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In a previous study, we demonstrated that myelin oligodendrocyte glycoprotein (MOG)-35-55 peptide could induce severe chronic experimental autoimmune encephalomyelitis (EAE) in HLA-DR2(+) transgenic mice lacking all mouse MHC class II genes. We used this model to evaluate clinical efficacy and mechanism of action of a novel recombinant TCR ligand (RTL) comprised of the alpha(1) and beta(1) domains of DR2 (DRB1*1501) covalently linked to the encephalitogenic MOG-35-55 peptide (VG312). We found that the MOG/DR2 VG312 RTL could induce long-term tolerance to MOG-35-55 peptide and reverse clinical and histological signs of EAE in a dose- and peptide-dependent manner. Some mice treated with lower doses of VG312 relapsed after cessation of daily treatment, but the mice could be successfully re-treated with a higher dose of VG312. Treatment with VG312 strongly reduced secretion of Th1 cytokines (TNF-alpha and IFN-gamma) produced in response to MOG-35-55 peptide, and to a lesser degree purified protein derivative and Con A, but had no inhibitory effect on serum Ab levels to MOG-35-55 peptide. Abs specific for both the peptide and MHC moieties of the RTLs were also present after treatment with EAE, but these Abs had only a minor enhancing effect on T cell activation in vitro. These data demonstrate the powerful tolerance-inducing therapeutic effects of VG312 on MOG peptide-induced EAE in transgenic DR2 mice and support the potential of this approach to inhibit myelin Ag-specific responses in multiple sclerosis patients.

Type

Journal article

Journal

J Immunol

Publication Date

01/07/2003

Volume

171

Pages

127 - 133

Keywords

Amino Acid Sequence, Animals, Chronic Disease, Cytokines, Dose-Response Relationship, Immunologic, Encephalomyelitis, Autoimmune, Experimental, Female, Genetic Vectors, Glycoproteins, Growth Inhibitors, HLA-DR2 Antigen, Humans, Immune Tolerance, Inflammation Mediators, Ligands, Male, Mice, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Knockout, Mice, Transgenic, Molecular Sequence Data, Myelin-Oligodendrocyte Glycoprotein, Peptide Fragments, Receptors, Antigen, T-Cell, Recombinant Proteins