performed during the initial period of funding. 1) Characterize the mechanisms of antigen internalization by gastric epithelial cells. In this aim we will (a) characterize the H. pylori antigens that are selectively internalized by human gastric epithelial cells and the mechanisms that promote their uptake; (b) define how internalized H. pylori antigens may alter various steps in the normal antigen processing (steps) and (c) identify the H. pylori peptides that are selective for presentation to T cells by gastric epithelial cells. 2) Characterize the mechanisms that allow gastric epithelial cells to influence CD4+ T cell function. In this aim we will (a) define the distribution of class II MHC in polarized gastric epithelial cells and (b) characterize the expression and function of Ii-CS, an essential co- receptor for CD44 on T cells, by human gastric epithelial cells. The overall goal of these studies is to better understand the interactions between H. pylori, the gastric epithelium and immune cells that determine the outcome of the infection. The studies may help explain why H. pylori infection persists and whether mechanisms that allow H. pylori to evade immune defenses may also permit the associated neoplasms to evade immune surveillance. Understanding the molecular basis for the regulation of the local immune response to natural infection will also facilitate the development of therapeutic or prophylactic vaccines against this clinically important pathogen.