The Use of VEE Replicons Encoding GAD65 to Treat IDDM

描述(由申请人提供) 越来越多的证据表明， 致病的Th1细胞和调节性Th细胞是导致 胰岛素依赖型糖尿病的发病机制。因此，一个 免疫治疗的途径是促进“免疫偏离”，其中 诱导细胞特异性调节性Th2细胞选择性抑制 相关的β细胞特异性Th1细胞的发育和效应功能。我们 而另一些人则表明，这种方法对预防和预防 抑制非肥胖型糖尿病(NOD)患者已建立的β细胞自身免疫 老鼠。然而，当前的挑战是建立P 细胞特异性免疫偏离诱导有效的、长期的保护 一种安全的临床应用方式。考虑到这一点，我们建议 研究使用委内瑞拉马脑炎病毒(VEE)的可行性 编码P细胞自身抗原的复制子和适当的细胞因子治疗IDDM 在NOD小鼠身上。VEE复制子技术为体内基因研究提供了一种新策略 递送，并具有许多可用于临床的特性 申请。然而，VEE最显著的特征是一种内在属性 在体内感染树突状细胞。我们计划使用VEE复制子介导的基因 转β细胞自身抗原GAD65和细胞因子的靶向表达 IL-4和IL-10在体内对树突状细胞的作用。通过这种方式，我们希望利用 树突状细胞强大的抗原提呈细胞功能 终止持续的调节性Th2细胞反应。有两个具体目标 已经成立了。首先，我们将评估VEE复制子的有效性 疫苗接种诱导GAD65特异性调节性Th2细胞，进而防止 并抑制已建立的P细胞自身免疫。第二个具体目标是 确定VEE复制子管理是否可以保护同基因胰岛 糖尿病NOD受体小鼠反复自身免疫的移植 毁灭。这项工作应该为可能的未来奠定基础 VEE复制子技术在治疗IDDM等方面的应用 组织特异性自身免疫性疾病。

DESCRIPTION (provided by applicant) There is growing evidence indicating that a functional imbalance between pathogenic Th1 and regulatory Th cells is a key contributing factor in the pathogenesis of insulin dependent diabetes mellitus (IDDM). Consequently, one approach of immunotherapy is to promote "immune deviation" in which beta cell-specific regulatory Th2 cells are induced to selectively suppress the development and effector function of relevant beta cell-specific Th1 cells. We and others have shown that this approach is effective for both preventing and suppressing established beta cell autoimmunity in the nonobese diabetic (NOD) mouse. The current challenge, however, is to establish strategies of P cell-specific immune deviation which induce effective, long-term protection in a safe manner for clinical application. With this in mind, we propose to investigate the feasibility of using Venezuelan equine encephalitis virus (VEE) replicons encoding P cell autoantigens and appropriate cytokines to treat IDDM in NOD mice. VEE replicon technology offers a novel strategy of in vivo gene delivery, and possesses a number of properties amenable for clinical application. The most salient feature of VEE, however, is an intrinsic property to infect dendritic cells in vivo. We plan to use VEE replicon mediated gene transfer to target expression of the beta cell autoantigen GAD65 and cytokines IL-4 and IL-10 to dendritic cells in vivo. In this way we hope to exploit the potent antigen presenting cell function of dendritic cells to mediate robust end persistent regulatory Th2 cell reactivity. Two Specific Aims have been established. In the first, we will assess the efficacy of VEE replicon vaccination to elicit GAD65-specific regulatory Th2 cells, and in turn prevent and suppress established P cell autoimmunity. The second Specific Aim will determine whether VEE replicon administration can protect syngeneic islet grafts implanted in diabetic NOD recipient mice from recurrent autoimmune destruction. This work should provide the foundation for possible future application of VEE replicon technology for the treatment of IDDM, and other tissue-specific autoimmune diseases.