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

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 her...

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Bibliographic Details
Published in:	The Journal of immunology (1950) Vol. 175; no. 9; pp. 6226 - 6234
Main Authors:	Ho, Peggy P, Fontoura, Paulo, Platten, Michael, Sobel, Raymond A, DeVoss, Jason J, Lee, Lowen Y, Kidd, Brian A, Tomooka, Beren H, Capers, Julien, Agrawal, Ashish, Gupta, Rohit, Zernik, Jonathan, Yee, Michael K, Lee, Byung J, Garren, Hideki, Robinson, William H, Steinman, Lawrence
Format:	Journal Article
Language:	English
Published:	United States Am Assoc Immnol 01-11-2005
Subjects:	Amino Acid Sequence Animals Autoantibodies - biosynthesis Encephalomyelitis, Autoimmune, Experimental - etiology Encephalomyelitis, Autoimmune, Experimental - pathology Encephalomyelitis, Autoimmune, Experimental - therapy Female Immunoglobulin G - classification Interleukin-4 - genetics Interleukin-4 - immunology Mice Mice, Inbred C57BL Molecular Sequence Data Myelin Proteins Myelin Proteolipid Protein - immunology Myelin-Associated Glycoprotein - immunology Myelin-Oligodendrocyte Glycoprotein Oligodeoxyribonucleotides - therapeutic use Peptide Fragments - immunology Th1 Cells - immunology Vaccination Vaccines, DNA - immunology
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Summary:	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.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0022-1767 1550-6606
DOI:	10.4049/jimmunol.175.9.6226