T Cell Initiated Gastric Pathology

T 细胞引发的胃病理学

• 批准号: 6573210
• 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/6573210
• 关键词: Helicobacter; T cell receptor; antigens; bacteria infection mechanism; bacterial cytopathogenic effect; bactericidal immunity; cell cell interaction; cell differentiation; cell proliferation; cytokine; cytokine receptors; disease /disorder model; gastritis; gastrointestinal epithelium; gene targeting; genetically modified animals; helper T lymphocyte; histopathology; host organism interaction; immunocytochemistry; inflammation; laboratory mouse; leukocyte activation /transformation; lipopolysaccharides; polymerase chain reaction; tissue /cell culture

DESCRIPTION (provided by applicant): 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-gamma, TNF-alpha, 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 culture 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.

描述（由申请人提供）：细菌幽门螺杆菌是一种主要的病原体，除了感染世界一半以上的人群外，还与胃溃疡和十二指肠溃疡，与粘膜相关的淋巴瘤和腺癌有关。幽门螺杆菌感染导致嗜中性粒细胞，巨噬细胞，CD4+ T细胞和B细胞的早期胃浸润。这些胃浸润伴随着胃粘膜细胞的胃gamma，TNF-Alpha和IL-1的水平升高，胃壁细胞，酶促细胞和胃粘膜细胞的发育异常的损失。关于这种胃浸润诱导随后的胃上皮病理的机制知之甚少。一种小型动物模型的螺旋杆菌感染模型，H。felis小鼠模型，紧密地模仿了人类疾病，因为严重的胃萎缩和胃腺癌在感染后发展。该模型允许仔细分析对螺旋杆菌感染的自适应免疫反应。我们使用一种新型的疾病收养模型，我们表明是宿主CD4+ T细胞反应对于H. felis相关胃病理学的发展至关重要。这将我们的注意力转移到CD4+ T细胞的作用及其潜在效应器机制中，在与螺旋细菌相关的胃皮细胞破坏和病理学的发展中。该赠款的应用集中在胃中CD4+ T细胞的募集和激活导致二次非抗原特异性胃皮细胞改变的假设。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CD4+ T细胞的抗原识别要求，对于开发与螺旋细菌相关的胃病理至关重要； 2）确定分泌或细胞表面产物在与螺旋杆菌相关的胃上皮病理学产生中的作用。这些研究将利用体内疾病模型，以及一种新型的原发性胃皮细胞培养系统。对宿主对螺旋杆菌免疫反应诱导胃上皮病理的基本机制的理解将为进一步研究炎症反应的进一步研究以及针对螺旋杆菌感染和相关消化疾病的免疫疗法的设计。