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A Suppressive Oligodeoxynucleotide Enhances the Efficacy of Myelin Cocktail/IL-4-Tolerizing DNA Vaccination and Treats Autoimmune Disease¹

Peggy P. Ho^2,*, Paulo Fontoura^2,3,*, Michael Platten^4,*, Raymond A. Sobel, Jason J. DeVoss^5,*, Lowen Y. Lee, Brian A. Kidd^,, Beren H. Tomooka^,, Julien Capers^*, Ashish Agrawal^*, Rohit Gupta^*, Jonathan Zernik^*, Michael K. Yee^*, Byung J. Lee^,, Hideki Garren^6,*, William H. Robinson^, and Lawrence Steinman^7,*

^* Department of Neurology and Neurological Sciences, Department of Pathology, and Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford CA 94305; and Geriatric Research, Education and Clinical Center, Palo Alto Veterans Affairs Health System, Palo Alto, CA 94304

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.

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