LYMPHOCYTE MIGRATION INTO THE CNS MODELED IN-VITRO - ROLES OF LFA-1, ICAM-1 AND VLA-4

We examined the changes in intercellular adhesion molecule-1 (ICAM-1) expression on brain endothelium in response to tumour necrosis factor- alpha (TNF-alpha) and interferon-gamma (IFN-gamma). ICAM-1 is normally present on these cells and is induced over 24 hr by both cytokines wi th a time-course which matches enhancement in lymphocyte adhesion. Ant i-lymphocyte function-associated antigen-1 (anti-LFA-1) (CD11a), anti- very late antigen-4 (anti-VLA-4) (CD49d) and anti-CD18 block binding o f mitogen-activated lymphocytes to brain endothelium and the effects o f anti-LFA-1 and anti-VLA-4 are additive. Anti-ICAM-1 does not however block adhesion, nor does depletion of endothelial ICAM-1 reduce lymph ocyte binding. Titration of the interacting cells indicated that the a ntibody blocking is due to interference in the endothelial/lymphocyte interaction. None of the antibodies affect the binding of non-activate d lymphocytes, which is itself normally much lower than that of activa ted cells. The time at which lymphocyte adhesiveness is greatest for t he endothelium corresponds with the time at which the lymphocytes expr ess highest levels of LFA-1 and VLA-4. The data show a role for LFA-1 and VLA-4 in the early interaction of activated lymphocytes with brain endothelium. Kinetic studies indicate that the ligand for VLA-4 is VC AM-1. The ligand for LFA-1 could not be determined with certainty, but if it is ICAM-1, the levels of ICAM-1 on brain endothelium are not cr itical.