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

基本信息

批准号：
7343179
负责人：
THOMAS G BLANCHARD
金额：
$ 17.76万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-02-01 至 2010-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7343179
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

项目摘要

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）定植于人类胃粘膜并在胃炎和消化性溃疡疾病的发展中发挥病因作用。尽管诱发组织学胃炎和特异性免疫反应，感染仍持续终生。在幽门螺杆菌小鼠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产生的炎症反应明显比受感染的野生型小鼠更强烈，并自发地清除胃粘膜中的细菌。此外，在攻击后从免疫小鼠中根除幽门螺杆菌也伴随着更强烈的炎症。因此，由于宿主在感染过程中无法产生足够强烈的炎症，幽门螺杆菌可能会持续存在。诱导下调 T 细胞可防止对结肠中非侵入性细菌的异常反应。这些机制可能在胃肠道中保守，并且可能在胃粘膜中活跃。该提案将检验以下假设：幽门螺杆菌感染期间胃粘膜 T 细胞的激活会诱导产生 IL-10 的调节性 T 细胞，抑制炎症反应，从而实现持续感染。与这一假设相关的是，疫苗接种通过激活淋巴组织中的 T 细胞，有效绕过这种下调，而淋巴组织中不利于诱导产生 IL-10 的 T 细胞。我们将通过以下方式解决这一假设：1) 表征感染小鼠和免疫小鼠胃 T 细胞的表面标记和细胞因子谱，以区分调节性 T 细胞和保护性 T 细胞。流式细胞术和 ELISA 斑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共受体和细胞因子与胃中 T 细胞激活的关系。 3) 研究调节性 T 细胞如何与其他细胞相互作用来下调炎症。调节性 T 细胞将在小鼠和体外进行研究，以确定其调节特性的程度。这些研究将增加我们对胃肠道免疫调节的理解和更好的免疫疗法的设计。