Dendritic Cells in Allergy and Immunotherapy

树突状细胞在过敏和免疫治疗中的应用

基本信息

批准号：
8660021
负责人：
Jody R Tversky
金额：
$ 12.95万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-15 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8660021
关键词：
Accounting Address Affect Affinity Allergen Immunotherapy Allergens Allergic Allergic Disease Allergic rhinitis Allergy to peanuts Area Asthma Cell Communication Cell physiology Clinical Data Dendritic Cells Dependence Diagnosis Diagnostic Disease Event Extrinsic asthma Flow Cytometry Food Food Hypersensitivity Functional disorder Goals HMGB1 gene Human Hypersensitivity IgE IgE Receptors Immune Immunologic Receptors Immunoprecipitation Immunotherapy In Vitro Individual Inflammatory Interferons Interleukin-10 Knowledge Link MAP Kinase Gene Mediating Modeling Nature Pathologic Pathology Pathway interactions Peanuts - dietary Peripheral Blood Mononuclear Cell Phenotype Pollen Population Process Production Receptor Signaling Research Role Serum Signal Pathway Signal Transduction Signaling Protein TNFSF4 gene TSLP gene Technology Therapeutic Toll-like receptors Venoms Western Blotting Work airborne allergen anti-IgE base career development cell type crosslink cytokine design human TLR7 protein immune function innate immune function oral immunotherapy osteopontin pyroglyphid receptor receptor expression receptor function receptor-mediated signaling response subcutaneous

项目摘要

DESCRIPTION (provided by applicant): A number of unique diagnostic and therapeutic advances in the area of human allergic disease are currently on the horizon. Ironically, our understanding the fundamental immune processes governing allergic disease pathology and treatment is still poorly understood. Anti-IgE, oral immunotherapy and CpG-based technologies have emerged as exciting treatment options for asthma, severe allergic rhinitis and food allergy. Preliminary evidence indicates that the immature human dendritic cell may be a critical target for these therapies (as well as classical subcutaneous immunotherapy). However, the mechanisms are not known. Studies have shown that dendritic cells express the high affinity IgE receptor (Fc(RI) and that this receptor correlates with serum IgE levels and allergic status. In addition, recent evidence has shown that the IgE receptor and the toll-like receptor may counter-regulate one another on dendritic cells. While it has long been understood that IgE mediated responses dominate in allergic disease, new evidence indicates that dendritic cells from allergic subjects have impaired toll-like receptor (TLR) mediated responses. These findings have led to the hypothesis that cross-regulatory mechanisms may exist between innate (TLR) and adaptive (IgE) immune receptors and their function on dendritic cells that may contribute to allergic disease manifestations. It has not yet been established whether there is a clinical correlate to the IgE/TLR interactions noted in vitro. For example, are TLR/IgE receptors on dendritic cells from allergic subjects phenotypically and/or functionally different from those of non-allergic individuals? Do dendritic cells obtained from one allergic disease population such as allergic rhinitis function distinctly from dendritic cells obtained from food allergic individuals or asthmatics? Does immunotherapy affect dendritic cell function or IgE/TLR receptor interactions? In this proposal we aim to define and contrast the major IgE and TLR receptor mediated responses in dendritic cells in three distinct disease groups namely; mild-moderate persistent asthma, peanut allergy and moderate-severe allergic rhinitis. We will compare the mechanisms governing dendritic cell function in each of these ailments in an effort to help uncover the pathologic basis of allergic disease. In doing so we aim to identify significant targets for therapy- some of which may already be exploited with classical and experimental versions of allergen immunotherapy. We will dissect the nature of the IgE receptor on human dendritic cells and construct a model for allergen interactions. We will analyze components of dendritic cell signaling events. Finally, we will specifically investigate dendritic cell immune mechanisms that are essential to clinically successful allergen immunotherapy. The goal of this project is to expand our knowledge of human dendritic cell immune function as it relates to allergic disease and mechanisms of allergen immunotherapy. This work will ultimately contribute to better diagnosis and treatment of food allergy, allergic rhinitis and asthma.

描述（由申请人提供）：人类过敏性疾病领域目前即将取得许多独特的诊断和治疗进展。讽刺的是，我们对控制过敏性疾病病理学和治疗的基本免疫过程仍然知之甚少。抗 IgE、口服免疫疗法和基于 CpG 的技术已成为治疗哮喘、严重过敏性鼻炎和食物过敏的令人兴奋的治疗选择。初步证据表明，未成熟的人类树突状细胞可能是这些疗法（以及经典皮下免疫疗法）的关键靶标。然而，其机制尚不清楚。研究表明，树突状细胞表达高亲和力 IgE 受体 (Fc(RI))，并且该受体与血清 IgE 水平和过敏状态相关。此外，最近的证据表明 IgE 受体和 Toll 样受体可能会对抗虽然人们早就知道 IgE 介导的反应在过敏性疾病中占主导地位，但新的证据表明来自过敏受试者的树突状细胞具有受损的 Toll 样受体 (TLR) 介导的反应。研究结果提出这样的假设：先天性（TLR）和适应性（IgE）免疫受体及其对树突状细胞的功能之间可能存在交叉调节机制，这可能导致过敏性疾病的临床表现。与体外观察到的 IgE/TLR 相互作用相关，例如，过敏受试者的树突状细胞上的 TLR/IgE 受体在表型和/或功能上是否与非过敏个体不同？从一种过敏性疾病人群（例如过敏性鼻炎）获得的树突状细胞的功能是否与从食物过敏个体或哮喘患者获得的树突状细胞不同？免疫疗法是否会影响树突状细胞功能或 IgE/TLR 受体相互作用？在本提案中，我们的目标是定义和对比三个不同疾病组中树突状细胞中主要 IgE 和 TLR 受体介导的反应，即：轻中度持续性哮喘、花生过敏和中重度过敏性鼻炎。我们将比较每种疾病中控制树突状细胞功能的机制，以帮助揭示过敏性疾病的病理基础。在此过程中，我们的目标是确定重要的治疗靶点——其中一些可能已经被经典和实验版本的过敏原免疫疗法所利用。我们将剖析人类树突状细胞上 IgE 受体的性质，并构建过敏原相互作用的模型。我们将分析树突状细胞信号传导事件的组成部分。最后，我们将专门研究对于临床成功的过敏原免疫治疗至关重要的树突状细胞免疫机制。该项目的目标是扩大我们对人类树突细胞免疫功能的了解，因为它与过敏性疾病和过敏原免疫治疗机制有关。这项工作最终将有助于更好地诊断和治疗食物过敏、过敏性鼻炎和哮喘。