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， 致病性Th 1和调节性Th细胞是导致免疫缺陷的关键因素。 胰岛素依赖型糖尿病（IDDM）的发病机制。因此，一 免疫疗法的方法是促进“免疫偏离”，其中β 细胞特异性调节性Th 2细胞被诱导以选择性地抑制 相关β细胞特异性Th 1细胞的发育和效应子功能。我们 其他研究表明，这种方法对预防和 抑制非肥胖型糖尿病（NOD）中已建立的β细胞自身免疫 老鼠.然而，目前的挑战是制定P 细胞特异性免疫偏离，诱导有效的，长期的保护， 临床应用安全。有见及此，我们建议 研究使用委内瑞拉马脑炎病毒（VEE） 编码P细胞自身抗原的复制子和适当的细胞因子以治疗IDDM NOD小鼠。VEE复制子技术提供了一种体内基因转移的新策略， 递送，并具有许多适合临床应用的性质。 应用程序.然而，VEE最显著的特征是固有属性 来感染体内的树突状细胞。我们计划使用VEE复制子介导的基因 β细胞自身抗原GAD 65和细胞因子的靶向表达转移 IL-4和IL-10对树突状细胞的作用。我们希望通过这种方式， 树突状细胞强大的抗原呈递细胞功能， 结束持续的调节性Th 2细胞反应性。有两个具体目标， 确立了习首先，我们将评估VEE复制子的功效。 疫苗接种以引发GAD 65特异性调节性Th 2细胞，并反过来预防 并抑制已建立的P细胞自身免疫。第二个具体目标将 确定VEE复制子施用是否可以保护同系胰岛 移植物植入糖尿病NOD受体小鼠， 杀伤性这项工作将为今后可能的 VEE复制子技术在治疗胰岛素依赖型糖尿病及其他疾病中的应用 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.