The pathophysiologic role of α4 integrins in vivo

Abstract

In this review we have summarized the rapidly mounting evidence for a central role for the integrins VLA4 and α4β7 in leukocyte pathophysiology. Five distinct α4 mAbs, each able to block α4-dependent adhesion in vitro, show beneficial effects in vivo in seven different species (mouse, rat, guinea pig, rabbit, sheep, and New-World and Old-World monkeys) and in a wide variety of organ systems, including colon, lung, skin, neural tissue, pancreas, peritoneum, and the vessel wall (Table I). A number of important issues remain to be addressed, including the relative importance of VLA4 and α4β7 and of their counterligands VCAM1, Fn, and MadCAM, in most in vivo settings; alternative mechanisms for mAb efficacy other than adhesion blockade; poor understanding of side effects of α4 blockade; and the role of integrin signaling rather than adhesion in function. Nevertheless, the data argue that α4 integrins will likely play critical roles in both normal physiology and pathology in man. To examine this issue, a humanized IgG4 isotype of mAb HP1/2 has been generated which retains full in vitro potency and in vivo efficacy (Lobb, R., D. Leone, B. Pepinsky, P. Tempest, F. Carr, W. Abraham, and S. Nourshargh, unpublished data). This mAb will enter clinical trials in the near future to extend in vivo studies to humans and to identify clinical areas of value. This area of leukocyte adhesion biology promises to remain a fruitful area of research and should continue to provide critical clues as to intervention points in human disease.