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和免疫刺激性CPG寡核苷酸（CPG-ODN）激活先天免疫系统以产生促炎性细胞因子。目前，刺激性CPG-MOTIF被证明是有效的Th1状佐剂，可作为各种传染病，肿瘤，过敏和自身免疫性疾病的动物模型的有效治疗疫苗。我们已经证明，使用编码IL-4和髓磷脂蛋白的DNA策略，可以使用共同疫苗接种策略诱导抗原特异性Th2免疫。这种方法改善并实际逆转了正在进行的EAE。我们最近发现，通过从CpG到GPG的单个基本开关的免疫抑制GPG-ODN的应用可以有效抑制其CpG-ODN对应物的免疫刺激反应。此外，这种抑制性GPG-ODN不仅能够抵消CpG-ODN体外的刺激作用，还能够抑制小鼠实验自身免疫性脑脊髓炎（EAE）的疾病严重程度，在Th1介导的动物疾病模型中，与多发性scerissis和DNA Co-con相同，以及DNA CO-co-co- 编码髓磷脂和IL-4 [Garren等，2001]。我们将探索GPG基序对自身免疫性疾病治疗的实用性，并检查其发挥作用的潜在机制。我们将扩展有关GPG-ODN诱导MHC II类表达，促进Th2偏移并增强抗原特异性TH2反应的机制的临床前研究。如果在慢性复发EAE中最初的急性发作后给出，我们将使用GPG-ODN加编码髓磷脂以预防和逆转急性EAE的基因来测试一种共同疫苗接种策略。我们将使用我们最近开发的蛋白质组学髓磷脂阵列来监测表位扩散和T细胞反应的性质，当使用编码髓磷脂蛋白的DNA疫苗用于治疗急性攻击后的复发恢复EAE。