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Role of Dendritic Cells in H pylori-induced Treg-mediated Host Immune Tolerance

树突状细胞在幽门螺杆菌诱导的 Treg 介导的宿主免疫耐受中的作用

基本信息

批准号：
8813558
负责人：
JOHN Y KAO
金额：
$ 38.41万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-02-04 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8813558
关键词：
Ablation Acute Address Adoptive Transfer Antigen-Presenting Cells Antigens Bacteria Bacterial Antigens Bone Marrow Cell Line Cells Chronic Chronic Gastritis Complex DNA Data Dendritic Cells Development Diet Disease Epithelial Equilibrium Funding Gastritis Gastrointestinal tract structure Goals Health Helicobacter Infections Helicobacter pylori Homeostasis Human IL2RA gene IRAK3 gene Immune Immune Tolerance Immune response In Vitro Individual Inflammation Inflammatory Interferons Interleukin-10 Intestines Knockout Mice Knowledge Lead Life Mediating Microbe Modeling Mono-S Mucosal Immunity Mucositis Mus Outcome Patients Peptic Ulcer Play Prevention approach Preventive Probiotics Process Property Regulatory T-Lymphocyte Research Role Sampling Signal Transduction Spleen Stomach Surface Symptoms System TLR2 gene Testing Therapeutic Therapeutic Intervention Tight Junctions Tissues Ulcer Work base body system cellular targeting commensal microbes conditioning gastrointestinal immunogenic in vivo innovation insight lymph nodes migration neutralizing antibody novel pathogen prebiotics programs receptor response therapy design uptake

项目摘要

DESCRIPTION (provided by applicant): Mucosal immune tolerance to luminal microbes is a highly regulated process a lack of which leads to chronic inflammation of the GI tract. H. pylori is a gastric pathogen able to cause severe chronic gastritis and ulcers in <15% of infected individuals, but the majority developed a mild gastritis without symptoms. The long-term objective of this proposal is to understand the mechanisms of mucosal tolerance in the stomach. We will build on our observations made during the K08 funding period studying the dendritic cells (DCs)-mediated mechanism of H. pylori immune escape and use the H. pylori colonization model to study gastric mucosal tolerance. Our preliminary results support the notion that Hp induction of regulatory T cells (Tregs) is mediated by DCs. Therefore, we hypothesize that H. pylori triggers a host tolerogenic response by interacting with DCs via a IRAK-M-mediated, TGF-ß-dependent mechanism which alters the H. pylori Teffector/Treg balance leading to the development of host tolerance to H. pylori and chronic colonization. The specific aims are: Aim 1) To Determine the role of tissue DCs in H. pylori tolerance. DC subset in the stomach will be characterized during acute H. pylori infection and mechanism of H. pylori uptake and lymph node migration by DC will be elucidated. The requirement of DCs in H. pylori uptake and tolerance induction will be studied using DC ablation. Aim 2) Investigate the role of DC TLR and intracellular modulators of tolerogenic DC programming. First we will determine whether H. pylori stimulated DCs induce Tregs requires immunogenic H. pylori. Next, the role of IRAK-M in Treg induction will be explored. The role of TLR9 will also be explored using H. pylori DNA stimulation and TLR9 null mice. Aim 3) To analyze the role of DC-Treg induction in modulating H. pylori tolerance. We will use in vivo adoptive transfer of H. pylori-stimulated BMDCs into mice to induce H. pylori- specific Tregs and then use CD25 neutralizing antibodies to study the effect of Treg depletion on H. pylori tolerance. The role of Th1 and Th17 cells in H. pylori tolerance will be studied using IFN-3 and Th17A null mice. The effect of modulation TGF-ß on Treg induction by H. pylori stimulated DCs will be studies using cell lines over-expressing TGF-ß or produces a TGF-ß receptor that neutralizes DCs in the microenvironment. The health relatedness of this proposal is to understand the mechanism of mucosal tolerance to H. pylori to begin to address the factors that lead to reduced tolerance. The finding of this project will provide not only provide novel insight into the mechanism of mucosal tolerance to luminal bacteria, but also enhance our understanding of the development of tolerance in the gastric immune compartment. New targets may be discovered useful for designing therapies to restored immune homeostasis in patients with chronic inflammatory conditions by targeting DCs regulatory mechanisms or by using bacterial products (e.g., prebiotics, probiotics).

描述（由申请人提供）：对腔内微生物的粘膜免疫耐受是一个高度调控的过程，缺乏该过程会导致胃肠道慢性炎症。幽门螺杆菌是一种胃部病原体，能够在 <15% 的感染者中引起严重的慢性胃炎和溃疡，但大多数人会发展为无症状的轻度胃炎。该提案的长期目标是了解胃粘膜耐受的机制。我们将基于 K08 资助期间的观察结果，研究树突状细胞 (DC) 介导的幽门螺杆菌免疫逃逸机制，并使用幽门螺杆菌定植模型来研究胃粘膜耐受性。我们的初步结果支持这样的观点：Hp 诱导调节性 T 细胞 (Treg) 是由 DC 介导的。因此，我们假设幽门螺杆菌通过 IRAK-M 介导的 TGF-β 依赖性机制与树突状细胞相互作用，从而触发宿主耐受性反应，该机制改变幽门螺杆菌 Teffector/Treg 平衡，导致宿主对幽门螺杆菌的耐受性和慢性定植的发展。具体目标是：目标 1) 确定组织 DC 在幽门螺杆菌耐受中的作用。将在急性幽门螺杆菌感染期间表征胃中的DC亚群，并阐明DC摄取幽门螺杆菌和淋巴结迁移的机制。将使用 DC 消融来研究 DC 在幽门螺杆菌摄取和耐受诱导中的需求。目标 2) 研究 DC TLR 和耐受性 DC 编程的细胞内调节剂的作用。首先，我们将确定幽门螺杆菌刺激的 DC 诱导 Tregs 是否需要免疫原性幽门螺杆菌。接下来，将探讨 IRAK-M 在 Treg 诱导中的作用。还将使用幽门螺杆菌 DNA 刺激和 TLR9 缺失小鼠来探索 TLR9 的作用。目的 3) 分析 DC-Treg 诱导在调节幽门螺杆菌耐受中的作用。我们将使用幽门螺杆菌刺激的 BMDC 体内过继转移到小鼠体内来诱导幽门螺杆菌特异性 Tregs，然后使用 CD25 中和抗体来研究 Treg 耗竭对幽门螺杆菌耐受性的影响。将使用 IFN-3 和 Th17A 无效小鼠研究 Th1 和 Th17 细胞在幽门螺杆菌耐受性中的作用。调节 TGF-β 对幽门螺杆菌刺激的 DC 诱导 Treg 的影响将使用过表达 TGF-β 或产生中和微环境中 DC 的 TGF-β 受体的细胞系进行研究。该提案的健康相关性是了解粘膜对幽门螺杆菌的耐受机制，以开始解决导致耐受性降低的因素。该项目的发现不仅将为粘膜对管腔细菌的耐受机制提供新的见解，而且还将增强我们对胃免疫区室耐受发展的理解。通过针对 DC 调节机制或使用细菌产品（例如益生元、益生菌），可能会发现新的靶点，可用于设计疗法以恢复慢性炎症患者的免疫稳态。