LYMPHOCYTE ADHESION AND TRANSENDOTHELIAL MIGRATION IN THE CENTRAL-NERVOUS-SYSTEM - THE ROLE OF LFA-1, ICAM-1, VLA-4 AND VCAM-1

Lymphocyte adhesion to and migration across endothelial cell (EC) mono layers, derived from the rat blood-retinal barrier (BRB), were measure d in vitro. The binding of concanavalin A (Con A)activated peripheral lymph node lymphocytes and the migration of CD4(+) T-cell lines could be significantly increased by treating the EC with interleukin-1 beta (IL-1 beta). To determine the role of various adhesion molecules durin g the processes of lymphocyte binding and transmonolayer migration (di apedesis), lymphocytes were treated with monoclonal antibody (mAb) spe cific for CD11a (alpha(L) subunit of leucocyte functional antigen-1; L FA-1), CD18 (beta(2) subunit of leucam family) and CD49d (alpha 4 subu nit of very late activation antigen-4; VLA-4) and EC with mAb specific for CD54 (intercellular adhesion molecule-1; ICAM-1) and CD106 (vascu lar cell adhesion molecule-1; VCAM-1). Binding of the highly adhesive but non-migratory Con A-activated lymphocytes was inhibited by mAb to CD11a (reduced to 73% and 65% of control lymphocyte adhesion) and CD18 (42% and 54%) on non-activated and IL-1 beta-treated EC, respectively , but not by mAb to ICAM-1 or VCAM-1. Diapedesis of the highly migrato ry T-cell line lymphocytes was also blocked by antibodies to CD11a (re duced to 11% and 10% of control T-cell migration), CD18 (29% and 43%) but in addition was also inhibited by anti-ICAM-1 (17% and 53%) on non -activated and IL-1 beta treated EC, respectively. Both anti-VLA-4 and anti-VCAM-1 were also effective in producing a smaller reduction in m igration, but only on IL-1 beta activated EC (66% and 58% of control m igration, respectively). These studies indicate that lymphocyte adhesi on to central nervous system (CNS) vascular EC is largely dependent on LFA-1 but not through its interaction with ICAM-1. in contrast, lymph ocyte diapedesis is mostly supported through the LFA-1/ICAM-1 pairing, with a small proportion being mediated by VLA-4/VCAM-1 on IL-1 beta-a ctivated EC. This latter pathway, however, also appears to be dependen t on LFA-1 interacting with the EC.