The role of alpha 4 integrins in lung pathophysiology.
The alpha 4 integrins are heterodimeric leucocyte cell surface molecules central to their cell and matrix adhesive interactions. The integrin 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 only VCAM-1 and fibronectin, but also the mucosal addressin cell 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 challenge models in several species demonstrate that alpha 4 integrins play a key role in eosinophil and T-cell recruitment, in the late phase response, and in airways hyperresponsiveness. In particular, MoAb HP1/2 is efficacious in a sheep model of allergic airways challenge, whether given intravenously or as aerosol. To evaluate the mechanism of action of this MoAb, Fab fragments were generated and shown to be equipotent in vitro and as efficacious in vivo as the intact immunoglobulin G (IgG). These data demonstrate that the in vivo efficacy of monoclonal antibody HP1/2 is not due to indirect effects, such as antigen cross-linking, but rather to blockade of alpha 4 integrin adhesive function. Humanized monoclonal antibody or other alpha 4 integrin antagonists may provide novel therapeutics for asthma.
Lobb
R R
RR
Biogen Inc., Cambridge Center, MA 02142, USA.
Pepinsky
B
B
Leone
D R
DR
Abraham
W M
WM
D017398:Alternative Splicing; D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology; D001249:Asthma / Q000503:physiopathology*; D016535:Bronchial Hyperreactivity / Q000503:physiopathology; D001985:Bronchial Provocation Tests; D015815:Cell Adhesion Molecules; D002465:Cell Movement; D004804:Eosinophils / Q000502:physiology; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D006168:Guinea Pigs; D000882:Haplorhini; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology; D007074:Immunoglobulin G / Q000494:pharmacology; D007136:Immunoglobulins / Q000378:metabolism; D039041:Integrin alpha4beta1; D016023:Integrins / Q000276:immunology / Q000378:metabolism* / Q000502:physiology*; D008168:Lung / Q000503:physiopathology*; D051379:Mice; D009088:Mucoproteins / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D016201:Receptors, Lymphocyte Homing / Q000276:immunology / Q000378:metabolism* / Q000502:physiology*; D012756:Sheep; D013601:T-Lymphocytes / Q000502:physiology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D015815:Cell Adhesion Molecules; D005353:Fibronectins; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D007136:Immunoglobulins; D039041:Integrin alpha4beta1; D016023:Integrins; C504265:MADCAM1 protein, human; C489082:Madcam1 protein, mouse; C504268:Madcam1 protein, rat; D009088:Mucoproteins; D016201:Receptors, Lymphocyte Homing; D019010:Vascular Cell Adhesion Molecule-1