Engineering Programmed Death Ligand-1/Cytotoxic T-Lymphocyte-Associated Antigen-4 Dual-Targeting Nanovesicles for Immunosuppressive Therapy in Transplantation
Engineering Programmed Death Ligand-1/Cytotoxic T-Lymphocyte-Associated Antigen-4 Dual-Targeting Nanovesicles for Immunosuppressive Therapy in Transplantation
复制标题
用于移植免疫抑制治疗的工程程序性死亡配体 1/细胞毒性 T 淋巴细胞相关抗原 4 双靶向纳米囊泡
DOI：
10.1021/acsnano.9b09065
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发表时间：
2020
期刊：
影响因子：
17.1
通讯作者：
Hongbo Chen
中科院分区：
文献类型：
--
作者：
Zhanxue Xu;Hsiang-i Tsai;Youmei Xiao;Yingyi Wu;D;an Su;Min Yang;Hualian Zha;Fuxia Yan;Xiaoyan Liu;Fang Cheng;Hongbo Chen
免疫同种异体识别激活T细胞是触发器官排斥反应的主要因素。器官移植后必须服用免疫抑制药物，但长期使用这些药物会增加感染和其他严重疾病的风险。在这里，我们显示了两个器官移植模型的脾中程序性细胞死亡配体1/程序性细胞死亡1(PD-L1/PD-1)和细胞毒性T淋巴细胞相关蛋白4/分化簇80(CTLA-4/CD80)的失调。利用生物工程方法，设计了展示PD-L1/CTLA-4双靶向载体的细胞外体样纳米粒，并证实了其与T细胞和树突状细胞表面的配体PD-1和CD80结合的特异性。因此，这些NV增强了PD-L1/PD-1和CTLA-4/CD80免疫抑制通路，这两个关键免疫检查点共同抑制T细胞激活和维持外周耐受。也证实了PD-L1/CTLA-4 Nvs在体内外均能抑制T细胞的活化和增殖。结果表明，PD-L1/CTLA-4Nvs可降低CD8+T细胞密度和细胞因子的产生，丰富调节性T细胞，延长小鼠皮肤和心脏移植物的存活时间。综上所述，这些数据支持PD-L1/CTLA-4双靶向NV发挥免疫抑制作用的观点，并可能作为一种有前景的免疫抑制剂用于器官移植。
T cell activation by immune allorecognition is a major contributing factor toward the triggering of organ rejection. Immunosuppressive drugs have to be taken after organ transplantation, but long-term use of these drugs increases the risks of infection and other serious disorders. Here, we showed dysregulation of programmed cell death-ligand 1/programmed cell death 1 (PD-L1/PD-1) and cytotoxic T-lymphocyte-associated protein 4/cluster of differentiation 80 (CTLA-4/CD80) in the spleen of two organ transplantation models. Using a bioengineering approach, cellular exosome-like nanovesicles (NVs) displaying PD-L1/CTLA-4 dual-targeting cargos were designed, and their specificity to bind their ligands PD-1 and CD80 on T cell and dendritic cell surfaces was confirmed. These NVs consequently enhanced PD-L1/PD-1 and CTLA-4/CD80 immune inhibitory pathways, two key immune checkpoints to co-inhibit T cell activation and maintain peripheral tolerance. It was also confirmed that PD-L1/CTLA-4 NVs led to the reduction of T cell activation and proliferationin vitroandin vivo. Finally, it was demonstrated that PD-L1/CTLA-4 NVs reduced density of CD8+T cells and cytokine production, enriched regulatory T cells, and prolonged the survival of mouse skin and heart grafts. Taken together, these data supported the idea that PD-L1/CTLA-4 dual-targeting NVs exert immune inhibitory effects and may be used as a prospective immunosuppressant in organ transplantation.