Allergy Protection by Active IgE B Cell Vaccines

描述（由申请人提供）：在这个国家，ige介导的过敏性哮喘、鼻炎、食物过敏、特应性皮炎、过敏反应每年花费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细胞因子和B细胞与Th2的同源相互作用协调的。IL-4通过扭曲Th2的发展来促进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。这提示了产品概念，即人类IgE B细胞表位可能被用作产生抗IgE的保护性疫苗，从而去除循环中的人类IgE。事实上，III期临床试验表明，给哮喘患者施用人源化单抗抗IgE可降低循环IgE水平，减轻过敏症状。培养针对IgE B细胞表位的抗体至关重要，这些表位可以阻断IgE与高亲和力I型IgE Fc受体（FceRI α）的结合，并阻止肥大细胞脱颗粒。在此，我们提出了保护性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β -褶片，它们约束不同区域的环。与IgE结合FceRI α相对应的环将被克隆和表达。在高通量实验（Aim I）中，针对受限抗原B细胞表位的抗体将阻断人IgE与重组人FceRI α受体的结合。在此，我们拟确定抗IgE的性质，以及诱导抗人IgE是否会改善IgE介导的小鼠变应性疾病。因此，我们将构建具有表达膜结合的人对硝基酚（NP）特异性IgE以及I型高亲和力IgE Fc受体α链（FceRI α）的转基因小鼠。我们将确定主动免疫是否会导致保护性抗IgE，然后从血清中去除NP特异性IgE。进一步，我们将确定这些小鼠的气道炎症程度（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)