中国组织工程研究

中国组织工程研究 ›› 2016, Vol. 20 ›› Issue (32): 4818-4824.doi: 10.3969/j.issn.2095-4344.2016.32.016

• 干细胞移植 stem cell transplantation • 上一篇    下一篇

单倍型异基因造血干细胞移植后大剂量环磷酰胺诱导免疫耐受治疗儿童重型再生障碍性贫血

郭  智1，童  春1，2，刘晓东1，杨  凯1，何学鹏1，张  媛1，陈  鹏1，楼金星1，陈惠仁1   

  1. 1解放军北京军区总医院血液科，北京市  100700
    2安徽医科大学附属北京军区总医院临床医学院，北京市  100700
  • 修回日期:2016-06-21 出版日期:2016-08-05 发布日期:2016-08-05
  • 通讯作者: 陈惠仁，主任医师，教授，博士生导师，解放军北京军区总医院血液科，北京市 100700
  • 作者简介:郭智，男，1977年生，湖北省武汉市人，2000年同济医科大学毕业，硕士，副主任医师，副教授，硕士生导师，主要从事造血干细胞移植相关基础及临床工作。 并列第一作者：童春，女，1989年生，安徽省安庆市人，汉族，安徽医科大学在读硕士，主要从事造血干细胞移植相关基础及临床工作。
  • 基金资助:

    国家自然科学基金：DKK-1在间充质干细胞诱导免疫耐受机制中的调控作用(31200686)；北京市首都临床特色课题：诱导耐受新方法造血干细胞移植治疗重型再生障碍性贫血的临床研究

High-dose cyclophosphamide-induced immunogenic tolerance following haploidentical allogeneic hematopoietic stem cell transplantation in severe aplastic anemia children

Guo Zhi1, Tong Chun1, 2, Liu Xiao-dong1, Yang Kai1, He Xue-peng1, Zhang Yuan1, Chen Peng1, Lou Jin-xing1, Chen Hui-ren1   

  1. 1Department of Hematology, General Hospital of Beijing Military Area, Beijing 100700, China
    2Clinical Medical College of General Hospital of Beijing Military Area, Anhui Medical University, Beijing 100700, China
  • Revised:2016-06-21 Online:2016-08-05 Published:2016-08-05
  • Contact: Chen Hui-ren, Chief physician, Professor, Doctoral supervisor, Department of Hematology, General Hospital of Beijing Military Area, Beijing 100700, China
  • About author:Guo Zhi, Master, Associate chief physician, Associate professor, Master’s supervisor, Department of Hematology, General Hospital of Beijing Military Area, Beijing 100700, China Tong Chun, Studying for master’s degree, Department of Hematology, General Hospital of Beijing Military Area, Beijing 100700, China; Clinical Medical College of General Hospital of Beijing Military Area, Anhui Medical University, Beijing 100700, China Guo Zhi and Tong Chun contributed equally to this work.
  • Supported by:

    the National Natural Science Foundation of China, No. 31200686; the Capital Clinical Project of Beijing

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摘要：

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文题释义：
移植失败：移植后28 d内外周血中性粒细胞绝对值没有达到0.5×109 L-1以上；初次植活并在移植后100 d内中性粒细胞绝对值又下降到0.5×109 L-1以下，血小板< 20×109 L-1，至少1周以上。原因可能系HLA不全相合移植，相合非亲缘移植，T淋巴细胞清除或移植前输血使受者致敏，供者骨髓中造血干细胞质量欠佳或祖细胞亚群不足，脐血移植治疗重型再生障碍性贫血在移植前输血次数过多，珠蛋白生成障碍性贫血，免疫缺陷或范可尼贫血，患者骨髓基质细胞在强烈放化疗后严重受损，存在移植并发症有各种病原微生物感染。
异基因造血干细胞移植治疗儿童重型再生障碍性贫血：儿童单倍型移植是具有中国特色的移植体系，在国际上处于领先水平，但移植后致死性的感染及移植物抗宿主病等并发症是影响移植预后的主要因素，最近临床治疗中发现，诱导免疫耐受新方法即移植后高剂量环磷酰胺应用于重型再生障碍性贫血，在移植中减少移植物抗宿主病和移植相关病死率取得显著成效，促进免疫重建的形成是解决异基因造血干细胞移植后并发症的根本途径。

 

摘要
背景：提出单倍型异基因造血干细胞移植后高剂量环磷酰胺诱导免疫耐受的新技术，理论与实践相结合，优化造血干细胞移植治疗儿童重型再生障碍性贫血的技术体系，为临床推广应用提供理论基础。
目的：探讨单倍型异基因造血干细胞移植后应用大剂量环磷酰胺诱导免疫耐受治疗儿童重型再生障碍性贫血的临床疗效和安全性。
方法：解放军北京军区总医院血液科2013年1月至2015年1月应用单倍型异基因造血干细胞移植治疗10例重型再生障碍性贫血患儿(治疗组)，预处理方案为环磷酰胺、氟达拉滨、白舒非联合抗人淋巴细胞免疫球蛋白，移植后+3 d用环磷酰胺(50 mg/kg•d)诱导免疫耐受，供者接受粒细胞集落刺激因子动员，采用骨髓联合外周血干细胞移植。移植物抗宿主病预防采用环孢素A、氨甲蝶呤、他克莫司等联合免疫抑制剂。选择同期行全相合造血干细胞移植治疗10例重型再生障碍性贫血患儿为对照组，统计两组患儿移植相关并发症及存活情况。
结果与结论：随访至2015年5月，治疗组中位随访时间18.1个月(5-28个月)，全部患儿均获造血重建，3例发生移植物抗宿主病、3例合并肺部感染，肺部感染死亡2例；对照组中位随访时间20.7个月(6-27个月)，全部患儿均获造血重建，2例发生移植物抗宿主病、4例合并肺部感染，移植物抗宿主病死亡1例、肺部感染死亡1例，两组患儿总生存率均为80%。结果表明单倍型异基因造血干细胞移植后大剂量环磷酰胺诱导免疫耐受治疗儿童重型再生障碍性贫血安全有效，临床疗效与全相合造血干细胞移植相当。

 

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
ORCID: 0000-0002-1164-9978(郭智)

关键词: 干细胞, 移植, 重型, 再生障碍性贫血, 单倍型, 异基因造血干细胞移植, 环磷酰胺, 免疫耐受, 移植物抗宿主病, 国家自然科学基金

Abstract:

BACKGROUND: High-dose cyclophosphamide (CTX)-induced immunogenic tolerance following haploidentical allogeneic hematopoietic stem cell transplantation (allo-HSCT) is developed to optimize the treatment of childhood severe aplastic anemia (SAA) using haplotype allo-HSCT, providing a theoretical basis for the clinical application.
OBJECTIVE: To investigate the clinical efficacy and safety of the use of high-dose CTX following haploidentical allo-HSCT in SAA children.
METHODS: Clinical data from 10 children with SAA undergoing haploidentical allo-HSCT at the Department of Hematology, General Hospital of Beijing Military Area from January 2013 to January 2015 were retrospectively analyzed. Pretreatment was CTX, fludarabine, Busulfex combined with anti-human lymphocyte immune globulin used for 2 consecutive days, and then 3 days after transplantation, CTX (50 mg/kg per day) was used to induce immunogenic tolerance. Combined use of cyclosporin A, methotrexate and tacrolimus functioned as a prophylaxis for graft-versus-host disease. Another 10 SAA children who underwent synchronous HLA-identical sibling HSCT served as controls. Complications and survival in children were statistically analyzed in the two groups.
RESULTS AND CONCLUSION: In the treatment group, children were followed up until May 2015, and the median follow-up period was 18.1 months (5-28 months). Hematopoietic reconstruction was successful in all cases, and there were three cases of graft-versus-host disease, three cases of pulmonary infection and two cases dying of pulmonary infection. In the control group, the median follow-up period was 20.7 months (6-27 months), and all the children received hematopoietic reconstruction. Additionally, there were two cases of graft-versus-host disease, four cases of pulmonary infection, one case dying of graft-versus-host disease and one case dying of pulmonary infection in the control group. The total survival rate in each group was 80%. In summary, high-dose CTX-induced immunogenic tolerance is safe and effective for SAA children undergoing haploidentical allo-HSCT, which makes the clinical efficacy of haploidentical allo-HSCT identical to that of matched HSCT.

 

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

Key words: Anemia, Aplastic, Haploidy, Hematopoietic Stem Cell Transplantation, Immune Tolerance, Cyclophosphamide, Tissue Engineering

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