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: 7252129
• 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/7252129
• 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; Transcriptional Activation; 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适应性病原体，可逃避宿主细菌防御（即胃酸和体液免疫），导致慢性感染。这个提议的广泛的，长期的目标是阐明导致初始宿主免疫反应失败的因素，以根除幽门螺杆菌。提出的研究背后的具体假设是，针对急性幽门螺杆菌感染的dc依赖性适应性免疫机制存在缺陷