In this 'double-blind', randomized, placebo-controlled phase II trial, we compared an altered peptide ligand of myelin basic protein with placebo, evaluating their safety and influence on magnetic resonance imaging in relapsing-remitting multiple sclerosis. A safety board suspended the trial because of hypersensitivity reactions in 9% of the patients. There were no increases in either clinical relapses or in new enhancing lesions in any patient, even those with hypersensitivity reactions. Secondary analysis of those patients completing the study showed that the volume and number of enhancing lesions were reduced at a dose of 5 mg. There was also a regulatory type 2 T helper-cell response to altered peptide ligand that cross-reacted with the native peptide.

No abstract

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.

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Experimental autoimmune encephalomyelitis (EAE), a demyelinating disease of the central nervous system that can be induced in susceptible strains of mice by immunization with myelin basic protein (MBP) or its immunodominant T cell determinants, serves as a model of human multiple sclerosis. Tolerance to MBP in adult mice was induced by intraperitoneal injection of synthetic peptides of immunodominant determinants of MBP and prevented MBP-induced EAE. Furthermore, tolerance-inducing regimens of peptides administered to mice after the disease had begun (10 days after induction with MBP) blocked the progression and decreased the severity of EAE. Peptide-induced tolerance resulted from the induction of anergy in proliferative, antigen-specific T cells.