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Suppression of IgE B Cells and IgE Binding to FcRI by Gene Therapy with Single-Chain Anti-IgE¹

Takayuki Ota^*, Miyo Aoki-Ota^*, Bao Hoa Duong^*, and David Nemazee^2,*

^* Department of Immunology and Microbial Science and Kellogg School of Science and Technology Doctoral Program in Chemical and Biological Sciences, The Scripps Research Institute, La Jolla, CA 92037

IgE plays a pivotal role in allergic reactions and asthma through its ability to bind to the mast cell FcR for IgE (FcRI). Current therapies to suppress such reactions include passive treatment with neutralizing Abs to IgE that block its binding to FcRI. In theory, induction of immune tolerance in the B lymphocytes that carry IgE Ag receptors and give rise to IgE-secreting cells should provide longer term efficacy. However, recent data have suggested that such memory cells may lack cell surface IgE. Using a gene therapy approach, we show that a recombinant single-chain neutralizing anti-IgE could not only neutralize circulating IgE, but also reduce IgE⁺ B cell numbers and H chain transcripts. Therapeutic anti-IgE stimulated a calcium response in primary B cells or in a B cell line expressing membrane IgE and suppressed IgE secretion in vitro, suggesting that active signaling through membrane IgE likely promoted tolerance. Interestingly, upon subsequent challenge of anti-IgE-treated mice with an IgE cross-linking reagent capable of inducing activation of IgE-decorated mast cells, an anaphylaxis reaction was induced, apparently via a FcRIII pathway involving recognition of anti-IgE Ab itself. These studies have important implications for the optimal design of safe and effective anti-IgE therapies and suggest that the IgE memory B cells may be targeted by such genetic Ab therapies.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant R21AI069866 and by a Pfizer Postdoctoral Fellowship (to T.O.).

² Address correspondence and reprint requests to Dr. David Nemazee, Department of Immunology and Microbial Science, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037. E-mail address: nemazee{at}scripps.edu

³ Abbreviations used in this paper: mIgE, membrane IgE; scFv, single-chain variable fragment; qPCR, quantitative PCR; TNP, 2,4,6-trinitrophenyl.

⁴ The online version of this article contains supplemental material.

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The JI 2009 182: 7329-7330. [Full Text]