Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University; Hubei Cardiovascular Medicine Clinical Research Center & Hubei Key Laboratory of Cardiology, 238# Jiefang Road, Wuchang District, Hubei Province, Wuhan, China.
Department of Critical Care Medicine, Jin Yin-tan Hospital, 1# Yin-Tan Road, Dongxihu District, Hubei Province, Wuhan, China.
Immunogenetics. 2020 Oct;72(8):423-430. doi: 10.1007/s00251-020-01180-8. Epub 2020 Oct 3.
We have previously demonstrated that Mettl3-silencing dendritic cells (DCs) exhibited immature properties and prolonged allograft survival in a murine heart transplantation model. Exosomes derived from donor DCs (Dex) are involved in the immune rejection of organ transplantation, and blocking Dex transfer may suppress immune rejection. Herein, this study aimed to investigate whether Mettl3 knockdown inhibits the secretion and activity of donor Dex, thereby inhibiting donor Dex-mediated immune rejection. The imDex, mDex, shCtrl-mDex, and shMettl3-mDex were obtained from the culture supernatant of DCs (immature DCs, mature DCs, shCtrl-infected mature DCs, shMettl3-infected mature DCs) derived from donor BALB/c mouse bone marrow and then co-cultured with splenic T cell lymphocyte suspension from recipient C57BL/6 mice in vitro or injected into recipient C57BL/6 mice before the cardiac transplantation. Donor shMettl3-mDex expressed lower concentration of exosomes and lower expression of Mettl3, Dex markers (ICAM-1, MHC-I, MHC-II), as well as lower ability to activate T cell immune response than shCtrl-mDex. Administration of donor shMettl3-mDex attenuated immune rejection after mouse heart transplantation and prolonged the allograft survival. In summary, Mettl3 knockdown inhibits the immune rejection of Dex in a mouse cardiac allograft model.
我们之前的研究表明，沉默 Mettl3 的树突状细胞（DC）表现出不成熟的特性，并延长了小鼠心脏移植模型中的同种异体移植物存活时间。供体 DC 来源的外泌体（Dex）参与器官移植的免疫排斥反应，阻断 Dex 的转移可能抑制免疫排斥反应。在此，本研究旨在探讨 Mettl3 敲低是否抑制供体 Dex 的分泌和活性，从而抑制供体 Dex 介导的免疫排斥反应。imDex、mDex、shCtrl-mDex 和 shMettl3-mDex 分别从供体 BALB/c 鼠骨髓来源的未成熟 DC（immature DC）、成熟 DC（mature DC）、shCtrl 感染的成熟 DC（shCtrl-infected mature DC）和 shMettl3 感染的成熟 DC（shMettl3-infected mature DC）的培养上清中获得，然后与来自受者 C57BL/6 鼠脾 T 细胞淋巴细胞悬液在体外共培养，或在心脏移植前注射到受者 C57BL/6 鼠体内。与 shCtrl-mDex 相比，供体 shMettl3-mDex 表达的外泌体浓度更低，Mettl3、Dex 标志物（ICAM-1、MHC-I、MHC-II）的表达水平更低，激活 T 细胞免疫反应的能力也更低。给予供体 shMettl3-mDex 可减轻小鼠心脏移植后的免疫排斥反应，并延长同种异体移植物的存活时间。综上所述，Mettl3 敲低可抑制小鼠心脏移植模型中 Dex 的免疫排斥反应。
