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Suppression of IgE B cells and IgE binding to Fc(epsilon)RI by gene therapy with single-chain anti-IgE

Academic Article
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Overview

related to degree

  • Duong, Bao Hoa, Ph.D. in Macromolecular and Cellular Structure and Chemistry, Scripps Research 2003 - 2009

authors

  • Ota, Takayuki
  • Aoki-Ota, M.
  • Duong, Bao Hoa
  • Nemazee, David

publication date

  • June 2009

journal

  • Journal of Immunology  Journal

abstract

  • IgE plays a pivotal role in allergic reactions and asthma through its ability to bind to the mast cell FcR for IgE (FcepsilonRI). Current therapies to suppress such reactions include passive treatment with neutralizing Abs to IgE that block its binding to FcepsilonRI. 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 FcgammaRIII 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.

subject areas

  • Anaphylaxis
  • Animals
  • B-Lymphocytes
  • Cell Line
  • Genetic Therapy
  • Humans
  • Immunization
  • Immunoglobulin E
  • Mice
  • Mice, Inbred BALB C
  • Protein Binding
  • Receptors, IgE
  • Recombinant Proteins
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Identity

PubMed Central ID

  • PMC2874974

International Standard Serial Number (ISSN)

  • 0022-1767

Digital Object Identifier (DOI)

  • 10.4049/jimmunol.0900300

PubMed ID

  • 19494337
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Additional Document Info

start page

  • 8110

end page

  • 8117

volume

  • 182

issue

  • 12

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