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
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, CA 94305, USA.
J Immunol. 2005 Nov 1;175(9):6226-34. doi: 10.4049/jimmunol.175.9.6226.
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.
用编码自身抗原的抗原特异性耐受DNA疫苗靶向致病性T细胞，是治疗Th1介导的自身免疫性疾病的一种强大且可行的治疗策略。然而，质粒DNA含有丰富的未甲基化CpG基序，可诱导强烈的Th1免疫反应。我们在此描述了一种新方法，以对抗用于Th1介导的自身免疫性疾病疫苗接种的质粒DNA的这种不良副作用。在慢性复发性实验性自身免疫性脑脊髓炎（EAE）中，将髓鞘混合物加IL-4耐受DNA疫苗与抑制性GpG寡脱氧核苷酸（GpG-ODN）联合使用，可使自身反应性T细胞反应向保护性Th2细胞因子模式转变。髓鞘微阵列表明，耐受DNA疫苗接种加GpG-ODN可进一步减少抗髓鞘自身抗体表位扩展，并使自身反应性B细胞反应转向保护性IgG1同种型。此外，在耐受DNA疫苗接种治疗中添加GpG-ODN可有效降低慢性复发性EAE和慢性进行性EAE小鼠模型的总体平均疾病严重程度。总之，抑制性GpG-ODN通过使自身攻击性T细胞和B细胞反应均偏向保护性Th2表型，有效对抗了Th1介导的自身免疫性疾病中耐受DNA疫苗不期望的CpG诱导的炎症效应。这些结果表明，抑制性GpG-ODN是一种简单且高效的新型治疗佐剂，可提高用于治疗Th1介导的自身免疫性疾病的抗原特异性耐受DNA疫苗的疗效。
