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.
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.
Vandenbark
Arthur A
AA
Neuroimmunology Research and Tykeson Multiple Sclerosis Research Laboratory, Veterans Affairs Medical Center and Oregon Health & Science University, Portland, OR 97239, USA.
Rich
Cathleen
C
Mooney
Jeff
J
Zamora
Alex
A
Wang
Chunhe
C
Huan
Jianya
J
Fugger
Lars
L
Offner
Halina
H
Jones
Richard
R
Burrows
Gregory G
GG
D000595:Amino Acid Sequence; D000818:Animals; D002908:Chronic Disease; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000378:metabolism; D004306:Dose-Response Relationship, Immunologic; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D005822:Genetic Vectors; D006023:Glycoproteins / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000276:immunology*; D006131:Growth Inhibitors / Q000008:administration & dosage; D015802:HLA-DR2 Antigen / Q000235:genetics*; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000008:administration & dosage* / Q000276:immunology / Q000378:metabolism*
D016207:Cytokines; D006023:Glycoproteins; D006131:Growth Inhibitors; D015802:HLA-DR2 Antigen; D018836:Inflammation Mediators; D008024:Ligands; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D011994:Recombinant Proteins; C445081:myelin oligodendrocyte glycoprotein (35-55)