title: A suppressive oligodeoxynucleotide enhances the efficacy of myelin cocktail/IL-4-tolerizing DNA vaccination and treats autoimmune disease.
abstract: Targeting pathogenic T cells with Ag-specific tolerizing DNA vaccines encoding autoantigens is a powerful and feasible therapeutic strategy for Th1-mediated autoimmune diseases. However, plasmid DNA contains abundant unmethylated CpG motifs, which induce a strong Th1 immune response. We describe here a novel approach to counteract this undesired side effect of plasmid DNA used for vaccination in Th1-mediated autoimmune diseases. In chronic relapsing experimental autoimmune encephalomyelitis (EAE), combining a myelin cocktail plus IL-4-tolerizing DNA vaccine with a suppressive GpG oligodeoxynucleotide (GpG-ODN) induced a shift of the autoreactive T cell response toward a protective Th2 cytokine pattern. Myelin microarrays demonstrate that tolerizing DNA vaccination plus GpG-ODN further decreased anti-myelin autoantibody epitope spreading and shifted the autoreactive B cell response to a protective IgG1 isotype. Moreover, the addition of GpG-ODN to tolerizing DNA vaccination therapy effectively reduced overall mean disease severity in both the chronic relapsing EAE and chronic progressive EAE mouse models. In conclusion, suppressive GpG-ODN effectively counteracted the undesired CpG-induced inflammatory effect of a tolerizing DNA vaccine in a Th1-mediated autoimmune disease by skewing both the autoaggressive T cell and B cell responses toward a protective Th2 phenotype. These results demonstrate that suppressive GpG-ODN is a simple and highly effective novel therapeutic adjuvant that will boost the efficacy of Ag-specific tolerizing DNA vaccines used for treating Th1-mediated autoimmune diseases.
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, CA 94305, USA.
authors.forename: Peggy P
authors.initials: PP
authors.lastname: Ho
authors.forename: Paulo
authors.initials: P
authors.lastname: Fontoura
authors.forename: Michael
authors.initials: M
authors.lastname: Platten
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Sobel
authors.forename: Jason J
authors.initials: JJ
authors.lastname: DeVoss
authors.forename: Lowen Y
authors.initials: LY
authors.lastname: Lee
authors.forename: Brian A
authors.initials: BA
authors.lastname: Kidd
authors.forename: Beren H
authors.initials: BH
authors.lastname: Tomooka
authors.forename: Julien
authors.initials: J
authors.lastname: Capers
authors.forename: Ashish
authors.initials: A
authors.lastname: Agrawal
authors.forename: Rohit
authors.initials: R
authors.lastname: Gupta
authors.forename: Jonathan
authors.initials: J
authors.lastname: Zernik
authors.forename: Michael K
authors.initials: MK
authors.lastname: Yee
authors.forename: Byung J
authors.initials: BJ
authors.lastname: Lee
authors.forename: Hideki
authors.initials: H
authors.lastname: Garren
authors.forename: William H
authors.initials: WH
authors.lastname: Robinson
authors.forename: Lawrence
authors.initials: L
authors.lastname: Steinman
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology / Q000473:pathology / Q000628:therapy*; D005260:Female; D007074:Immunoglobulin G / Q000145:classification; D015847:Interleukin-4 / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009185:Myelin Proteins; D018991:Myelin Proteolipid Protein / Q000276:immunology; D018992:Myelin-Associated Glycoprotein / Q000276:immunology; D063308:Myelin-Oligodendrocyte Glycoprotein; D009838:Oligodeoxyribonucleotides / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D014611:Vaccination; D019444:Vaccines, DNA / Q000276:immunology*
chemical_list: D001323:Autoantibodies; C408982:CPG-oligonucleotide; D007074:Immunoglobulin G; C571327:Mog protein, mouse; D009185:Myelin Proteins; D018991:Myelin Proteolipid Protein; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D009838:Oligodeoxyribonucleotides; D010446:Peptide Fragments; D019444:Vaccines, DNA; C435023:myelin proteolipid protein (139-151); D015847:Interleukin-4