T Cell Initiated Gastric Pathology

T 细胞引发的胃病理学

• 批准号: 6832252
• 负责人: Robinna Gail Lorenz
• 金额: $ 27.55万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-10 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6832252
• 关键词: Cell; Initiated; Gastric; Pathology

EXCEED THE SPACE PROVIDED. The bacteria Helicobacter pylori is a major pathogen which, in addition to infecting over half of the world's population, is linked to gastric and duodenal ulcer disease, mucosal-associated lymphomas, and adenocarcinoma. Infection with H. pylori results in an early gastric infiltration of neutrophils, macrophages, CD4+ T cells, and B cells. These gastric infiltrates are accompanied by increased levels of gastric IFN-y, TNF- 0_,and IL-1 and by loss of gastric parietal cells, zymogenic cells, and dysplasia of gastric mucosal cells. Very little is known about the mechanisms by which this gastric infiltrate induces subsequent gastric epithelial pathology. A small animal model of Helicobacter infection, the H. felis mouse model, closely mimics the human disease in that severe gastric atrophy and gastric adenocarcinoma develops after infection. This model has allowed a careful analysis of the adaptive immune response to Helicobacter infection. Using a novel adoptive transfer model of disease, we have shown that it is the host CD4+ T cell response which is crucial for the development of H. felis-associated gastric pathology. This has directed our attention to the role of the CD4+ T cell, and its potential effector mechanisms, in the development of Helicobacter-associated gastric epithelial cell destruction and pathology. This grant application focuses on the hypothesis that recruitment and activation of CD4+ T cells in the stomach results in secondary non-antigen specific gastric epithelial cell alterations. These changes in epithelial cell proliferation and differentiation lead to gastric dysplasia and cancer formation. In order to elucidate this immune / epithelial cell relationship and its sequelae, we propose to: 1) characterize the antigen recognition requirements of the CD4+ T cell critical for the development of Helicobacter-associated gastric pathology; and 2) determine the role of secreted or cell-surface products in the generation of Helicobacter-associated gastric epithelial pathology. These studies will utilize both in vivo models of disease, as well as a novel primary gastric epithelial cell cul_tre system. The understanding of the basic mechanisms by which the host immune response to Helicobacter induces gastric epithelial pathology will lay the foundation for further studies on the regulation of the inflammatory response and the design of immunotherapies for Helicobacter infection and associated digestive diseases _ERFORMANCE SITE(S) (organization, city, state) Washington University 660 South Euclid Avenue St. Louis, MO 63110 KEY PERSONNEL ========================================Section End===========================================

超出所提供的空间。 幽门螺杆菌是一种主要病原体，它除了感染世界上一半以上的人口外，还与胃和十二指肠溃疡病、粘膜相关淋巴瘤和腺癌有关。幽门螺杆菌感染导致中性粒细胞、巨噬细胞、CD4+ T 细胞和 B 细胞早期胃浸润。这些胃浸润伴随着胃IFN-γ、TNF-0_和IL-1水平的增加以及胃壁细胞、酶原细胞的损失和胃粘膜细胞的发育不良。对于这种胃浸润引起随后的胃上皮病理的机制知之甚少。幽门螺杆菌感染的小动物模型，即猫幽门螺杆菌小鼠模型，与人类疾病非常相似，感染后会出现严重的胃萎缩和胃腺癌。该模型可以仔细分析对螺杆菌感染的适应性免疫反应。使用一种新的疾病过继转移模型，我们发现宿主 CD4+ T 细胞反应对于猫嗜血杆菌相关胃病理学的发展至关重要。这促使我们关注 CD4+ T 细胞在螺杆菌相关胃上皮细胞破坏和病理学发展中的作用及其潜在效应机制。 该拨款申请的重点是这样的假设：胃中 CD4+ T 细胞的募集和激活导致继发性非抗原特异性胃上皮细胞改变。上皮细胞增殖和分化的这些变化导致胃发育不良和癌症形成。为了阐明这种免疫/上皮细胞关系及其后遗症，我们建议：1）表征对于螺杆菌相关胃病理学的发展至关重要的CD4+T细胞的抗原识别要求； 2) 确定分泌物或细胞表面产物在幽门螺杆菌相关胃上皮病理产生中的作用。这些研究将利用疾病的体内模型以及新型原代胃上皮细胞培养系统。了解宿主对螺杆菌的免疫反应诱导胃上皮病理的基本机制将为进一步研究炎症反应的调节以及螺杆菌感染和相关消化疾病的免疫疗法的设计奠定基础_ERFORMANCE SITE(S)（组织、城市、州）Washington University 660 South Euclid Avenue St. Louis, MO 63110 关键人员 =========================================章节结束==============================================