Adaptive immune mechanism in acute H. pylori infection

急性幽门螺杆菌感染的适应性免疫机制

• 批准号: 7637483
• 负责人: JOHN Y KAO
• 金额: $ 13.21万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-15 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7637483
• 关键词: Acute; Address; Antibodies; Antigen-Presenting Cells; Antigens; Bacteria; Bacterial Outer Membrane Proteins; Blood; C57BL/6 Mouse; CCL2 gene; CD209 gene; CD4 Positive T Lymphocytes; CD80 gene; Cells; Chronic; Chronic Gastritis; Coculture Techniques; Development; Diphtheria Toxin; Epithelium; Failure; Fluorochrome; Gastric Acid; Gastric mucosa; Gastritis; Goals; Health; Helicobacter; Helicobacter Infections; Helicobacter pylori; Helper-Inducer T-Lymphocyte; Humoral Immunities; Immune; Immune response; Immunity; Individual; Infection; Inflammation; Intestines; Invaded; Label; Lead; Leukocytes; Ligands; Listeria; Lymphatic; Lymphoid; MHC Class II Genes; Malignant Neoplasms; Mediating; Microbe; Modeling; Mucous body substance; Mus; Organ; Organism; Pathogenesis; Pattern Recognition; Peptic Ulcer; Phagocytosis; Play; Predisposition; Prevention strategy; Pylorus; Research; Research Personnel; Risk; Role; Sampling; Secondary to; Serum; Sorting - Cell Movement; Stomach; Surface; T-Lymphocyte; TNFRSF5 gene; Time; Tissues; Transgenic Mice; Transgenic Organisms; Up-Regulation; Vaccines; base; chemokine; cytokine; immunoregulation; in vivo; indium arsenide; lymph nodes; macrophage; migration; novel; pathogen; programs; receptor; response; trafficking

Helicobacter pylori is a highly adaptive pathogen that escapes host bacterial defenses (i.e., gastric acid and humoral immunity) leading to chronic infection. The broad, long-term objective of this proposal is to elucidate the factors contributing to the failure of the initial host immune response to eradicate H. pylori. The specific hypothesis behind the proposed research is that a defective DC-dependent adaptive immune mechanism against acute H. pylori infection leads to a failure to eradicate H. pylori. This hypothesis is based on the following observations. First, DCs are the most potent antigen presenting cells (APCs) that upon activation can migrate to secondary lymphoid organs to prime an adaptive T cell response. Second, many studies have implicated the involvement of DCs in the pathogenesis/response to a variety of intestinal bacterial pathogens. Third, a type 1 T helper (Th1) response, induced by APCs, has recently been shown to be crucial for vaccine-induced protection against H. pylori. The specific aims are to: 1. Determine the time course of DC recruitment from blood to H. pylori infected stomach and the role of CCR2 and its ligand, MCP-1, in DC recruitment. Transgenic CD11cp-DTR-GFP C57BL/6 mice orally challenged with H. pylori will be assessed for DC recruitment by FACS analysis. The role of CCR2 and tissue MCP-1 in DC recruitment will be studied using CCR2-/- mice and neutralization of MCP-1. 2. Dissect the steps in the DC-H. pylori interaction in vivo and in DC migration to secondary lymphoid organs. DCs from stomach associated lymph nodes of H. pylori-infected mice will be isolated FACS sorting and their reactivity against H.pylori will be assess by coculturing DCs with H. pylori-specific T cells from immune mice. In vivo trafficking of H. pylori via DC will be assessed by red fluorochrome-labeled H. pylori. 3. Determine the functional significance of DCs in H. pylori gastritis. Transgenic mice with diphtheria toxin-sensitive DCs will be used to assess the effect of transient DC depletion during acute and chronic H. pylori infection by administrating diphtheria toxin. The role of CCR2 in acute and chronic H. pylori gastritis will also be addressed using CCR2-/- mice. The health relatedness of the project is to understand the immune dysregulation that underlies H. pylori-induced chronic gastritis which may lead to novel targets or vaccine strategies for the prevention or treatment of emerging antibioticresistant H. pylori.

幽门螺杆菌是一种高度适应性的病原体，其逃避宿主细菌防御（即，胃酸和体液免疫）导致慢性感染。这个建议的广泛的、长期的目标是阐明导致最初宿主免疫应答未能根除H.幽门。这项研究背后的具体假设是，一种有缺陷的DC依赖性适应性免疫机制对急性H。幽门感染导致 无法根除H幽门。这一假设基于以下观察。首先，DC是最有效的抗原呈递细胞（APC），其在活化后可以迁移到次级淋巴器官以引发适应性T细胞应答。第二，许多研究已经暗示DC参与多种肿瘤的发病机制/应答， 肠道细菌病原体。第三，由APC诱导的1型辅助性T细胞（Th 1）反应最近被证明对疫苗诱导的抗H。幽门。 具体目标是： 1.确定DC从血液到H募集的时间过程。pylori感染的胃以及CCR 2及其配体MCP-1在DC募集中的作用。用H.将通过FACS分析评估幽门螺杆菌的DC募集。将使用CCR 2-/-小鼠和MCP-1的中和来研究CCR 2和组织MCP-1在DC募集中的作用。 2.仔细分析DC-H中的步骤。pylori相互作用和DC向次级淋巴器官的迁移。DC来源于H. pylori感染的小鼠将被分离，并通过将DC与H.pylori共培养来评估它们对H.pylori的反应性。来自免疫小鼠的幽门特异性T细胞。H.将通过红色荧光染料标记的H.幽门。 3.确定DC在H.幽门螺杆菌性胃炎.白喉毒素敏感树突状细胞转基因小鼠 将用于评估急性和慢性H.白喉毒素引起的幽门螺杆菌感染。CCR 2在急性和慢性H.还将使用CCR 2-/-小鼠解决幽门螺杆菌胃炎。该项目的健康相关性是了解H.幽门螺杆菌引起的慢性 胃炎，这可能导致新的目标或疫苗策略，用于预防或治疗新出现的耐药H。幽门。