The adhesion cascade and anti-adhesion therapy: an overview.

Abstract

Investigations in the past decade have greatly advanced our knowledge of both the molecular pathways of leukocyte adhesion and the contribution of leukocytes to a wide range of organ injuries. As a result, it is now possible to separate the leukocyte adhesion/emigration process into discrete steps, defined by specific molecular interactions. The multistep process of leukocyte-endothelial adhesion (cell activation, leukocyte rolling, firm adhesion, and transendothelial migration) presents a number of potential therapeutic targets. In the appropriate clinical setting, disruption of the adhesion cascade may prevent or limit leukocyte-mediated injuries. Several approaches — monoclonal antibodies, soluble oligosaccharides and polypeptides, small molecules, and antisense oligonucleotides — have demonstrated efficacy in vitro or in animal models. There are, however, several potential obstacles to the use of these agents in clinical settings. Adhesion blockade may interfere with normal leukocyte-mediated defense against microbial organisms and pose a significant risk of infection. Given the multiple adhesion pathways that appear to be involved in some inflammatory or immune disorders, it is not certain whether therapy directed at a single adhesion molecule will be of significant benefit. Although less extensively investigated to date, blockade of VLA-4-mediated leukocyte adhesion is of particular interest due to the likely importance of this pathway in leukocyte recruitment in a wide variety of acute and chronic diseases, immune disorders, and malignant processes.