Antileukocyte adhesion therapy

Leukocytes appear to potentiate CNS reperfusion injury by clogging the microcirculation and infiltrating into the brain, where they release free radicals and other substances toxic to neurons. The initial step in these processes is leukocyte to endothelial cell adhesion. Both the microcirculation obstruction and the brain infiltration can be decreased by the use of specific monoclonal antibodies directed against leukocyte adhesion receptors. Experimental studies have found reduced stroke damage when antibodies that bind to either the CD-18 leukocyte adhesion molecule or its endothelial cell ligand, intercellular adhesion molecule-1 (ICAM-1), are used. Here we review the components of leukocyte to endothelial adhesion, preclinical studies of antileukocyte adhesion agents, and preclinical studies investigating combining anti-adhesion therapy with thrombolytics.

Leukocyte to endothelial cell adhesion. The migration of leukocytes from the blood into the brain is a multistep process. First, primary leukocyte-endothelial interaction (rolling) occurs. This process is mediated by P-selectin and E-selectin on the surface of the endothelial cells and by L-selectin on leukocytes¹ (figure 1). On activation, firm adherence of leukocytes to the endothelial lining(sticking) is subsequently mediated by a leukocyte membrane glyco-protein receptor complex, termed CD-18 or β₂-integrin, and its endothelial ligand, the ICAM-1.^2,3 The CD-18 integrin complex consists of three heterodimers. All three share an identical β-subunit(also frequently called CD-18) and are distinguished from each other by distinct α-subunits. The three α-subunits are termed leukocyte function antigen (LFA-1 or CD-11a, present on all leukocytes), MAC-1 (CD-11b, present mostly on PMNs and monocytes), and P150 (CD-11c, present on neutrophils and monocytes). The corresponding counter-receptors for the CD-18 integrin complex are the ICAM family of adhesion molecules. Whereas ICAM-1 is widely expressed on many cells and binds to LFA-1 and MAC-1, ICAM-2 is expressed only on endothelial cells and leukocytes and is recognized only by LFA-1.⁴ Unlike …