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 activation antigen-4 (VLA-4) on IL5-induced airway hyperresponsiveness in vivo and eosinophil accumulation into guinea pig airways. IL5 has been shown to be important in the development of airway hyperresponsiveness and eosinophil accumulation in the guinea pig. Eosinophils, unlike neutrophils, express VLA-4 which mediates the adhesion to vascular cell adhesion molecule-1 on endothelial cells. Thus VLA-4 seems to be an important adhesion molecule in the infiltration of eosinophils from the vasculature into the airway tissue. In addition, it has been shown that IL5 activates VLA-4 on eosinophils to facilitate their adhesion. In the present study, IL5 (1 microg, twice on one day) or vehicle were administered intranasally. Monoclonal antibody (mAb) to VLA-4 (HP1/2) or the isotype-matched control mAb (1E6) were injected 1 hour before each IL5 or vehicle treatment at a dose of 2.5 mg/kg body weight. The next day in vivo bronchial reactivity, eosinophil number in bronchoalveolar lavage (BAL) fluid, and eosinophil peroxidase (EPO) activity in cell-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 IL5: 69 (11 to 99) x 10(5) cells, p < 0.05) and an increase of 35% +/- 14% in EPO activity in cell-free BAL fluid. Intravenous administration of anti-VLA-4 mAb, but not of the control antibody, completely inhibits 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 conclusion, for the development of IL5-induced airway hyperresponsiveness in the guinea pig, the VLA-4-dependent infiltration and activation of eosinophils in the bronchial tissue seems to be essential.
Kraneveld
A D
AD
Department of Pharmacology and Pathophysiology, Utrecht Institute of Pharmaceutical Sciences, Utrecht University, The Netherlands.
van Ark
I
I
Van Der Linde
H J
HJ
Fattah
D
D
Nijkamp
F P
FP
Van Oosterhout
A J
AJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D016535:Bronchial Hyperreactivity / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D004802:Eosinophilia / Q000139:chemically induced / Q000473:pathology; D004804:Eosinophils / Q000473:pathology*; D006168:Guinea Pigs; D039041:Integrin alpha4beta1; D016023:Integrins / Q000276:immunology*; D015848:Interleukin-5 / Q000633:toxicity*; D007962:Leukocytes / Q000473:pathology; D008168:Lung / Q000473:pathology; D008297:Male; D016201:Receptors, Lymphocyte Homing / Q000276:immunology*
D000911:Antibodies, Monoclonal; D039041:Integrin alpha4beta1; D016023:Integrins; D015848:Interleukin-5; D016201:Receptors, Lymphocyte Homing