J Immunol. 2003 Jul 1;171(1):127-133
Vandenbark AA, Rich C, Mooney J, Zamora A, Wang C, Huan J, Fugger L, Offner H, Jones R, Burrows GG.
Neuroimmunology Research and Tykeson Multiple Sclerosis Research Laboratory, Veterans Affairs Medical Center and Oregon Health & Science University, Portland, OR 97239. Neurology and Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, OR 97239. Department of Clinical Immunology, Aarhus University Hospital, Skejby Sygehus, Aarhus, Denmark. Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford, U.K.
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.