Allergy Protection by Active IgE B Cell Vaccines

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、过敏反应每年在美国造成180亿美元的医疗费用和生产力损失。 B细胞对IgE产生的调节由Th 2细胞因子以及B细胞和Th 2的同源相互作用协调。 IL-4通过扭曲Th 2发育而促进IgE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IgE B细胞表位可以用作产生抗IgE的保护性疫苗，其随后去除循环的人IgE。 事实上，III期临床试验显示，给予哮喘患者的人源化MAb抗IgE降低了循环IgE水平并减轻了过敏症状。 产生针对IgE B细胞表位的抗体是至关重要的，所述抗体阻断IgE与高亲和力I型IgE Fc受体（FceRI α）的结合，并防止肥大细胞脱粒。 因此，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含有11个β-折叠片，其约束不同区域的环。 将克隆和表达对应于IgE结合FceRIa的环。 针对限制性抗原化B细胞表位产生的抗体将在高通量测定中阻断人IgE与重组人FceRI α受体的结合（Aim I）。在此，我们提出确定抗IgE的性质以及抗人IgE的诱导是否将改善小鼠中IgE介导的过敏性疾病。 因此，我们将用表达对硝基苯酚（NP）特异性的膜结合人IgE以及I型高亲和力IgE Fc受体α链（FceRI α）的B细胞构建转基因小鼠。 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。 此外，我们将确定这些小鼠的气道炎症程度（目的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)