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)
| Gong, Jian; Yang, Ning-Sun; Croft, Michael et al. (2010) The antigen presentation function of bone marrow-derived mast cells is spatiotemporally restricted to a subset expressing high levels of cell surface FcepsilonRI and MHC II. BMC Immunol 11:34 |
| Chen, Swey-Shen; Barankiewicz, Teresa J; Yang, Yong-Min et al. (2008) IgE peptide-specific CTL inhibit IgE production: a transient IgE suppression model in wild-type and HLA-A2.1 transgenic mice. Cell Immunol 254:28-38 |
| Yang, Yong-Min; Barankiewicz, Teresa J; He, Mingyue et al. (2007) Selection of antigenic markers on a GFP-Ckappa fusion scaffold with high sensitivity by eukaryotic ribosome display. Biochem Biophys Res Commun 359:251-7 |
