Efficacy of IL-13 neutralization in a sheep model of experimental asthma.
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-13Ralpha2-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, kappa), 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.
Kasaian
Marion T
MT
Department of Inflammation, Wyeth Research, 200 CambridgePark Drive, Cambridge, MA 02140, USA. mkasaian@wyeth.com
Donaldson
Debra D
DD
Tchistiakova
Lioudmila
L
Marquette
Kimberly
K
Tan
Xiang-Yang
XY
Ahmed
Ashfaq
A
Jacobson
Bruce A
BA
Widom
Angela
A
Cook
Timothy A
TA
Xu
Xin
X
Barry
Anthony B
AB
Goldman
Samuel J
SJ
Abraham
William M
WM
D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D017165:Ascaris suum / Q000502:physiology; D001249:Asthma / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology* / Q000503:physiopathology; D001483:Base Sequence; D016535:Bronchial Hyperreactivity / Q000469:parasitology / Q000473:pathology; D016084:Bronchoconstriction / Q000187:drug effects / Q000276:immunology; D002217:Carbachol / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D019073:HT29 Cells; D006801:Humans; D018793:Interleukin-13 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D007700:Kinetics; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D053660:Receptors, Interleukin-13 / Q000378:metabolism; D034561:Sheep, Domestic / Q000276:immunology* / Q000469:parasitology; D012995:Solubility / Q000187:drug effects; D020349:Surface Plasmon Resonance; D013997:Time Factors
D000906:Antibodies; D018793:Interleukin-13; D053660:Receptors, Interleukin-13; D002217:Carbachol