FcERI Expression, Cellular Sensitivity, In vivo Response

FcERI 表达、细胞敏感性、体内反应

• 批准号: 7150225
• 负责人: Donald W MacGlashan
• 金额: $ 24.62万
• 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: 2006-07-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7150225
• 关键词: allergens; antibody receptor; antibody titering; antigen antibody reaction; basophils; biological signal transduction; cooperative study; histamine; human subject; immediate hypersensitivity; immunoglobulin E; laboratory mouse; mast cell; monoclonal antibody; pathologic process; patient oriented research; protein quantitation /detection; protein structure; protein structure function; receptor expression

Immediate hypersensitivity reactions result from the activation of mast cells at the interface between the outside environment and tissues such as airways, gastrointestinal tract and skin. IgE antibody binds to mast cells and basophils and upon aggregation of the receptor for IgE antibody, FceRI, the cell is activated to secrete a variety of mediators that cause the local and systemic response characteristic of allergies. It is well accepted that IgE mediates this kind of reaction but translation of this knowledge to the expression of allergic disease is poor. The question addressed in this project is how much IgE is necessary and what parameters adequately predict a response in an individual patient. Indirectly, this project asks whether these parameters alone are sufficient to account for responsiveness in vivo. The first aim directly addresses the issue and posits three critical parameters, IgE density on basophils or mast cells (which is itself regulated by IgE and other factors to be explored), the antigen-specific to total IgE ratio and the basophil (mast cell) sensitivity - a new parameter that is defined as the number of antigen-specific IgE molecules required for a 50% maximum response. A test of the importance of these three parameters is proposed which uses the drug omalizumab in cat allergic patients to manipulate IgE levels into each patients critical response region while measuring basophil and mast cell responses. The second aim focuses on the role of the beta subunit of FceRI on controlling basophil sensitivity to antigen stimulation and FceRI expression. This aim will also propose a manipulation of IgE levels in vivo to optimize changes induced by an experimental allergen challenge in vivo that is expected to alter cytokine levels that control FceRI beta expression. The primary goal is to assess the quantitative rates of receptor expression in vivo. The final two aims are related to aims 1 and 2; they examine the changes in signaling molecule expression during modulation of IgE in vivo and assess the rate of FceRI a synthesis in vivo using a unique method of analysis based on omalizumab-induced decay of FceRI expression.

肥大细胞在界面上激活肥大细胞引起的直接超敏反应 外部环境和组织，例如气道，胃肠道和皮肤。 IgE抗体结合 肥大细胞和嗜碱性粒细胞，以及在IgE抗体FCERI的受体聚集后，该细胞被激活 分泌各种导致过敏的局部和系统反应特征的介体。它 被公认为IgE介导了这种反应，但将这种知识转化为表达 过敏性疾病很差。该项目中解决的问题是需要多少IgE以及什么 参数可以充分预测单个患者的反应。间接地，这个项目询问是否 仅这些参数就足以说明体内响应能力。第一个目标直接 解决该问题并提出三个关键参数，即嗜碱性粒细胞或肥大细胞上的IgE密度（这是 由IgE和其他要探索的因素的调节），特定于抗原的总IgE比和 嗜碱性粒细胞（肥大细胞）灵敏度 - 一种定义为抗原特异性IgE数量的新参数 最大响应50％所需的分子。测试这三个参数的重要性是 提出了使用猫过敏患者中使用药物瘤的药物来操纵每种IgE水平的 患者在测量嗜碱性粒细胞和肥大细胞反应的同时关键反应区域。第二个目标 侧重于FCERI的Beta亚基在控制嗜碱性粒细胞对抗原刺激和的敏感性方面的作用 FCERI表达。这个目标还将提出对体内IgE水平的操纵，以优化变化 由实验过敏原挑战体内诱导的，该挑战预计会改变控制的细胞因子水平 FCERI Beta表达。主要目标是评估体内受体表达的定量速率。 最后两个目标与目标1和2有关；他们检查信号分子的变化 在体内调制IgE期间的表达，并使用A在体内评估FCERI的合成速率 基于球核酸诱导的FCERI表达衰减的独特分析方法。