A NOVEL T-CELL-REGULATED MECHANISM MODULATING ALLERGEN-INDUCED AIRWAYS HYPERREACTIVITY IN BALB C MICE INDEPENDENTLY OF IL-4 AND IL-5/

The immunoregulatory functions of IL-4 and IL-5 have identified these cytokines as primary targets for the resolution of airways inflammatio n and bronchial hyperreactivity in asthma. However, the individual con tribution of each of these cytokines and of IL-5-regulated eosinophili a to the induction of airways hyperreactivity in mouse models of asthm a remains highly controversial. In this investigation, we have used IL -4- and IL-5-deficient mice of the same genetic background in combinat ion with inhibitory mAbs to these cytokines to identify unequivocally the contribution of these factors to the induction of airways hyperrea ctivity. Sensitization and aeroallergen challenge of wild-type mice wi th OVA induced pathological changes to the respiratory epithelium, air ways eosinophilia, and hyperreactivity to beta-methacholine. Inhibitio n of the actions of IL-4 and/or IL-5 did not abolish airways hyperreac tivity, and in the case of IL-4-deficient mice pretreated with anti-IL -5 mAb, airways hyperreactivity persisted in the absence of pronounced airways inflammation. Airways hyperreactivity was abolished only by a nti-CD4(+) mAb treatment. However, aeroallergen challenge of IL-5(-/-) mice showed that morphologic changes to the airways were critically l inked to IL-5 and eosinophilia, This investigation demonstrates the ex istence in BALB/c mice of a novel CD4(+) T cell pathway for modulating airways hyperreactivity. These findings may provide an explanation fo r the dissociation of airways eosinophilia from the development of air ways hyperreactivity observed in some cases of asthma and in animal mo dels of this disease.