The science of leukocyte adhesion began with the observations of children with what we now call leukocyte adhesion molecule 1 (LAD 1) disease. Affected children have recurrent infections, delayed umbilical cord separation, leukocytosis, and a paucity of leukocytes in infected tissue (1). Molecular elucidation of the deficiency in CD11/CD18 expression in these children coupled with the recognition and characterization of other leukocyte adhesion molecules (LAMs) such as integrins, immunoglobulin supergene family, selectin and addressin families has led to the burgeoning field of leukocyte adhesion biology. Leukocyte adhesion molecules have been demonstrated to mediate a myriad of cellular processes, ranging from “inside-out signaling” to regulation of transcription and apoptosis (2). Nevertheless, whenever studies have been performed to evaluate the role of LAMs in mediating inflammatory diseases, most of the tissue effects have been associated with and attributed to leukocyte migration: either the presence or absence of a particular cell type after blockade, or genetically deleting a leukocyte adhesion pathway. This emphasis on leukocyte recruitment, stemming from the initial observations of impaired leukocyte recruitment in children with LAD 1, has to some degree impeded the translational studies on the role of LAMs in inflammatory diseases, with clinically relevant research lagging sorely behind the rapid developments in basic adhesion biology.

Asthma is a disease of increased incidence and severity associated with industrialization. With the abundance of inflammatory cells in bronchiolar lavage and airway tissue biopsies associated with airway hyperreactivity (AHR) to inhaled cholinergic and other bronchoconstrictive agonists, testing the utility of LAM blockade in models of asthma is a logical step. The VLA-4 molecule is particularly attractive to block because it is expressed on eosinophils and lymphocytes, which have been implicated in the late allergic airway response of asthma. Simplistically thinking, blocking leukocytes from entering the lung from the circulation in sensitized individuals could abrogate airway inflammation and AHR. Surprisingly, VLA-4 or combined CD11a and CD11b antibodies given to sensitized rats block the early airway response (EAR) to allergen provocation testing, which is an event that is dependent on mast cell activation and degranulation (3). Expression of adhesion molecules on mast cell surface presumably accounts for this finding and suggests a mechanism of action related to interference with cell activation rather than migration. In previous studies, VLA-4 antibody given intravenously blocked the late airway response (LAR), suggesting the importance of cell migration in the phenomenon. However, this treatment did not have much influence on the migration of leukocytes into airway tissues or airway lumen (3). Similar effects were seen with combined CD11a and CD11b blockade. The discrepancy between the inhibition of the LAR by anti–VLA-4 and insignificant effects on leukocyte migration was confirmed in sheep and suggestive evidence of an effect on