Allergy Protection by Active IgE B Cell Vaccines

活性 IgE B 细胞疫苗的过敏保护

• 批准号: 6585616
• 负责人: Swey-Shen Chen
• 金额: $ 25.31万
• 依托单位: IGE THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-01 至 2004-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6585616
• 关键词: B lymphocyte; active immunization; antiallergic agents; gene expression; genetically modified animals; green fluorescent proteins; hypersensitivity; immunoglobulin E; immunologic substance development /preparation; laboratory mouse; molecular cloning; vaccine development

DESCRIPTION (provided by applicant): IgE-mediated allergic asthma, rhinitis, food allergy, atopic dermatitis, anaphylaxis cost annual 18 billions in medical costs and loss of productivity in this country. Regulation of IgE production by B cells is orchestrated by Th2 cytokines, and cognate interactions of B cells and Th2. IL-4 contributes to IgE production by skewing Th2 development. In animal model, our early studies demonstrated that IgE production can be down-regulated by IgE immunization. This prompts the product concept that human IgE B cell epitopes may be employed as protective vaccines for generating anti-lgE, which subsequently removes circulating human IgE. Indeed phase III clinical trial showed that humanized MAb, anti-IgE administered to asthmatic patients reduces levels of circulating IgE and alleviates allergic symptoms. It is critically important to raise antibodies against IgE B cell epitopes that block IgE binding to high affinity type I IgE Fc receptor (FceRI alpha, and prevent mast cell degranulation. Herein we propose the study that protective IgE B cell epitopes may be constrained in the loops of scaffold of green fluorescent protein (GFP). GFP contains 11 beta-pleated sheets which constrain loops of distinct regions. Loops corresponding to the IgE binding to FceRI alpha will be cloned and expressed. Antibodies raised to the constrained antigenized B cell epitopes will block human IgE binding to recombinant human FceRI alpha receptor in a high throughput assay (Aim I).Herein, we propose to determine the nature of anti-IgE and whether induction of anti-human IgE will ameliorate the IgE-mediated allergic diseases in mice. Thus, we will construct transgenic mice with B cells expressing membrane bound human IgE specific for nitrophenol (NP) as well as type I high affinity IgE Fc receptor alpha chain (FceRI alpha. We will determine whether active immunization will lead to protective anti-lgE which then removes NP specific IgE from the sera. Further, we will determine the degree of airway inflammation of these mice (Aim II)

描述（由申请人提供）：IgE介导的过敏性哮喘，鼻炎，食物过敏，特应性皮炎，过敏反应每年为180亿次医疗费用和该国的生产力损失。 B细胞对IgE产生的调节是由Th2细胞因子策划的，而B细胞与Th2的同源相互作用。 IL-4通过歪曲TH2开发促进IGE生产。在动物模型中，我们的早期研究表明，IgE免疫可以下调IgE的产生。 这促使产品概念是，人IgE B细胞表位可以用作产生抗LGE的保护性疫苗，随后消除了循环的人IgE。 实际上，第三阶段的临床试验表明，对哮喘患者的人性化mAb，抗神经抗体，降低了循环IgE的水平并减轻过敏症状。 提出针对IgE B细胞表位的抗体的抗体非常重要与IgE结合的不同区域的循环将被克隆并表达，并表达与约束的抗原抗原B细胞表位的抗体。因此，IgE介导的小鼠过敏性疾病。这些小鼠的炎症（AIM II）