文獻(xiàn)名：PD-L1 cellular nanovesicles carrying rapamycin inhibit alloimmune responses in transplantation

作者： Min Yang,   ^a   Zhanxue Xu,   ^a   Hailan Yan,   ^a   Hsiang-i Tsai,  ^a   Dandan Su,  ^a   Fuxia Yan,  ^a   Qiumei Lu,  ^a   Jianhua Feng,  ^b   Weiwei Zeng,  ^a   Lifang Xi,  ^a   Hualian Zha,  ^a   Yunzhi Ling,  ^a   Chao He,  ^a   Yingyi Wu,  ^a   Xiaowei Xu,  ^c   Gang Zheng,  ^d   Gan Liu,  ^a   Hongbo Chen  ^a  and  Fang Cheng  ^a  

^a School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, China

^b Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, China

^c Clinical Neuroscience Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China

^d XuZhou Central Hospital Affiliated to Medical School of Southeast University, XuZhou, China

摘要：Organ transplantation has been employed upon serious injuries, but a T-cell-mediated potent inflammatory immune response often leads to graft rejection. Immunosuppressive drugs such as rapamycin (RAPA) have to be taken after organ transplantation, but long-term use of these drugs causes severe adverse effects. Immune checkpoint pathways such as the programmed death-receptor 1/programmed death-ligand 1 (PD-1/PD-L1) provides an immunosuppressive environment, preventing excessive tissue destruction due to inflammatory immune responses. In this study, we bioengineered cell membrane-derived PD-L1 nanovesicles (PD-L1 NVs) to carry low doses of RAPA. These NVs inhibited T-cell activation and proliferation in vitro, by enhancing the PD-1/PD-L1 immune co-inhibitory signaling axis and inhibiting the mTOR pathway. Importantly, PD-L1 NVs encapsulated with rapamycin exerted stronger effects on inhibiting T-cell proliferation than PD-L1 NVs or rapamycin alone. This can be recapitulated in a mouse skin transplantation model, leading to the weakened alloimmune response and allograft tolerance. We also found that PD-L1/rapamycin vesicles have additional function to induce regulatory T cells in the recipient spleens. Our study highlighted the power of combining low-dose rapamycin and PD-L1 in the nanovesicles as immunosuppressants to promote allograft acceptance.

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