Dendritic Cells in Allergy and Immunotherapy

描述(由申请人提供)：在人类过敏性疾病领域的一些独特的诊断和治疗进展目前正在酝酿之中。具有讽刺意味的是，我们对控制过敏性疾病病理和治疗的基本免疫过程的了解仍然很少。抗IgE、口服免疫疗法和基于CpG的技术已成为哮喘、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(以及经典的皮下免疫疗法)的关键靶点。然而，其机制尚不清楚。研究表明，树突状细胞表达高亲和力的IgE受体(Fc(RI))，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样受体可能在树突状细胞上相互逆调节。虽然长期以来人们一直认为IgE介导的反应在变态反应性疾病中占主导地位，但新的证据表明，来自变态反应者的树突状细胞损害了Toll样受体(TLR)介导的反应。这些发现导致假设先天(TLR)和获得性(IgE)免疫受体之间可能存在交叉调节机制及其在树突状细胞上的功能，这可能有助于过敏性疾病的表现。目前还没有确定在体外是否存在与IgE/TLR相互作用的临床相关性。例如，过敏者树突状细胞上的TLR/IgE受体是否与非过敏者在表型和/或功能上不同？从过敏性鼻炎等过敏性疾病人群中获得的树突状细胞与从食物过敏者或哮喘患者中获得的树突状细胞功能是否完全相同？免疫治疗是否影响树突状细胞功能或IgE/TLR受体的相互作用？在这项建议中，我们旨在定义和对比三种不同疾病组中树突状细胞中主要的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-重度变应性鼻炎。我们将比较树突状细胞在每种疾病中的作用机制，以帮助揭示过敏性疾病的病理基础。在这样做的时候，我们的目标是确定治疗的重要靶点--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。我们将剖析人树突状细胞上的IgE受体的性质，并构建一个过敏原相互作用的模型。我们将分析树突状细胞信号事件的成分。最后，我们将专门研究对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。这个项目的目标是扩大我们对人类树突状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的机制有关。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。

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.