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IL-10 modified mRNA monotherapy prolongs survival after composite facial allografting through the induction of mixed chimerism
Molecular Therapy - Nucleic Acids ( IF 6.5 ) Pub Date : 2023-02-16 , DOI: 10.1016/j.omtn.2023.02.016
Ana Elena Aviña , Dante De Paz , Shu-Chun Huang , Kuan-Hung Chen , Yun-Ching Chang , Chin-Ming Lee , Chia-Hsien Lin , Fu-Chan Wei , Aline Yen Ling Wang

Vascularized composite allotransplantation has great potential in face transplantation by supporting functional restoration following tissue grafting. However, the need for lifelong administration of immunosuppressive drugs still limits its wide use. Modified mRNA (modRNA) technology provides an efficient and safe method to directly produce protein in vivo. Nevertheless, the use of IL-10 modRNA-based protein replacement, which exhibits anti-inflammatory properties, has not been shown to prolong composite facial allograft survival. In this study, IL-10 modRNA was demonstrated to produce functional IL-10 protein in vitro, which inhibited pro-inflammatory cytokines and in vivo formation of an anti-inflammatory environments. We found that without any immunosuppression, C57BL/6J mice with fully major histocompatibility complex (MHC)-mismatched facial allografts and local injection of IL-10 modRNA had a significantly prolonged survival rate. Decreased lymphocyte infiltration and pro-inflammatory T helper 1 subsets and increased anti-inflammatory regulatory T cells (Tregs) were seen in IL-10 modRNA-treated mice. Moreover, IL-10 modRNA induced multilineage chimerism, especially the development of donor Treg chimerism, which protected allografts from destruction because of recipient alloimmunity. These results support the use of monotherapy based on immunomodulatory IL-10 cytokines encoded by modRNA, which inhibit acute rejection and prolong allograft survival through the induction of donor Treg chimerism.



中文翻译:

IL-10 修饰的 mRNA 单一疗法通过诱导混合嵌合体延长复合面部同种异体移植后的生存期

血管化复合同种异体移植通过支持组织移植后的功能恢复,在面部移植中具有巨大潜力。然而,终生服用免疫抑制药物的需要仍然限制了它的广泛应用。修饰的 mRNA (modRNA) 技术提供了一种高效、安全的体内直接生产蛋白质的方法。然而,使用具有抗炎特性的基于 IL-10 modRNA 的蛋白质替代品尚未显示可延长复合面部同种异体移植物的存活时间。在这项研究中,IL-10 modRNA 被证明可以在体外产生功能性 IL-10 蛋白,从而抑制促炎细胞因子和体内形成抗炎环境。我们发现,在没有任何免疫抑制的情况下,具有完全主要组织相容性复合体 (MHC) 不匹配的面部同种异体移植物和局部注射 IL-10 modRNA 的 C57BL/6J 小鼠的存活率显着延长。在 IL-10 modRNA 处理的小鼠中观察到淋巴细胞浸润和促炎性 T 辅助细胞 1 亚群减少以及抗炎调节性 T 细胞 (Tregs) 增加。此外,IL-10 modRNA 诱导多谱系嵌合,尤其是供体 Treg 嵌合的发展,它保护同种异体移植物免于因受体同种免疫而受到破坏。这些结果支持使用基于 modRNA 编码的免疫调节 IL-10 细胞因子的单一疗法,它通过诱导供体 Treg 嵌合体抑制急性排斥反应并延长同种异体移植物存活。

更新日期:2023-02-16
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