Allergy Protection by Active IgE B Cell Vaccines

描述(申请人提供)：免疫球蛋白介导的过敏性哮喘、鼻炎、食物过敏、特应性皮炎、过敏反应在这个国家每年造成180亿美元的医疗费用和生产力损失。B细胞对IgE产生的调节是由Th2细胞因子以及B细胞和Th2的同源相互作用调节的。IL-4通过扭曲Th2细胞的发育促进IgE的产生。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。这引发了这样的产品概念，即人IgE B细胞表位可能被用作保护性疫苗，用于产生抗LGE，从而清除循环中的人IgE。事实上，第三阶段临床试验表明，人源化单抗、抗IgE应用于哮喘患者可降低循环中的IgE水平，并缓解过敏症状。提高针对IgE B细胞表位的抗体，以阻断IgE与高亲和力的I型IgE Fc受体(FceRIα)的结合，并防止肥大细胞脱颗粒，是至关重要的。在此，我们提出了保护性的IgE B细胞表位可能被限制在绿色荧光蛋白(GFP)支架环中的研究。GFP包含11个Beta折叠的薄片，限制了不同区域的环路。与FceRIα结合的IgE对应的环将被克隆和表达。针对受限制的抗原化B细胞表位的抗体将在高通量试验(Aim I)中阻断人IgE与重组人FceRIα受体的结合。因此，我们建议确定抗IgE的性质以及诱导抗人IgE是否能改善IgE介导的变态反应性疾病。因此，我们将构建表达膜结合的人硝基酚(NP)特异性IgE和I型高亲和力IgE Fc受体α链(FceRIα)的B细胞转基因小鼠。我们将确定主动免疫是否会产生保护性的抗LGE抗体，然后从血清中去除NP特异性的IgE。此外，我们将确定这些小鼠的呼吸道炎症程度(AIM II)

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)