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Published ahead of print on August 11, 2004, doi:10.1164/rccm.200405-681OC

Am. J. Respir. Crit. Care Med., Volume 170, Number 10, November 2004, 1043-1048

A more recent version of this article appeared on November 15, 2004
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Submitted on June 1, 2004
Accepted on August 6, 2004

Effects of Anti-Cytokine Therapy in a Mouse Model of Chronic Asthma

Rakesh K Kumar1*, Cristan Herbert1, Dianne C Webb2, Lily Li3, and Paul S Foster4

1 Department of Pathology, University of New South Wales, Sydney, NSW, Australia, 2 Division of Molecular Biosciences, Australian National University, John Curtin School of Medical Research, Canberra, ACT, Australia, 3 Immunobiology Research, Centocor Inc., Malvern, PA, USA, 4 Division of Molecular Biosciences, Australian National University, John Curtin School of Medical Research, Canberra, ACT, Australia; Discipline of Immunology and Microbiology, University of Newcastle, Faculty of Health, Newcastle, NSW, Australia

* To whom correspondence should be addressed. E-mail: r.kumar{at}unsw.edu.au.

The relative contribution of Th2 and Th1 cytokines to the pathogenesis of lesions of chronic asthma remains poorly understood. To date, therapeutic inhibition of Th2 cytokines has proved disappointing. We used a clinically relevant model of chronic allergic asthma in mice, to compare the effects of administering neutralizing antibodies to interleukin-13, interleukin-5 and interferon-{gamma} to animals with established disease. As has been observed in clinical studies, anti-interleukin-5 inhibited both inflammation and remodeling, but had no effect on airway responsiveness to methacholine. Anti-interleukin-13 effectively suppressed eosinophil recruitment and accumulation of chronic inflammatory cells in the airways. This treatment also partially suppressed changes of airway wall remodeling, including goblet cell hyperplasia/metaplasia and subepithelial fibrosis, but had limited ability to inhibit airway hyper-reactivity. In contrast, treatment with anti-interferon-{gamma} markedly suppressed airway hyper-reactivity. This antibody inhibited accumulation of chronic inflammatory cells but did not affect eosinophil recruitment or changes of remodeling. We conclude that inhibition of interleukin-5 is beneficial and inhibition of interleukin-13 has considerable potential as a therapeutic strategy in chronic asthma; that interferon-{gamma} may play an important role in the pathogenesis of airway hyper-reactivity; and that co-operative interaction between Th2 and Th1 cytokines contributes to the pathogenesis of the lesions of chronic asthma.
Key words: interleukin-5, interleukin-13, interferon-{gamma}, bronchial hyperreactivity, airway remodeling




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