H. PYLORI-SPECIFIC REGULATORY T CELLS THAT LIMIT HOST RESPONSE

H. 限制宿主反应的幽门螺杆菌特异性调节 T 细胞

• 批准号: 7173722
• 负责人: THOMAS G BLANCHARD
• 金额: $ 0.82万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7173722
• 关键词: Address; Animals; Bacteria; Biological Assay; Bypass; C57BL/6 Mouse; CD4 Positive T Lymphocytes; Celiac Disease; Cells; Chronic; Clinic; Coculture Techniques; Colon; Cytokine Receptors; Data; Development; Disease; Down-Regulation; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Food Hypersensitivity; Gastric mucosa; Gastritis; Gastrointestinal tract structure; Genus Cola; Genus Felis; Helicobacter Infections; Helicobacter Pylori-Associated Gastritis; Helicobacter pylori; Histologic; Human; Immune; Immune response; Immunity; Immunologics; Immunotherapy; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Interleukin-10; Intestinal Mucosa; Knowledge; Laboratories; Life; Lymphoid Tissue; Modeling; Mucous Membrane; Mus; NADPH Oxidase; Natural Immunity; Nose; Numbers; Oral; Peptic Ulcer; Play; Process; Property; Pylorus; Regulation; Role; Route; SCID Mice; Spleen; Spottings; Stomach; Surface; T-Cell Activation; T-Lymphocyte; Testing; Transgenic Mice; Vaccinated; Vaccination; Vaccines; Week; Wild Type Mouse; cytokine; design; gastrointestinal; immunoregulation; mouse model; pathogen; prevent; reconstitution; rectal; research study; response

DESCRIPTION (provided by applicant): Helicobacter pylori (H. pylori) colonizes the human gastric mucosa and plays an etiologic role in the development of gastritis and peptic ulcer disease. Infection persists for life despite the induction of histologic gastritis and specific immune responses. Similar observations have been made in the H. pylori-mouse model. However, mice lacking either IL-10 or NADPH oxidase develop inflammation in response to H. pylori that is significantly more intense than infected wild type mice, and spontaneously clear the bacteria from the gastric mucosa. Additionally, eradication of H. pylori from immunized mice following challenge is also accompanied by more intense inflammation. Therefore, H. pylori may persist due to the inability of the host to develop sufficiently intense inflammation during infection. The induction of down-regulatory T-cells that prevent aberrant responses to noninvasive bacteria in the colon has been described. These mechanisms may be conserved along the gastrointestinal tract and may be active in the gastric mucosa. This proposal will test the hypothesis that activation of T-cells at the gastric mucosa during H. pylori infection induces IL-10 producing regulatory T cells that suppress the inflammatory response, thus allowing for persistent infection. A correlate of this hypothesis is that vaccination effectively bypasses this down-regulation by activating T-cells in lymphoid tissue where the induction of IL-10 producing T-cells is not favored. We will address this hypothesis by: 1) Characterizing surface markers and cytokine profiles of gastric T cell from infected and immune mice to distinguish regulatory T-cells from protective T-cells. Flow cytometry and ELISA spot assays will be used to examine freshly isolated T-cells. 2) Identify the factors in the gastric mucosa that contribute to the induction of these regulatory cells. Transgenic mice and co-culture models will be used to explore the relationship of specific co-receptors and cytokines to T-cell activation in the stomach. 3) Investigate how regulatory T-cells interact with other cells to down-regulate inflammation. Regulatory T-cells will be studied in mice and in vitro to define the extent of their regulatory properties. These studies will increase our understanding of gastrointestinal immunoregulation and the design of better immunotherapies.

描述（由申请人提供）：幽门螺杆菌（H. Pylori）在人类的胃粘膜上定居，并在胃炎和消化性溃疡疾病的发展中起病因的作用。尽管诱导了组织学胃炎和特定的免疫反应，但感染仍然存在生命。 在幽门螺杆菌模型中也进行了类似的观察。然而，缺乏IL-10或NADPH氧化酶的小鼠对幽门螺杆菌的响应会出现炎症，这比感染的野生型小鼠明显更强烈，并且自发清除胃粘膜的细菌。另外，在挑战后消除从免疫小鼠中消除幽门螺杆菌，还伴随着更严重的炎症。因此，由于宿主无法在感染过程中出现足够强烈的炎症，幽门螺杆菌可能会持续存在。已经描述了结肠中对非侵入性细菌异常反应的下调T细胞的诱导。这些机制可以沿胃肠道保守，并且可以在胃粘膜中活跃。该提案将检验以下假设：幽门螺杆菌感染期间胃粘膜上T细胞的激活诱导IL-10产生抑制炎症反应的调节性T细胞，从而允许持续感染。该假设的一个相关性是，疫苗接种通过激活淋巴组织中的T细胞有效地绕过了这种下调，而淋巴组织中的T细胞不受青睐，而IL-10产生T细胞的诱导不受青睐。 我们将通过以下方式解决这一假设：1）表征来自感染和免疫小鼠的胃T细胞的表面标记和细胞因子谱，以将调节性T细胞与保护性T细胞区分开。 流式细胞仪和ELISA点测定将用于检查新鲜分离的T细胞。 2）确定胃粘膜中有助于诱导这些调节细胞的因素。转基因小鼠和共培养模型将用于探索特定的共受体和细胞因子与胃中T细胞活化的关系。 3）调查调节T细胞如何与其他细胞相互作用以下调炎症。将在小鼠和体外研究调节性T细胞，以定义其调节性质的程度。 这些研究将增加我们对胃肠道免疫调节和更好免疫疗法的设计的理解。