A Short Pulse of IL-4 Delivered by DCs Electroporated With Modified mRNA Can Both Prevent and Treat Autoimmune Diabetes in NOD Mice
A Short Pulse of IL-4 Delivered by DCs Electroporated With Modified mRNA Can Both Prevent and Treat Autoimmune Diabetes in NOD Mice
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DOI：
10.1038/mt.2010.146
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发表时间：
2010-12-01
影响因子：
12.4
通讯作者：
Fathman, C. Garrison
中科院分区：
文献类型：
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作者：
Creusot, Remi J.;Chang, Pearl;Fathman, C. Garrison
骨髓来源的树突状细胞（DC）是免疫系统的细胞，其已被用作增强、调节或抑制免疫应答的工具。在自身免疫的情况下，DC可以被修饰以表达由转基因编码的免疫调节产物，并在过继细胞疗法中治疗性地使用。经慢病毒转导（lt）表达白细胞介素4（IL-4）的DC可显著延迟或预防非肥胖糖尿病（NOD）小鼠中自身免疫性糖尿病的发作。然而，使用病毒载体修饰细胞具有致癌性或免疫原性的双重风险。该研究表明，尽管IL-4分泌量减少且持续时间较短，但用“免疫增强的”IL-4 mRNA（eDC/IL-4）电穿孔的NOD DC在治疗上可以同样有效。此外，在高血糖症发作后不久在NOD小鼠中单次注射eDC/IL-4能够在相当一部分治疗小鼠中维持稳定的血糖长达数月。用eDC/IL-4处理增强调节性T（TcB）细胞功能并调节T辅助细胞应答以降低致病性。因此，用经修饰的IL-4 mRNA电穿孔以表达IL-4长达24小时的DC治疗构成了用于调节自身免疫性糖尿病的可行的细胞治疗方法，作为使用病毒载体的优选替代方案。
Bone marrow-derived dendritic cells (DCs) are cells of the immune system that have been used as a tool to boost, modulate, or dampen immune responses. In the context of autoimmunity, DCs can be modified to express immuno-regulatory products encoded by transgenes, and used therapeutically in adoptive cellular therapy. DCs that were lentivirally transduced (lt) to express interleukin 4 (IL-4) can significantly delay or prevent the onset of autoimmune diabetes in nonobese diabetic (NOD) mice. However, modifying cells using viral vectors carries the dual risk of oncogenicity or immunogenicity. This study demonstrates that NOD DCs, electroporated with "translationally enhanced" IL-4 mRNA (eDC/IL-4), can be equally efficient therapeutically, despite the reduced amount and shorter duration of IL-4 secretion. Moreover, a single injection of eDC/IL-4 in NOD mice shortly after the onset of hyperglycemia was able to maintain stable glycemia for up to several months in a significant fraction of treated mice. Treatment with eDC/IL-4 boosted regulatory T (Tregs) cell functions and modulated T helper responses to reduce pathogenicity. Thus, treatment with DCs, electroporated with modified IL-4 mRNA to express IL-4 for up to 24 hours, constitutes a viable cellular therapy approach for the regulation of autoimmune diabetes, as a preferred alternative to the use of viral vectors.