Low-dose tacrolimus combined with donor-derived mesenchymal stem cells after renal transplantation: a prospective, non-randomized study.
Low-dose tacrolimus combined with donor-derived mesenchymal stem cells after renal transplantation: a prospective, non-randomized study.
复制标题
DOI：
10.18632/oncotarget.7725
复制
发表时间：
2016-03-15
期刊：
影响因子：
--
通讯作者：
Liu LS
中科院分区：
文献类型：
--
作者：
Pan GH;Chen Z;Xu L;Zhu JH;Xiang P;Ma JJ;Peng YW;Li GH;Chen XY;Fang JL;Guo YH;Zhang L;Liu LS
钙调磷酸酶抑制剂，包括他克莫司，主要负责异体移植的进展。然而，与这些免疫抑制剂相关的肾毒性损害了患者移植肾后的长期生存。因此，减少甚至消除钙调磷酸酶抑制剂的新方案可以改善移植结果。在这项初步研究中，我们研究了低剂量他克莫司联合间充质干细胞（MSCs）的使用，MSCs在实验性器官移植模型中具有免疫抑制作用并延长同种异体移植物的存活时间。供体来源的骨髓间充质干细胞联合保留剂量的他克莫司（0.04-0.05 mg/kg/天）给予16名新生活体肾移植受者；另外16例患者接受标准剂量的他克莫司（0.07-0.08 mg/kg/天）。在肾移植后≥24个月评估MSC输注的安全性、急性排斥反应、移植物功能、移植物存活和患者生存。随访24个月，所有患者均存活，肾功能稳定。低剂量他克莫司联合MSCs在维持移植后至少2年的移植物存活方面与标准剂量他克莫司一样有效。此外，两组移植后7天至24个月的尿素、尿蛋白、尿红细胞、尿白细胞、24小时尿蛋白和肌酐清除率相似。此外，淋巴细胞、CD19、CD3、CD34、CD38和自然杀伤细胞的比例在对照组和实验组之间没有差异。MSC受体均未出现治疗的即时或长期毒性。这一初步数据表明，添加间充质干细胞可以在肾移植后使用较低剂量的肾毒性钙调磷酸酶抑制剂。
Calcineurin inhibitors, including tacrolimus, are largely responsible for advances in allotransplantation. However, the nephrotoxicity associated with these immunosuppressants impairs patients' long-term survival after renal allograft. Therefore, novel regimens that minimize or even eliminate calcineurin inhibitors could improve transplantation outcomes. In this pilot study, we investigated the use of low-dose tacrolimus in combination with mesenchymal stem cells (MSCs), which are immunosuppressive and prolong allograft survival in experimental organ transplant models. Donor-derived, bone marrow MSCs combined with a sparing dose of tacrolimus (0.04-0.05 mg/kg/day) were administered to 16 de novo living-related kidney transplant recipients; 16 other patients received a standard dose of tacrolimus (0.07-0.08 mg/kg/day). The safety of MSC infusion, acute rejection, graft function, graft survival, and patient survival were evaluated over ≥24 months following kidney transplantation. All patients survived and had stable renal function at the 24 month follow-up. The combination of low-dose tacrolimus and MSCs was as effective as standard dose tacrolimus in maintaining graft survival at least 2 years after transplantation. In addition, both groups had similar urea, urine protein, urinary RBC, urinary WBC, 24-h urine protein, and creatinine clearance rates from 7 days to 24 months after transplantation. Furthermore, no differences in the proportion of lymphocytes, CD19, CD3, CD34, CD38, and natural killer cells were detected between the control and experimental groups. None of the MSC recipients experienced immediate or long-term toxicity from the treatment. This preliminary data suggests that the addition of MSCs permits the use of lower dosages of nephrotoxic calcineurin inhibitors following renal transplantation.