Lentiviral-mediated transcriptional targeting of dendritic cells for induction of T cell tolerance in vivo
Lentiviral-mediated transcriptional targeting of dendritic cells for induction of T cell tolerance in vivo
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DOI：
10.4049/jimmunol.181.7.4495
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发表时间：
2008-10-01
影响因子：
4.4
通讯作者：
Brocker, Thomas
中科院分区：
文献类型：
--
作者：
Dresch, Christiane;Edelmann, Stephanie L.;Brocker, Thomas
树突状细胞（Dendritic cells，DCs）是重要的抗原递呈细胞（APCs），能诱导机体产生免疫耐受和免疫应答。因此，DC是免疫干预的有吸引力的靶点。然而，离体产生和操作足够数量的DC而不改变其原始表型和功能特征是主要障碍。为了在体内操纵DC，我们开发了一种新的DC特异性自失活慢病毒载体系统，该系统使用来自DC-STAMP基因的5'非翻译区作为推定的启动子区。我们表明，这些DC-STAMP-慢病毒载体的基因治疗方法在体内产生长期和细胞选择性的转基因表达。此外，转录靶向的DC在体内诱导功能性Ag特异性CD 4和CD 8 T细胞耐受，这不能被病毒免疫打破。在小鼠自身免疫模型系统中，耐受的CTL不能诱导自身免疫性糖尿病。因此，利用病毒载体将转基因特异性地递送至DC可能是基因治疗的一个有前途的工具。
Dendritic cells (DCs) are important APCs able to induce both tolerance and immunity. Therefore, DCs are attractive targets for immune intervention. However, the ex vivo generation and manipulation of DCs at sufficient numbers and without changing their original phenotypic and functional characteristics are major obstacles. To manipulate DCs in vivo, we developed a novel DC-specific self-inactivating lentiviral vector system using the 5' untranslated region from the DC-STAMP gene as a putative promoter region. We show that a gene therapy approach with these DC-STAMP-lentiviral vectors yields long-term and cell-selective transgene expression in vivo. Furthermore, transcriptionally targeted DCs induced functional, Ag-specific CD4 and CD8 T cell tolerance in vivo, which could not be broken by viral immunization. Tolerized CTL were unable to induce autoimmune diabetes in a murine autoimmune model system. Therefore, delivering transgenes specifically to DCs by using viral vectors might be a promising tool in gene therapy.