Efficacy and Safety of Bone Marrow-Derived Mesenchymal Stem Cells for Chronic Antibody-Mediated Rejection After Kidney Transplantation- A Single-Arm, Two-Dosing-Regimen, Phase I/II Study.
Efficacy and Safety of Bone Marrow-Derived Mesenchymal Stem Cells for Chronic Antibody-Mediated Rejection After Kidney Transplantation- A Single-Arm, Two-Dosing-Regimen, Phase I/II Study.
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骨髓间充质干细胞治疗肾移植后慢性抗体介导的排斥反应的功效和安全性——单臂、两次给药方案、I/II 期研究
DOI：
10.3389/fimmu.2021.662441
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发表时间：
2021
影响因子：
7.3
通讯作者：
Wang C
中科院分区：
文献类型：
--
作者：
Wei Y;Chen X;Zhang H;Su Q;Peng Y;Fu Q;Li J;Gao Y;Li X;Yang S;Ye Q;Huang H;Deng R;Li G;Xu B;Wu C;Wang J;Zhang X;Su X;Liu L;Xiang AP;Wang C
探讨骨髓间充质干细胞（BM - MSCs）对肾移植慢性活动性抗体介导排斥反应（cABMR）的有效性和安全性。
在这项开放标签、单臂、单中心、两种给药方案的I/II期临床试验中，经活检证实为cABMR的肾移植受者接受了同种异体第三方BM - MSCs治疗。在方案1（n = 8）中，BM - MSCs以1.0×10⁶个细胞/千克的剂量每月静脉注射，连续4个月；而在方案2（n = 15）中，BM - MSCs剂量为1.0×10⁶个细胞/千克，每周注射，连续4周。主要终点是治疗24个月后估计肾小球滤过率（eGFR）相对于基线的绝对变化（ΔeGFR）以及与BM - MSCs给药相关的不良事件发生率。同时期未接受BM - MSCs的cABMR患者作为对照组进行回顾性分析（n = 30）。
23名cABMR受者接受了BM - MSCs治疗。在BM - MSCs治疗2年后，所有接受BM - MSCs治疗患者的ΔeGFR中位数为 - 4.3 ml/min/1.73m²（四分位间距，IQR - 11.2至1.2）（P = 0.0233）。2年时最大供体特异性抗体（maxDSA）的Δ中位数为 - 4310（IQR - 9187至1129）（P = 0.0040）。对照组在诊断2年后的ΔeGFR中位数为 - 12.7 ml/min/1.73m²（IQR - 22.2至 - 3.5），大于接受BM - MSCs治疗组（P = 0.0342）。肝酶升高、BK多瘤病毒（BKV）感染、巨细胞病毒（CMV）感染的发生率分别为17.4%、17.4%、8.7%。BM - MSCs给药后无发热、过敏反应、静脉炎或静脉血栓形成、心血管并发症或恶性肿瘤。流式细胞术分析显示，MSCs治疗后CD27 - IgD - 双阴性B细胞亚群呈显著下降趋势，CD3⁺CD4⁺PD - 1⁺/淋巴细胞群有增加趋势。多重分析发现，MSCs治疗后TNF - α、CXCL10、CCL4、CCL11和RANTES降低。
患有cABMR的肾移植受者对BM - MSCs耐受。免疫抑制药物联合静脉注射BM - MSCs可延缓移植肾功能恶化，可能是通过降低DSA水平和减轻DSA诱导的损伤。其潜在机制可能涉及MSCs对外周B细胞和T细胞亚群的免疫调节作用。
To investigate the efficacy and safety of bone marrow-derived mesenchymal stem cells (BM-MSCs) on chronic active antibody-mediated rejection (cABMR) in the kidney allograft. Kidney recipients with biopsy-proven cABMR were treated with allogeneic third-party BM-MSCs in this open-label, single-arm, single-center, two-dosing-regimen phase I/II clinical trial. In Regimen 1 (n=8), BM-MSCs were administered intravenously at a dose of 1.0×106 cells/kg monthly for four consecutive months, while in Regimen 2 (n=15), the BM-MSCs dose was 1.0×106 cells/kg weekly during four consecutive weeks. The primary endpoints were the absolute change of estimated glomerular filtration rate (eGFR) from baseline (delta eGFR) and the incidence of adverse events associated with BM-MSCs administration 24 months after the treatment. Contemporaneous cABMR patients who did not receive BM-MSCs were retrospectively analyzed as the control group (n =30). Twenty-three recipients with cABMR received BM-MSCs. The median delta eGFR of the total BM-MSCs treated patients was -4.3 ml/min per 1.73m2 (interquartile range, IQR -11.2 to 1.2) 2 years after BM-MSCs treatment (P=0.0233). The median delta maximum donor-specific antibody (maxDSA) was -4310 (IQR -9187 to 1129) at 2 years (P=0.0040). The median delta eGFR of the control group was -12.7 ml/min per 1.73 m2 (IQR -22.2 to -3.5) 2 years after the diagnosis, which was greater than that of the BM-MSCs treated group (P=0.0342). The incidence of hepatic enzyme elevation, BK polyomaviruses (BKV) infection, cytomegalovirus (CMV) infection was 17.4%, 17.4%, 8.7%, respectively. There was no fever, anaphylaxis, phlebitis or venous thrombosis, cardiovascular complications, or malignancy after BM-MSCs administration. Flow cytometry analysis showed a significant decreasing trend of CD27-IgD- double negative B cells subsets and trend towards the increase of CD3+CD4+PD-1+/lymphocyte population after MSCs therapy. Multiplex analysis found TNF-α, CXCL10, CCL4, CCL11 and RANTES decreased after MSCs treatment. Kidney allograft recipients with cABMR are tolerable to BM-MSCs. Immunosuppressive drugs combined with intravenous BM-MSCs can delay the deterioration of allograft function, probably by decreasing DSA level and reducing DSA-induced injury. The underlying mechanism may involve immunomodulatory effect of MSCs on peripheral B and T cells subsets.
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影响因子：
8.8
作者：
Matas, A. J.;Smith, J. M.;Kasiske, B. L.
通讯作者：
Kasiske, B. L.
影响因子：
4.3
作者：
Ban TH;Lee S;Kim HD;Ko EJ;Kim BM;Kim KW;Chung BH;Yang CW
通讯作者：
Yang CW
影响因子：
7.3
作者：
Khare, Drirh;Or, Reuven;Avni, Batia
通讯作者：
Avni, Batia
DOI：
10.2215/cjn.04950610
发表时间：
2011-02-01
影响因子：
9.8
作者：
Perico, Norberto;Casiraghi, Federica;Remuzzi, Giuseppe
通讯作者：
Remuzzi, Giuseppe
影响因子：
7.3
作者：
Carreras-Planella, Laura;Monguio-Tortajada, Marta;Franquesa, Marcella
通讯作者：
Franquesa, Marcella