Elsevier

Cytokine

Volume 28, Issue 6, 21 December 2004, Pages 224-232
Cytokine

Anti-IL-13 monoclonal antibody inhibits airway hyperresponsiveness, inflammation and airway remodeling

https://doi.org/10.1016/j.cyto.2004.08.007Get rights and content

Abstract

Asthma is a chronic inflammatory disease characterized by reversible bronchial constriction, pulmonary inflammation and airway remodeling. Current standard therapies for asthma provide symptomatic control but fail to target the underlying disease pathology. Furthermore, no therapeutic agent is effective in preventing airway remodeling. Interleukin 13 (IL-13) is a pleiotropic cytokine produced mainly by T cells. A substantial amount of evidence suggests that IL-13 plays a critical role in the pathogenesis of asthma. Therefore, a neutralizing anti-IL-13 monoclonal antibody could provide therapeutic benefits to asthmatic patients. To test the concept we have generated a neutralizing rat anti-mouse IL-13 monoclonal antibody, and evaluated its effects in a chronic mouse model of asthma. Chronic asthma-like response was induced in ovalbumin (OVA) sensitized mice by repeated intranasal OVA challenges. After weeks of challenge, mice developed airway hyperresponsiveness (AHR) to methacholine stimulation, severe airway inflammation, hyper mucus production, and subepithelial fibrosis. When given at the time of each intranasal OVA challenge, anti-IL-13 antibody significantly suppressed AHR, eosinophil infiltration, proinflammatory cytokine/chemokine production, serum IgE, and most interestingly, airway remodeling. Taken together, these results strongly suggest that a neutralizing anti-human IL-13 monoclonal antibody could be an effective therapeutic agent for asthma.

Introduction

Asthma is a chronic disease characterized by reversible airway obstruction, pulmonary inflammation and airway remodeling [1]. Although current standard therapies (including corticosteroids and β2 receptor agonists) effectively provide symptomatic control for the majority of asthma patients, patients with severe or difficult asthma do not respond well to these therapies [2]. Furthermore, no therapeutic agent is effective in preventing airway remodeling, which involves epithelial damage, mucus gland hyperplasia, airway smooth muscle hypertrophy, and subepithelial fibrosis [3]. These structural changes of the airway, caused by chronic airway inflammation and a repeated damage/repair process, are fundamental components for the development of irreversible airway hyperresponsiveness and directly contribute to the severity of asthma [4]. Therefore, developing therapeutic agents that can suppress airway tissue remodeling would fulfill a significant unmet medical need in the treatment of asthma.

IL-13 is an immunomodulating cytokine produced by activated T cells and many other cell types [5]. The involvement of IL-13 in asthma pathogenesis has been extensively studied [6]. In humans, IL-13 levels are upregulated in asthmatics both systemically and in the lungs during asthmatic attacks [7]. Certain IL-13 polymorphisms are associated with high serum IgE levels and high risk for asthma development [8]. Furthermore, IL-13 exhibits stimulatory activity to multiple cell types that are involved in asthma, including B cells, mast cells, eosinophils, pulmonary epithelial cells, fibroblasts and airway smooth muscle cells [5]. In animal studies, direct administration of recombinant IL-13 or overexpression of IL-13 in the lungs induced asthma-like airway inflammation and airway remodeling [9], [10]. Blockade of IL-13 using a receptor fusion protein inhibited the allergic asthma response in mice [11], [12]. Taken together, these results strongly suggest that IL-13 plays a crucial role in the pathogenesis of asthma. Therefore, a neutralizing monoclonal antibody (mAb) to IL-13 could provide therapeutic benefits to asthmatic patients.

A neutralizing rat anti-mouse IL-13 mAb was generated using standard hybridoma technology. To fully evaluate the impact of this anti-IL-13 mAb on different pathological aspects of asthma, especially on airway remodeling, a chronic asthma model was developed using repeated intranasal antigen (Ag) challenge to sensitized mice. After 5 weeks of weekly challenge, the mice developed multiple pathological features that represented those of human asthma, including airway hyperresponsiveness (AHR), severe pulmonary inflammation and airway remodeling. When administered at the same time as each Ag challenge, anti-IL-13 antibody effectively suppressed AHR, eosinophil infiltration, goblet cell hyperplasia, excessive mucus production, as well as subepithelial fibrosis. These results indicated that a neutralizing mAb to human IL-13 could potentially control asthma symptoms as well as preserve normal airway structure and function.

Section snippets

Neutralizing anti-IL-13 mAb inhibits AHR to methacholine stimulation

Increased airway responsiveness and sensitivity to nonspecific stimulation is a major pathological characteristic of human asthma. To evaluate the effect of anti-IL-13 mAb on airway constriction, whole body plethysmography was used to measure airway resistance to incremental concentrations of methacholine. Mice that were sensitized with OVA but challenged with PBS for 5 weeks revealed a low baseline airway resistance (represented as Penh) and the Penh values were slightly increased upon

Discussion

IL-13 is a pleiotropic cytokine that is involved in multiple physiological and pathological processes [5]. To date accumulating evidence indicates that IL-13 plays a key role in the pathogenesis of asthma [6], which makes it a very attractive target for the treatment of asthma. In this report, using a mouse model of chronic asthma, we found that the anti-IL-13 mAb significantly inhibited methacholine induced AHR, pulmonary inflammation, multiple cytokine/chemokine production, goblet cell

Mice

Naïve BALB/c mice were purchased from Charles Rivers Laboratories (Raleigh NC). All mice were maintained under specific pathogen free conditions, and all experimental protocols were approved by the Institutional Animal Care and Use Committee of Centocor.

Reagents

Ovalbumin (OVA) and methacholine were purchased from Sigma (St. Louis, MO).

Normal rat IgG and peroxidase-conjugated streptavidin were from Jackson ImmunoResearch (West Grove, PA). ELISA reagents for measuring serum immunoglobulin isotypes were

References (44)

  • S.T. Holgate et al.

    Roles of cysteinyl leukotrienes in airway inflammation, smooth muscle function, and remodeling

    J Allergy Clin Immunol

    (2003)
  • T.A. Wynn

    IL-13 effector functions

    Annu Rev Immunol

    (2003)
  • M. Wills-Karp et al.

    Interleukin-13 in asthma

    Curr Opin Pulm Med

    (2003)
  • D. Vercelli

    Genetics of IL-13 and functional relevance of IL-13 variants

    Curr Opin Allergy Clin Immunol

    (2002)
  • M. Yang et al.

    Interleukin-13 mediates airways hyperreactivity through the IL-4 receptor-alpha chain and STAT-6 independently of IL-5 and eotaxin

    Am J Respir Cell Mol Biol

    (2001)
  • Z. Zhu et al.

    Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production

    J Clin Invest

    (1999)
  • M. Wills-Karp et al.

    Interleukin-13: central mediator of allergic asthma

    Science

    (1998)
  • G. Grunig et al.

    Requirement for IL-13 independently of IL-4 in experimental asthma

    Science

    (1998)
  • J.A. Elias et al.

    Airway remodeling in asthma

    J Clin Invest

    (1999)
  • S.T. Holgate et al.

    Bronchial epithelium as a key regulator of airway allergen sensitization and remodeling in asthma

    Am J Respir Crit Care Med

    (2000)
  • D.M. Walter et al.

    Critical role for IL-13 in the development of allergen-induced airway hyperreactivity

    J Immunol

    (2001)
  • D.C. Webb et al.

    Integrated signals between IL-13, IL-4, and IL-5 regulate airways hyperreactivity

    J Immunol

    (2000)
  • Cited by (171)

    • Inhaled Janus Kinase (JAK) inhibitors for the treatment of asthma

      2019, Bioorganic and Medicinal Chemistry Letters
    • Therapeutic efficacy of a co-blockade of IL-13 and IL-25 on airway inflammation and remodeling in a mouse model of asthma

      2017, International Immunopharmacology
      Citation Excerpt :

      The induction of goblet cell metaplasia and mucus hyperproduction by IL-13 [24] or IL-25 [20] has been confirmed by previous studies. The current findings are consistent with and extend previous observations that neutralization of IL-13 [31] and IL-25 [17] alone both successfully attenuate mucus production and goblet cell hyperplasia. Moreover, the combination therapy exhibited additional effectiveness in our study.

    View all citing articles on Scopus
    View full text