ANTIBODY TO VERY LATE ACTIVATION ANTIGEN-4 PREVENTS INTERLEUKIN-5-INDUCED AIRWAY HYPERRESPONSIVENESS AND EOSINOPHIL INFILTRATION IN THE AIRWAYS OF GUINEA-PIGS

This study examines the effect of monoclonal antibody to very late act ivation antigen-4 (VLA-4) on IL5-induced airway hyperresponsiveness in vivo and eosinophil accumulation into guinea pig airways, IL5 has bee n shown to be important in the development of airway hyperresponsivene ss and eosinophil accumulation in the guinea pig. Eosinophils, unlike neutrophils, express VLA-4 which mediates the adhesion to vascular cel l adhesion molecule-1 on endothelial cells, Thus VLA-4 seems to be an important adhesion molecule in the infiltration of eosinophils from th e vasculature into the airway tissue, In addition, it has been shown t hat IL5 activates VLA-4 on eosinophils to facilitate their adhesion, I n the present study, IL5 (1 mu g, twice on one day) or vehicle were ad ministered intranasally, Monoclonal antibody (mAb) to VLA-4 (HP1/2) or the isotype-matched control mAb (1E6) were injected 1 hour before eac h IL5 or vehicle treatment at a dose of 2.5 mg/kg body weight. The nex t day in vivo bronchial reactivity, eosinophil number in bronchoalveol ar lavage (BAL) fluid, and eosinophil peroxidase (EPO) activity in cel l-free BAL fluid were determined. IL5 induces an increase in bronchial reactivity to histamine, which is associated with an accumulation of eosinophils into BAL fluid (control: 12 (5 to 42) x 10(5) cells and IL 5: 69 (11 to 99) x 10(5) cells, p < 0.05) and an increase of 35% +/- 1 4% in EPO activity in cell-free BAL fluid. Intravenous administration of anti-VLA-4 mAb, but not of the control antibody, completely inhibit s the bronchial hyperresponsiveness as well as the airway eosinophilia found after intraairway application of IL5, HP1/2 also suppresses the IL5-induced increase in EPO activity in cell-free BAL fluid, In concl usion, for the development of IL5-induced airway hyperresponsiveness i n the guinea pig, the VLA-4-dependent infiltration and activation of e osinophils in the bronchial tissue seems to be essential.