DataSheet_1_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.docx

ObjectiveTo 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.
MethodsKidney 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).
ResultsTwenty-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.
ConclusionKidney 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.

研究目的：探究骨髓间充质干细胞（bone marrow-derived mesenchymal stem cells, BM-MSCs）对肾移植移植物慢性活动性抗体介导排斥反应（chronic active antibody-mediated rejection, cABMR）的治疗效果与安全性。
研究方法：本研究为一项开放标签、单臂、单中心、含两种给药方案的I/II期临床试验，纳入经活检证实为cABMR的肾移植受者，给予异体第三方骨髓间充质干细胞（BM-MSCs）治疗。方案1（n=8）：以1.0×10^6 细胞/kg的剂量静脉输注BM-MSCs，每月1次，连续输注4个月；方案2（n=15）：以相同剂量每周1次，连续输注4周。本研究的主要终点为治疗后24个月时估算肾小球滤过率（estimated glomerular filtration rate, eGFR）较基线的绝对变化值（ΔeGFR），以及与BM-MSCs输注相关的不良事件发生率。同期未接受BM-MSCs治疗的cABMR患者作为回顾性分析对照组（n=30）。
研究结果：本研究共纳入23例接受BM-MSCs治疗的cABMR肾移植受者。接受BM-MSCs治疗的全部患者术后2年的ΔeGFR中位数为-4.3 ml/(min·1.73m²)（四分位距IQR：-11.2~1.2），差异具有统计学意义（P=0.0233）。其供体特异性抗体峰值（maxDSA）的Δ中位数为-4310（IQR：-9187~1129），术后2年时差异同样具有统计学意义（P=0.0040）。对照组患者确诊后2年的ΔeGFR中位数为-12.7 ml/(min·1.73m²)（IQR：-22.2~-3.5），其肾功能下降程度显著高于BM-MSCs治疗组（P=0.0342）。治疗相关不良事件发生率分别为：肝酶升高17.4%、BK多瘤病毒（BK polyomaviruses, BKV）感染17.4%、巨细胞病毒（cytomegalovirus, CMV）感染8.7%；未观察到发热、过敏反应、静脉炎或静脉血栓形成、心血管并发症及恶性肿瘤等不良事件。流式细胞术分析显示，MSC治疗后外周血CD27-IgD-双阴性B细胞亚群比例呈显著下降趋势，CD3+CD4+PD-1+淋巴细胞占比呈升高趋势。多重免疫分析结果显示，肿瘤坏死因子-α（TNF-α）、C-X-C基序趋化因子配体10（CXCL10）、C-C基序趋化因子配体4（CCL4）、C-C基序趋化因子配体11（CCL11）及激活调节正常T细胞表达和分泌因子（RANTES）水平在MSC治疗后显著降低。
研究结论：肾移植术后合并cABMR的受者对静脉输注BM-MSCs具有良好耐受性。免疫抑制方案联合静脉输注BM-MSCs可延缓移植肾功能恶化，其潜在机制可能与降低供体特异性抗体（donor-specific antibody, DSA）水平、减轻DSA介导的移植物损伤有关，核心机制可能涉及MSC对外周血B、T细胞亚群的免疫调节作用。