中国组织工程研究 ›› 2021, Vol. 25 ›› Issue (31): 4921-4927.doi: 10.12307/2021.131

• 脐带脐血干细胞 umbilical cord blood stem cells •    下一篇

人脐带间充质干细胞治疗难治性急性移植物抗宿主病的单臂临床研究

许慧敏,张素平,曹伟杰,李  丽,张  然,王怡然,万鼎铭   

  1. 郑州大学第一附属医院血液科造血干细胞移植中心,河南省郑州市  450052
  • 收稿日期:2020-10-28 修回日期:2020-10-30 接受日期:2020-12-18 出版日期:2021-11-08 发布日期:2021-04-25
  • 通讯作者: 万鼎铭,博士,教授,主任医师,硕士生导师,郑州大学第一附属医院血液科造血干细胞移植中心,河南省郑州市 450052
  • 作者简介:许慧敏,女,1995年生,河南省商丘市人,汉族,郑州大学在读硕士,主要从事血液病与造血干细胞移植的基础和临床研究。
  • 基金资助:
    河南省高等学校重点科研项目计划(20A320021),项目负责人:张然

Human umbilical cord blood-derived mesenchymal stem cells in the treatment of refractory acute  graft-versus-host disease: a single-arm clinical study

Xu Huimin, Zhang Suping, Cao Weijie, Li Li, Zhang Ran, Wang Yiran, Wan Dingming   

  1. Department of Hematology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
  • Received:2020-10-28 Revised:2020-10-30 Accepted:2020-12-18 Online:2021-11-08 Published:2021-04-25
  • Contact: Wan Dingming, MD, Professor, Chief physician, Master’s supervisor, Department of Hematology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
  • About author:Xu Huimin, Master candidate, Department of Hematology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
  • Supported by:
    the Major Scientific Research Project of Henan Provincial Universities, No. 20A320021 (to ZR)

摘要:

文题释义
脐带间充质干细胞:间充质干细胞来源于胚胎发育的中胚层,能从骨髓、脐带、脂肪等组织分离而得,是一类具有自我更新及多向分化能力的非造血干细胞,可对多种免疫细胞进行免疫调节。脐带间充质干细胞从脐带分离而得,与其他来源间充质干细胞相比较,可表达多种胚胎干细胞特有的分子标志,具有分化潜力大、增殖能力强、免疫原性低、取材方便、易于基因工程化制备等优点,目前已成为间充质干细胞的主要来源。
急性移植物抗宿主病:是供者来源免疫细胞攻击受者脏器造成的组织损伤,是异基因造血干细胞移植后特有的和最常见的并发症。经典的急性移植物抗宿主病指发生在移植或供者淋巴细胞输注后100 d内,以斑丘疹、胃肠道症状或瘀胆型肝炎为临床表现的移植物抗宿主病;持续、复发或晚发的急性移植物抗宿主病指具有典型急性移植物抗宿主病临床表现,发生于移植或供者淋巴细胞输注100 d后。
难治性急性移植物抗宿主病:糖皮质激素和(或)二线免疫抑制剂治疗无效。由于急性移植物抗宿主病本身及其治疗的不良反应如肝肾毒性、机会性感染、原发病复发、继发移植失败等的作用,难治性移植物抗宿主病患者的2年总体生存率仅0-10%,严重影响移植疗效,是移植后相关死亡的主要原因之一。

背景:异基因造血干细胞移植是众多血液系统疾病治愈的重要甚至唯一手段,但移植后急性移植物抗宿主病仍然是致死性并发症之一,且对于难治性急性移植物抗宿主病尚缺乏有效的标准化治疗。不少研究提示间充质干细胞可能通过免疫调节功能治疗急性移植物抗宿主病,但实际疗效尚缺乏足够临床证据支持。

目的:探讨人脐带间充质干细胞治疗难治性急性移植物抗宿主病的疗效、安全性及与疗效有关的影响因素。

方法:研究共入组难治性急性移植物抗宿主病24例患者,其中儿童8例,成人16例;Ⅱ度10例,Ⅲ-Ⅳ度14例,均在郑州大学第一附属医院造血干细胞移植中心用第三方来源人脐带间充质干细胞治疗,观察其疗效、输注相关不良反应、原发病复发、继发感染及长期生存情况。

结果与结论:①脐带间充质干细胞中位输注总剂量2.7×106/kg[(2.02-6.00)×106/kg],中位输注次数2.5次(2-6次),急性移植物抗宿主病发生与首次脐带间充质干细胞输注的中位间隔时间为12.5 d(8-36 d);②首次脐带间充质干细胞应用后第28天的总体有效率为83%(20/24),2年总体生存率33.3%;完全缓解组与部分缓解/无效组2年总体生存率分别为57%,0%(P < 0.000 1),两组在长期生存方面差异有显著性意义;③Ⅱ度难治性急性移植物抗宿主病的疗效优于Ⅲ-Ⅳ度(P=0.024);年龄、急性移植物抗宿主病累及器官的部位及数量、原发疾病的类型、脐带间充质干细胞输注次数对疗效无显著影响;④结果表明,人脐带间充质干细胞治疗难治性急性移植物抗宿主病安全、有效。

https://orcid.org/0000-0003-4931-3596(万鼎铭);https://orcid.org/0000-0002-2430-8945(许慧敏)

中国组织工程研究杂志出版内容重点:干细胞;骨髓干细胞;造血干细胞;脂肪干细胞;肿瘤干细胞;胚胎干细胞;脐带脐血干细胞;干细胞诱导;干细胞分化;组织工程

关键词: 干细胞, 脐带间充质干细胞, 异基因造血干细胞移植, 难治性急性移植物抗宿主病, 疗效, 生存

Abstract: BACKGROUND: Allogeneic hematopoietic stem cell transplantation is an important or even the only potentially curative treatment for many hematological diseases. However, acute graft-versus-host disease is still one of the life-threatening complications after allogeneic hematopoietic stem cell transplantation. There is no standardized treatment for refractory acute graft-versus-host disease. Many studies indicated that mesenchymal stem cells may be used for treating acute graft-versus-host disease through the immunomodulatory effect; however, the actual effect is still to be confirmed.
OBJECTIVE: To explore the efficacy and safety of human umbilical cord blood-derived mesenchymal stem cells in the treatment of refractory acute graft-versus-host disease and the related factors for the efficacy.
METHODS:  Totally 24 patients who were diagnosed with refractory acute graft-versus-host disease patients and treated with third-party derived human umbilical cord blood-derived mesenchymal stem cells at the Hematopoietic Stem Cell Transplantation Center of the First Affiliated Hospital of Zhengzhou University were included in the present study. Among them, 8 cases were children, and 16 cases were adults; 10 cases were grade II acute graft-versus-host disease, and 14 cases were grades III-IV. The efficacy, adverse effects, recurrence of primary disease, secondary infection and long-term survival of these patients were observed.  
RESULTS AND CONCLUSION: (1) The median dose of total infused human umbilical cord blood-derived mesenchymal stem cells was 2.7×106/kg [(2.02-6.00)×106/kg] with a median of 2.5 infusions (range, 2-6 times). The median time from the onset of acute graft-versus-host disease to first human umbilical cord blood-derived mesenchymal stem cells infusion was 12.5 days (range, 8-36 days). (2) The overall response rate at 28 days after infusion was 83% (20/24). The probability of 2-year overall survival was 33.3%. The 2-year overall survival for patients achieving complete remission and partial remission/non-remission were 57% and 0%, respectively (P < 0.000 1). There was significant difference between these two groups. (3) The efficacy for patients with grade II refractory acute graft-versus-host disease was better than grades III-IV (P=0.024). There was no remarkable difference in terms of age, involved organs, primary diseases and the number of infusions of human umbilical cord blood-derived mesenchymal stem cells. (4) In conclusion, treatment with human umbilical cord blood-derived mesenchymal stem cells is a safe and effective option for patients with refractory acute graft-versus-host disease.

Key words: stem cells, umbilical cord blood-derived mesenchymal stem cells, allogeneic hematopoietic stem cell transplantation, refractory acute graft-versus-host disease, efficacy, survival

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