Recombinant TCR ligand induces tolerance to myelin oligodendrocyte glycoprotein 35-55 peptide and reverses clinical and histological signs of chronic experimental autoimmune encephalomyelitis in HLA-DR2 transgenic mice

J Immunol. 2003 Jul 1;171(1):127-33. doi: 10.4049/jimmunol.171.1.127.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Chronic Disease
  • Cytokines / antagonists & inhibitors
  • Cytokines / metabolism
  • Dose-Response Relationship, Immunologic
  • Encephalomyelitis, Autoimmune, Experimental / genetics
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Encephalomyelitis, Autoimmune, Experimental / prevention & control*
  • Female
  • Genetic Vectors
  • Glycoproteins / administration & dosage
  • Glycoproteins / antagonists & inhibitors
  • Glycoproteins / immunology*
  • Growth Inhibitors / administration & dosage
  • HLA-DR2 Antigen / genetics*
  • Humans
  • Immune Tolerance* / genetics
  • Inflammation Mediators / antagonists & inhibitors
  • Inflammation Mediators / metabolism
  • Ligands
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Mice, Knockout
  • Mice, Transgenic
  • Molecular Sequence Data
  • Myelin-Oligodendrocyte Glycoprotein
  • Peptide Fragments / administration & dosage
  • Peptide Fragments / antagonists & inhibitors
  • Peptide Fragments / immunology*
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / metabolism*
  • Recombinant Proteins / administration & dosage*
  • Recombinant Proteins / immunology
  • Recombinant Proteins / metabolism*

Substances

  • Cytokines
  • Glycoproteins
  • Growth Inhibitors
  • HLA-DR2 Antigen
  • Inflammation Mediators
  • Ligands
  • Myelin-Oligodendrocyte Glycoprotein
  • Peptide Fragments
  • Receptors, Antigen, T-Cell
  • Recombinant Proteins
  • myelin oligodendrocyte glycoprotein (35-55)