Inhibition of the IL-4/1613 receptor system prevents allergic sensitization without affecting established allergy in a mouse model for allergic asthma

Background: IL-4 and IL-13 are considered as key regulators for the development of atopic disease. Objective: This study addresses the therapeutic potential of an IL-4/IL-13 inhibitor on the basis of a mutated IL-4 variant (Q116D, Y119D) during allergic sensitization and in established disease in a murine asthma model with persistent airway pathologic condition. Methods: BALB/c mice were sensitized with ovalbumin intranasally. Mice were treated with the IL-4/IL-13 inhibitor during the sensitization phase or alternatively after ovalbumin allergy was established. Specific antibodies were measured, and histologic lung sections were examined for goblet cell metaplasia. In addition, bronchoalveolar lavages were performed and checked for airway eosinophilia, IL-5 levels, and the number of IL-4 secreting CD4(+) T cells. Furthermore, airway responsiveness to inhaled methacholine was assessed. Results: The inhibition of the IL-4/IL-13 system during allergic sensitization resulted in a dose-dependent reduction of ovalbumin-specific IgEs and inhibition of airway eosinophilia together with decreased IL-5 levels and decreased numbers of IL-4 secreting CD4+ T cells. Moreover, goblet cell metaplasia and airway responsiveness to methacholine could be reduced significantly by the IL-4/IL-13 inhibitor. However, the inhibition of the IL-4/IL-13 system at various time points after allergy as established showed only little effect on all measured allergic parameters. Conclusion: Although the inhibition of the IL-4/IL-13 system can efficiently prevent the development of the allergic phenotype, these cytokines seem to play a minor role in established allergy. This is relevant for estimating the therapeutic effects of 1L-4/IL-13 inhibitors in patients with allergic asthma. (J Allergy Clin Immunol 2003;711:1361-9.).