THE ROLE OF ALPHA-4 INTEGRINS IN LUNG PATHOPHYSIOLOGY

The alpha 4 Integrins are heterodimeric leucocyte cell surface molecul es central to their cell and matrix adhesive interactions, The integri n alpha 4 beta 1 interacts with the immunoglobulin superfamily member vascular cell adhesion molecule-1 (VCAM-1), and with an alternatively spliced form of fibronectin. The integrin alpha 4 beta 7 binds not onl y VCAM-1 and fibronectin, but also the mucosal addressin fell adhesion molecule (MAdCAM). Certain monoclonal antibodies (MoAbs) to the alpha 4 chain of alpha 4 beta 1 and alpha 4 beta 7 can block their in vitro adhesive function, In vivo studies with these MoAbs in lung antigen c hallenge models in several species demonstrate that alpha 4 integrins play a key role in eosinophil and T-cell recruitment, in the late phas e response, and in airways hyperresponsiveness. In particular, MoAb HP 1/2 is efficacious in a sheep model of allergic airways challenge, whe ther given intravenously or as aerosol. To evaluate the mechanism of a ction of this MoAb, Fab fragments were generated and shown to be equip otent in vitro and as efficacious in vivo as the intact immunoglobulin G (IgG). These data demonstrate that the in vivo efficacy of monoclon al antibody HP1/2 is not due to indirect effects, such as antigen cros s-linking, but rather to blockade of alpha 4 integrin adhesive functio n, Humanized monoclonal antibody or other alpha 4 integrin antagonists may provide novel therapeutics for asthma.