Efficacy of IgE in Mediating Allergic Reactions in Vivo

IgE 在介导体内过敏反应中的功效

• 批准号: 7134190
• 负责人: Donald W MacGlashan
• 金额: $ 111.7万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7134190
• 关键词: clinical research; cooperative study; human subject; hypersensitivity; immunoglobulin E; immunoregulation; patient oriented research

DESCRIPTION (provided by applicant): The central element in allergic diseases such as asthma, rhinitis and eczema, is the presence of IgE antibody. While there is general acceptance of the central role for IgE in these diseases, there remains only a poor understanding of the quantitative requirements for IgE in the expression of these diseases. This application focuses on obtaining better quantitative insights on several aspects of the problem. In project by Bochner, two underlying hypotheses are examined, 1) that it is the ratio of antigen-specific IgE to total IgE that is a critical determinant of an in vivo response to allergen challenge and 2) that mast cells are a central determinant in early tissue localized reactions like those in the nose while basophils are involved in food reactions where antigen exposure is likely to occur in the blood. Project 2 offers an extended hypothesis for critical parameters, that not only is the specific to total IgE ratio important, but cellular sensitivity (the quantitative assessment of a cell's ability to respond to antigen) also defines the response. Other aims in project by Macglashan address issues of FceRI expression, how the beta subunit of this receptor is controlled and its influence on overall expression of FceRI and how other early signaling molecule expression is regulated by IgE antibody. A common theme in these studies as well as a theme that binds the various projects together is that the regulation is quantitatively different in vivo than in vitro and we will be assessing these differences and how they influence our understanding of disease expression. In one respect, project by Shroeder re-examines quantitative aspects of basophil and mast cell responses. While staying with the theme of IgE centrality, Project 3 examines the FceRI-bearing antigen-presenting cells and the interaction of FceRI and innate immune receptors. Aims in this project will examine how changes in IgE antibody alter expression of FceRI on dendritic cells and whether this results in changes in the expression and profile of cytokines elaborated by these cells. Changes in the expression and function of innate receptors on dendritic cells and basophils will also be a focus of this project. Finally, this project will examine the influence of IgE on the systemic effects of large local reactions by examining various parameters of basophil and dendritic cell function following in vivo manipulation of IgE and experimental antigen exposure. All projects will modulate IgE levels in vivo to make quantitative determinations of the effects these changes have on various outcomes associated with allergic diseases. Beyond the required administrative core (A), there are two scientific Cores. The Subject Characterization and Recruitment Core provides the comprehensive subject recruitment and characterization that is required for all three projects. The Diagnostics Core provides the comprehensive diagnostic and laboratory assays needed for all three projects.

描述（由申请人提供）： 过敏性疾病如哮喘、鼻炎和湿疹的中心因素是IgE抗体的存在。虽然人们普遍接受IgE在这些疾病中的核心作用，但对IgE在这些疾病表达中的定量要求仍然缺乏了解。这个应用程序的重点是在问题的几个方面获得更好的定量见解。在Bochner的项目中，检查了两个基本假设，1）抗原特异性IgE与总IgE的比率是体内对过敏原激发反应的关键决定因素，2）肥大细胞是早期组织局部反应（如鼻内反应）的中心决定因素，而嗜碱性粒细胞参与食物反应，其中抗原暴露可能发生在血液中。项目2为关键参数提供了一个扩展假设，即不仅特异性IgE与总IgE的比率很重要，而且细胞敏感性（细胞对抗原应答能力的定量评估）也定义了应答。Macglashan项目的其他目标解决了FceRI表达的问题，该受体的β亚基如何被控制及其对FceRI整体表达的影响，以及其他早期信号分子表达如何被IgE抗体调节。这些研究中的一个共同主题以及将各种项目结合在一起的主题是，体内调控与体外调控在数量上不同，我们将评估这些差异以及它们如何影响我们对疾病表达的理解。一方面，Shroeder的项目重新检查了嗜碱性粒细胞和肥大细胞反应的定量方面。在坚持IgE中心性主题的同时，项目3研究了携带FceRI的抗原呈递细胞以及FceRI与先天免疫受体的相互作用。本项目的目的是研究IgE抗体的变化如何改变树突状细胞上FceRI的表达，以及这是否会导致这些细胞产生的细胞因子的表达和谱发生变化。树突状细胞和嗜碱性粒细胞上先天受体的表达和功能的变化也将是该项目的重点。最后，本项目将研究IgE对大的局部反应的全身效应的影响，通过检查各种参数的嗜碱性粒细胞和树突状细胞功能后，在体内操作的IgE和实验抗原暴露。所有项目都将在体内调节IgE水平，以定量测定这些变化对与过敏性疾病相关的各种结果的影响。除了所需的行政核心（A）之外，还有两个科学核心。受试者特征描述和招募核心提供了所有三个项目所需的全面受试者招募和特征描述。诊断核心提供了所有三个项目所需的全面的诊断和实验室检测。