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.

[1]  P. Sly,et al.  Animal models of asthma , 2007, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[2]  R. Puri,et al.  IL-13 signaling through the IL-13alpha2 receptor is involved in induction of TGF-beta1 production and fibrosis. , 2006, Nature medicine.

[3]  C. Mccusker,et al.  Interleukin‐13‐dependent bronchial hyper‐responsiveness following isolated upper‐airway allergen challenge in a murine model of allergic rhinitis and asthma , 2005, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[4]  D. Eidelman,et al.  IL-13 may mediate allergen-induced hyperresponsiveness independently of IL-5 or eotaxin by effects on airway smooth muscle. , 2005, American journal of physiology. Lung cellular and molecular physiology.

[5]  S. Hemmerich,et al.  Therapeutic targeting of endothelial ligands for L-selectin (PNAd) in a sheep model of asthma. , 2005, The American journal of pathology.

[6]  Jian Li,et al.  Anti-IL-13 monoclonal antibody inhibits airway hyperresponsiveness, inflammation and airway remodeling. , 2004, Cytokine.

[7]  M. Wills-Karp,et al.  Interleukin‐13 in asthma pathogenesis , 2004, Immunological reviews.

[8]  H. Ikeda,et al.  STAT6-mediated signaling in Th2-dependent allergic asthma: critical role for the development of eosinophilia, airway hyper-responsiveness and mucus hypersecretion, distinct from its role in Th2 differentiation. , 2004, International immunology.

[9]  Lauren Cohn,et al.  Asthma: mechanisms of disease persistence and progression. , 2004, Annual review of immunology.

[10]  A. Musani,et al.  Bronchoalveolar lavage fluid concentrations of transforming growth factor (TGF)‐β1, TGF‐β2, interleukin (IL)‐4 and IL‐13 after segmental allergen challenge and their effects on α‐smooth muscle actin and collagen III synthesis by primary human lung fibroblasts , 2004, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[11]  V. Koteliansky,et al.  A Monoclonal Antibody to α1β1 Blocks Antigen-induced Airway Responses in Sheep , 2004 .

[12]  V. Koteliansky,et al.  A monoclonal antibody to alpha1beta1 blocks antigen-induced airway responses in sheep. , 2004, American journal of respiratory and critical care medicine.

[13]  Qing Yang,et al.  The negative-feedback regulation of the IL-13 signal by the IL-13 receptor alpha2 chain in bronchial epithelial cells. , 2003, Cytokine.

[14]  R. Panettieri,et al.  IL‐13 enhances agonist‐evoked calcium signals and contractile responses in airway smooth muscle , 2003, British journal of pharmacology.

[15]  T. Wynn.  IL-13 effector functions. , 2003, Annual review of immunology.

[16]  A. Choi.  American journal of respiratory cell and molecular biology: Introduction , 2003 .

[17]  F. Finkelman,et al.  Dependence of IL-4, IL-13, and Nematode-Induced Alterations in Murine Small Intestinal Smooth Muscle Contractility on Stat6 and Enteric Nerves1 , 2003, The Journal of Immunology.

[18]  Ray Jupp,et al.  Molecular Characterization of Antigen‐Induced Lung Inflammation in a Murine Model of Asthma , 2002, Annals of the New York Academy of Sciences.

[19]  S. Shore,et al.  Effects of cytokines on contractile and dilator responses of airway smooth muscle , 2002, Clinical and experimental pharmacology & physiology.

[20]  D. Sheppard,et al.  Direct effects of interleukin-13 on epithelial cells cause airway hyperreactivity and mucus overproduction in asthma , 2002, Nature Medicine.

[21]  P. Foster,et al.  Role of interleukin‐13 in eosinophil accumulation and airway remodelling in a mouse model of chronic asthma , 2002, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[22]  D. Romberger,et al.  Th2 cytokine regulation of type I collagen gel contraction mediated by human lung mesenchymal cells. , 2002, American journal of physiology. Lung cellular and molecular physiology.

[23]  M. Vogelbaum,et al.  IL-13R(alpha)2, a decoy receptor for IL-13 acts as an inhibitor of IL-4-dependent signal transduction in glioblastoma cells. , 2002, Cancer research.

[24]  S. Collins,et al.  Role of IL-4, IL-13, and STAT6 in inflammation-induced hypercontractility of murine smooth muscle cells. , 2002, American journal of physiology. Gastrointestinal and liver physiology.

[25]  D. Corry,et al.  The Th2 lymphocyte products IL-4 and IL-13 rapidly induce airway hyperresponsiveness through direct effects on resident airway cells. , 2002, American journal of respiratory cell and molecular biology.

[26]  K. Haley,et al.  Effects of IL-13 on airway responses in the guinea pig. , 2002, American journal of physiology. Lung cellular and molecular physiology.

[27]  D. Umetsu,et al.  Critical Role for IL-13 in the Development of Allergen-Induced Airway Hyperreactivity1 , 2001, The Journal of Immunology.

[28]  T. Horie,et al.  IL-4 and IL-13 induce myofibroblastic phenotype of human lung fibroblasts through c-Jun NH2-terminal kinase-dependent pathway. , 2001, The Journal of allergy and clinical immunology.

[29]  Yongbok Kim,et al.  Enhanced Airway Th2 Response After Allergen Challenge in Mice Deficient in CC Chemokine Receptor-2 (CCR2)1 , 2001, The Journal of Immunology.

[30]  E. Gelfand,et al.  Temporal association between airway hyperresponsiveness and airway eosinophilia in ovalbumin-sensitized mice. , 2001, American journal of respiratory and critical care medicine.

[31]  Philip Smith,et al.  IL-13 Overexpression Predisposes to Anaphylaxis Following Antigen Sensitization1 , 2001, The Journal of Immunology.

[32]  H. Oettgen.  Regulation of the IgE isotype switch: new insights on cytokine signals and the functions of ε germline transcripts , 2000 .

[33]  A. Gill,et al.  A Small-Molecule, Tight-binding Inhibitor of the Integrin α4β1 Blocks Antigen-induced Airway Responses and Inflammation in Experimental Asthma in Sheep , 2000 .

[34]  A. Gill,et al.  A small-molecule, tight-binding inhibitor of the integrin alpha(4)beta(1) blocks antigen-induced airway responses and inflammation in experimental asthma in sheep. , 2000, American journal of respiratory and critical care medicine.

[35]  H. Oettgen.  Regulation of the IgE isotype switch: new insights on cytokine signals and the functions of epsilon germline transcripts. , 2000, Current opinion in immunology.

[36]  R. Homer,et al.  Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production. , 1999, The Journal of clinical investigation.

[37]  W. Fokkens,et al.  Increase in IL-8, IL-10, IL-13, and RANTES mRNA levels (in situ hybridization) in the nasal mucosa after nasal allergen provocation. , 1999, The Journal of allergy and clinical immunology.

[38]  R. Dixon,et al.  Selectin blockade prevents antigen-induced late bronchial responses and airway hyperresponsiveness in allergic sheep. , 1999, American journal of respiratory and critical care medicine.

[39]  D B Corry,et al.  Requirement for IL-13 independently of IL-4 in experimental asthma. , 1998, Science.

[40]  D D Donaldson,et al.  Interleukin-13: central mediator of allergic asthma , 1998 .

[41]  D D Donaldson,et al.  The murine IL-13 receptor alpha 2: molecular cloning, characterization, and comparison with murine IL-13 receptor alpha 1. , 1998, Journal of immunology.

[42]  K C Lin,et al.  Very late antigen 4 (VLA4) antagonists as anti-inflammatory agents. , 1998, Current opinion in chemical biology.

[43]  S. Durham,et al.  IL-13 mRNA and immunoreactivity in allergen-induced rhinitis: comparison with IL-4 expression and modulation by topical glucocorticoid therapy. , 1997, American journal of respiratory cell and molecular biology.

[44]  S. Durham,et al.  Associations between IL-13 and IL-4 (mRNA and protein), vascular cell adhesion molecule-1 expression, and the infiltration of eosinophils, macrophages, and T cells in allergen-induced late-phase cutaneous reactions in atopic subjects. , 1997, Journal of immunology.

[45]  R. Moritz,et al.  Identification, Purification, and Characterization of a Soluble Interleukin (IL)-13-binding Protein , 1997, The Journal of Biological Chemistry.

[46]  L. Notarangelo,et al.  A novel 4‐kb interleukin‐13 receptor α mRNA expressed in human B, T, and endothelial cells encoding an alternate type‐II interleukin‐4/ interleukin‐13 receptor , 1997, European journal of immunology.

[47]  R. Puri,et al.  IL-13 induces phosphorylation and activation of JAK2 Janus kinase in human colon carcinoma cell lines: similarities between IL-4 and IL-13 signaling. , 1996, Journal of immunology.

[48]  J. Butterfield,et al.  Role of tryptase in immediate cutaneous responses in allergic sheep. , 1995, Journal of applied physiology.

[49]  P. Ferrara,et al.  IL‐13 and IL‐4 share signal transduction elements as well as receptor components in TF‐1 cells , 1995, FEBS letters.

[50]  G. Nilsson,et al.  Effects of interleukin (IL)‐13 on immediate‐early response gene expression, phenotype and differentiation of human mast cells. Comparison with IL‐4 , 1995, European journal of immunology.

[51]  C. Benjamin,et al.  Alpha 4-integrins mediate antigen-induced late bronchial responses and prolonged airway hyperresponsiveness in sheep. , 1994, The Journal of clinical investigation.

[52]  R. de Waal Malefyt,et al.  Interleukin 13, a T-cell-derived cytokine that regulates human monocyte and B-cell function. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[53]  J. Stevenson,et al.  Nedocromil sodium in allergen-induced bronchial responses and airway hyperresponsiveness in allergic sheep. , 1988, Journal of applied physiology.

[54]  P. O'Byrne,et al.  Late asthmatic responses. , 1987, The American review of respiratory disease.