Following induction of experimental encephalomyelitis with a T-cell clone, L10C1, that is specific for the myelin basic protein epitope p87-99, the inflammatory infiltrate in the central nervous system contains a diverse collection of T cells with heterogeneous receptors. We show here that when clone L10C1 is tolerized in vivo with an analogue of p87-99, established paralysis is reversed, inflammatory infiltrates regress, and the heterogeneous T-cell infiltrate disappears from the brain, with only the T-cell clones that incited disease remaining in the original lesions. We found that antibody raised against interleukin-4 reversed the tolerance induced by the altered peptide ligand. Treatment with this altered peptide ligand selectively silences pathogenic T cells and actively signals for the efflux of other T cells recruited to the site of disease as a result of the production of interleukin-4 and the reduction of tumour-necrosis factor-alpha in the lesion.

The role of various adhesion molecules in lymphocyte homing to the brain and in inf lammatory autoimmune disease of the central nervous system (CNS) was examined in mice. Activated T cell lines and clones expressed CD44 and integrin ␣ 4 , but not L-selectin, and entered the CNS independent of their antigen specificity. mAbs directed against CD44 and integrin ␣ 4 prevented the transfer of experimental autoimmune encephalomyelitis (EAE) by myelin basic protein-specific T cells. T cells preincubated with anti-CD44 or antiintegrin ␣ 4 were blocked only partially from entering the brain parenchyma. However, both antibodies efficiently prevented CNS inf lammation and clinical expression of EAE when injected in vivo. This effect lasted as long as antibodies were administered. Antibodies specific for Lselectin had no effect on homing of encephalitogenic T cells to the brain or development of EAE. Antiintegrin ␣ 4 and anti-CD44 did not impair the activation and function of encephalitogenic T cells in vitro and did not deplete integrin ␣ 4 -or CD44-positive cells in vivo. These data suggest that, in the absence of leukocyte recruitment, the entry of a reduced number of activated myelin basic protein-reactive T cells in the CNS is not sufficient for the development and expression of EAE. We propose that antibodies to integrin ␣ 4 and CD44 prevent clinical disease by partially targeting the primary inf lux of encephalitogenic T cells and by preventing the secondary inf lux of leukocytes to lesions initiated by the transferred T cells.