Engineered Small Extracellular Vesicles as a FGL1/PD-L1 Dual-Targeting Delivery System for Alleviating Immune Rejection.
Engineered Small Extracellular Vesicles as a FGL1/PD-L1 Dual-Targeting Delivery System for Alleviating Immune Rejection.
复制标题
DOI：
10.1002/advs.202102634
复制
发表时间：
2022-01
期刊：
影响因子：
--
通讯作者：
Chen H
中科院分区：
文献类型：
--
作者：
Tsai HI;Wu Y;Liu X;Xu Z;Liu L;Wang C;Zhang H;Huang Y;Wang L;Zhang W;Su D;Khan FU;Zhu X;Yang R;Pang Y;Eriksson JE;Zhu H;Wang D;Jia B;Cheng F;Chen H
由于器官移植后长期使用广泛的免疫抑制剂的毒性，迫切需要开发新的免疫抑制剂。全面的样本分析显示，在同种异体心脏移植小鼠和临床肾移植患者中，FGL 1/LAG-3和PD-L1/PD-1免疫检查点失调。为了增强这两个免疫抑制信号轴，开发了一种生物工程策略，以在小细胞外囊泡（sEV）的表面上同时展示FGL 1/PD-L1（FP）。在各种细胞来源中，来源于间充质干细胞（MSC）的FP sEV不仅富集FGL 1/PD-L1表达，而且保持未修饰的MSC sEV的免疫调节特性。接下来，证实sEV上的FGL 1和PD-L1与靶细胞上的其受体LAG-3和PD-1特异性结合。重要的是，FP sEV在体外和心脏同种异体移植模型中显著抑制T细胞活化和增殖。此外，用低剂量FK 506包封的FP sEV（FP sEVs@FK506）在抑制T细胞增殖、减少脾和心脏移植物中的CD 8 + T细胞密度和细胞因子产生、诱导淋巴结中的调节性T细胞以及延长移植物存活方面发挥更强的作用。总之，双靶向sEV有可能协同增强免疫抑制信号并减缓移植排斥反应。包封在FK 506中的MSC衍生的FGL 1/PD-L1 sEV表现出强烈的抑制T细胞活化和增殖的能力，并且还在器官受体小鼠中诱导T细胞活化。提供了一种新的干预策略的实验基础，该策略利用靶向递送sEV的功能协同增强两个免疫抑制轴并重建免疫耐受，最终促进器官接受。
There is an urgent need for developing new immunosuppressive agents due to the toxicity of long‐term use of broad immunosuppressive agents after organ transplantation. Comprehensive sample analysis revealed dysregulation of FGL1/LAG‐3 and PD‐L1/PD‐1 immune checkpoints in allogeneic heart transplantation mice and clinical kidney transplant patients. In order to enhance these two immunosuppressive signal axes, a bioengineering strategy is developed to simultaneously display FGL1/PD‐L1 (FP) on the surface of small extracellular vesicles (sEVs). Among various cell sources, FP sEVs derived from mesenchymal stem cells (MSCs) not only enriches FGL1/PD‐L1 expression but also maintain the immunomodulatory properties of unmodified MSC sEVs. Next, it is confirmed that FGL1 and PD‐L1 on sEVs are specifically bound to their receptors, LAG‐3 and PD‐1 on target cells. Importantly, FP sEVs significantly inhibite T cell activation and proliferation in vitro and a heart allograft model. Furthermore, FP sEVs encapsulated with low‐dose FK506 (FP sEVs@FK506) exert stronger effects on inhibiting T cell proliferation, reducing CD8+ T cell density and cytokine production in the spleens and heart grafts, inducing regulatory T cells in lymph nodes, and extending graft survival. Taken together, dual‐targeting sEVs have the potential to boost the immune inhibitory signalings in synergy and slow down transplant rejection. MSC‐derived FGL1/PD‐L1 sEVs encapsulated in FK506 exhibited a strong ability to inhibit T cell activation and proliferation, and also induced Tregs in organ recipient mice. An experimental basis for a novel intervention strategy is provided that leverages the function of target delivery sEVs to synergistically enhance two immunosuppression axes and reestablish immune tolerance, ultimately promoting organ acceptance.
登录
查看更多内容
PD-1和PD-L1检查点信号传导抑制癌症免疫疗法：机制，组合和临床结果。
影响因子：
5.6
作者：
Alsaab HO;Sau S;Alzhrani R;Tatiparti K;Bhise K;Kashaw SK;Iyer AK
通讯作者：
Iyer AK
LAG3和PD1共同抑制分子合作，以限制鼠卵巢癌模型中的CD8+ T细胞信号传导和抑制抗肿瘤免疫。
影响因子：
--
作者：
Huang RY;Eppolito C;Lele S;Shrikant P;Matsuzaki J;Odunsi K
通讯作者：
Odunsi K
外泌体 PD-L1 有助于免疫抑制并与抗 PD-1 反应相关
影响因子：
64.8
作者：
Chen G;Huang AC;Zhang W;Zhang G;Wu M;Xu W;Yu Z;Yang J;Wang B;Sun H;Xia H;Man Q;Zhong W;Antelo LF;Wu B;Xiong X;Liu X;Guan L;Li T;Liu S;Yang R;Lu Y;Dong L;McGettigan S;Somasundaram R;Radhakrishnan R;Mills G;Lu Y;Kim J;Chen YH;Dong H;Zhao Y;Karakousis GC;Mitchell TC;Schuchter LM;Herlyn M;Wherry EJ;Xu X;Guo W
通讯作者：
Guo W
影响因子：
16.6
作者：
Jandl C;Liu SM;Cañete PF;Warren J;Hughes WE;Vogelzang A;Webster K;Craig ME;Uzel G;Dent A;Stepensky P;Keller B;Warnatz K;Sprent J;King C
通讯作者：
King C
影响因子：
56.9
作者：
ElTanbouly, Mohamed A.;Zhao, Yanding;Noelle, Randolph J.
通讯作者：
Noelle, Randolph J.