DNA Vaccination for Autoimmunity Immunoinhibitory GpG Mo

自身免疫免疫抑制性 GpG Mo 的 DNA 疫苗接种

• 批准号: 6746106
• 负责人: LAWRENCE STEINMAN
• 金额: $ 23.4万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6746106
• 关键词: CpG islands; MHC class II antigen; SDS polyacrylamide gel electrophoresis; T cell receptor; autoimmunity; bacterial DNA; cell proliferation; experimental allergic encephalomyelitis; flow cytometry; gene expression; gene therapy; helper T lymphocyte; immune response; interleukin 4; laboratory mouse; multiple sclerosis; myelin; myelin basic proteins; myelin proteolipid; phosphorylation; polymerase chain reaction; proteomics; vector vaccine; western blottings

Bacterial DNA and immunostimulatory CpG oligonucleotides (CpG-ODN) activate the innate immune system to produce proinflammatory cytokines. Shown to be potent Th1-like adjuvants, stimulatory CpG-motifs are currently utilized as effective therapeutic vaccines for various animal models of infectious diseases, tumors, allergies, and autoimmune diseases. We have shown that it is possible to induce antigen specific Th2 immunity to myelin, using a co-vaccination strategy with DNA encoding IL-4 and myelin proteins. This approach ameliorated and actually reversed ongoing EAE. We recently discovered that the application of an immunoinhibitory GpG-ODN, with a single base switch from CpG to GpG, can effectively inhibit the immunostimulatory response of its CpG-ODN counterpart. Moreover, this inhibitory GpG-ODN is not only capable of counteracting the stimulatory effect of CpG-ODN in vitro, it is also capable of suppressing the disease severity of experimental autoimmune encephalomyelitis (EAE) in mice, a Th1-mediated animal disease model for multiple sclerosis, and inducing a Th2 shift, much as DNA co-vaccination with genes encoding myelin and IL-4 [Garren et al, 2001]. We will explore the utility of the GpG motif for therapy of autoimmune disease, and examine the underlying mechanism whereby it exerts its effects. We will extend pre-clinical studies on the mechanism whereby GpG-ODN induces reduced expression of MHC class II, promotes a Th2 shift, and enhances antigen specific Th2 responses. We will test a co-vaccination strategy using GpG-ODN plus genes encoding myelin to prevent and reverse acute EAE, and to block further relapses, if given after the initial acute attack in chronic relapsing EAE. We will use our recently developed proteomic myelin array to monitor epitope spreading and the nature of the T cell response, when DNA vaccines encoding myelin proteins are used to treat relapsing remitting EAE after the acute attack.

细菌DNA和免疫刺激CpG寡核苷酸（CpG- odn）激活先天免疫系统产生促炎细胞因子。刺激性cpg基序被证明是强效的th1样佐剂，目前被用作各种传染病、肿瘤、过敏和自身免疫性疾病动物模型的有效治疗性疫苗。我们已经证明，使用编码IL-4和髓磷脂蛋白的DNA的联合接种策略，可以诱导抗原特异性Th2对髓磷脂的免疫。这种方法改善并实际上逆转了正在进行的EAE。我们最近发现，应用一种具有免疫抑制作用的GpG- odn，通过从CpG到GpG的单一碱基转换，可以有效地抑制其CpG- odn对应物的免疫刺激反应。此外，这种抑制GpG-ODN不仅能够在体外抵消CpG-ODN的刺激作用，还能够抑制实验性自身免疫性脑脊髓炎（EAE）小鼠（th1介导的多发性硬化症动物疾病模型）的疾病严重程度，并诱导Th2转移，就像DNA与基因共接种一样