BLOCKADE OF LATE-PHASE AIRWAY RESPONSES AND AIRWAY HYPERRESPONSIVENESS IN ALLERGIC SHEEP WITH A SMALL-MOLECULE PEPTIDE INHIBITOR OF VLA-4

The leukocyte integrin very late antigen-4 (VLA-4) (alpha(4) beta(1) C D49d/CD29) is an adhesion receptor predominantly expressed on lymphocy tes, monocytes, and eosinophils, but not on neutrophils. Recent studie s with monoclonal antibodies against VLA-4 suggest that antigen-induce d late responses and airway hyperresponsiveness (AHR) may depend on th e recruitment and/or activation of VLA-4-expressing leukocytes. To fur ther test this hypothesis, we administered by aerosol either a potent small-molecule inhibitor of VLA-4, which prevents VLA-4-mediated bindi ng to fibronectin (CS-1 ligand mimic), or an inactive control (30 mg t wice daily for 3 d, and on the fourth day 0.5 h before and 4 h after a ntigen challenge) to six sheep with airway hypersensitivity to Ascaris suum antigen. Treatment with the small-molecule VLA-4 inhibitor resul ted in a significant decrease in the early antigen-induced bronchial r esponse (40%, p < 0.05), and almost complete blockade of the late-phas e airway response (88%, p < 0.05). Moreover, at 24 h after antigen cha llenge, AHR to inhaled carbachol was not observed when the animals wer e dosed with the small-molecule VLA-4 inhibitor. In accord with protec tion against the functional abnormalities associated with antigen chal lenge, analysis of biopsy specimens taken 24 h after challenge indicat ed that the total numbers of VLA-4-positive cells (lymphocytes, eosino phils, and metachromatic-staining cells) in the group treated with the VLA-4 inhibitor did not increase, whereas these cells increased in th e control group. The active agent, but not the inactive control, signi ficantly blocked macrophage adherence to fibronectin (FN), indicating that the CS-1 ligand interfered with VLA-4-mediated adhesion in sheep cells. These results support our previous findings with a monoclonal a ntibody to VLA-4, and demonstrate that a small-molecule VLA-4 inhibito r, when given by aerosol, has a protective effect against antigen-indu ced late responses and AHR in allergic sheep.