Efficacy of IL-13 neutralization in a sheep model of experimental asthma

Marion T. Kasaian, Debra D. Donaldson, Lioudmila Tchistiakova, Kimberly Marquette, Xiang Yang Tan, Ashfaq Ahmed, Bruce A. Jacobson, Angela Widom, Timothy A. Cook, Xin Xu, Anthony B. Barry, Samuel J. Goldman, William M. Abraham

Research output: Contribution to journalArticle

52 Scopus citations

Abstract

IL-13 contributes to airway hyperresponsiveness, mucus secretion, inflammation, and fibrosis, suggesting that it plays a central role in asthma pathogenesis. Neutralization of IL-13 with sIL-13Rα2-Fc (sIL-13R) reduces allergen-induced airway responses in rodent models of respiratory disease, but its efficacy in a large animal model has not been previously reported. In this study, we determined whether two different strategies for IL-13 neutralization modified experimental asthma in sheep. Sheep with natural airway hypersensitivity to Ascaris suum antigen were treated intravenously either with sIL-13R, a strong antagonist of sheep IL-13 bioactivity in vitro, or with IMA-638 (IgG1, κ), a humanized antibody to human IL-13. Higher doses of IMA-638 were used because, although it is a potent antagonist of human IL-13, this antibody has 20 to 30 times lower binding and neutralization activity against sheep IL-13. Control animals received human IgG of irrelevant specificity. Sheep were treated 24 h before inhalation challenge with nebulized A. suum. The effects on antigen-induced early and late bronchial responses, and antigen-induced hyperresponsiveness, were assessed. Both sIL-13R and IMA-638 provided dose-dependent inhibition of the antigen-induced late responses and airway hyperresponsiveness. The highest dose of IMA-638 also reduced the early phase response. These findings suggest that IL-13 contributes to allergen-induced airway responses in this sheep model of asthma, and that neutralization of IL-13 is an effective strategy for blocking these A. suum-induced effects.

Original languageEnglish (US)
Pages (from-to)368-376
Number of pages9
JournalAmerican journal of respiratory cell and molecular biology
Volume36
Issue number3
DOIs
StatePublished - Mar 1 2007

Keywords

  • Airway hyperresponsiveness
  • Ascaris suum
  • Late phase
  • Sheep

ASJC Scopus subject areas

  • Cell Biology
  • Pulmonary and Respiratory Medicine
  • Molecular Biology

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  • Cite this

    Kasaian, M. T., Donaldson, D. D., Tchistiakova, L., Marquette, K., Tan, X. Y., Ahmed, A., Jacobson, B. A., Widom, A., Cook, T. A., Xu, X., Barry, A. B., Goldman, S. J., & Abraham, W. M. (2007). Efficacy of IL-13 neutralization in a sheep model of experimental asthma. American journal of respiratory cell and molecular biology, 36(3), 368-376. https://doi.org/10.1165/rcmb.2006-0244OC