IMPAIRED TUMOR IMMUNITY DURING H PYLORI INFECTION

幽门螺杆菌（Helicobacter pylori，Hp）是一种重要的致病菌， 慢性胃炎、胃溃疡和十二指肠溃疡以及胃溃疡 癌虽然幽门螺杆菌感染的胃上皮 增强免疫反应，深入了解调节免疫反应的机制， 这些对策的发展有限。最近的研究表明 粘膜上皮细胞是免疫系统的积极参与者， 对粘膜病原体的反应。胃窦上皮 组成型表达II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， 是抗原呈递细胞所必需的。我们注意到， 体外和体内的上皮细胞表达CD 86共刺激分子， 分子，这种表达增加与上升平行， 局部CD 4 + T细胞数量和上皮II类MHC表达 与局部CD 4 + T细胞数量的增加平行增加， 感染H.幽门。我们 最近的研究表明，幽门螺杆菌抗原被 胃上皮细胞并被转运到含有 HLA-DM是II类MHC介导的抗原所必需的分子 对病原体的呈递和免疫。因此，胃上皮细胞 具有抗原呈递细胞的关键功能元件。以来 抗原加工和呈递是免疫系统中的关键事件， 免疫反应的发展，我们的观察使我们 假设胃上皮细胞是胃粘膜的中枢调节者， H. hp感染与 这些反应的性质受到细菌的影响。到 为了检验这一假设，我们将讨论以下具体目标， 自然延伸的研究在初期阶段进行 经费 1)胃粘膜抗原内化机制的研究 上皮细胞在这个目标中，我们将（a）表征H。幽门 被人胃上皮细胞选择性内化的抗原 细胞和促进其吸收的机制;（B）定义如何 内化H.幽门螺杆菌抗原可以改变正常细胞的各个步骤， 抗原处理（步骤）和（c）鉴定H.幽门肽， 选择性地通过胃上皮细胞呈递给T细胞。 2)描述了胃上皮细胞 影响CD 4 + T细胞功能。为此，我们将（a）定义 II类MHC在极化胃上皮细胞中的分布， (b)表征Ii-CS的表达和功能，Ii-CS是一种重要的协同蛋白， 人胃上皮细胞对T细胞上的CD 44受体的作用。 这些研究的总体目标是更好地了解 H之间的相互作用幽门螺杆菌、胃上皮细胞和免疫细胞 决定了感染的结果这些研究可能会有所帮助 解释为什么H。幽门螺杆菌感染持续存在，是否机制， 允许H.幽门螺杆菌逃避免疫防御也可能允许相关的 肿瘤逃避免疫监视。了解分子 调节局部免疫反应的基础， 感染也将促进治疗或 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.