自体外周血造血干细胞移植治疗重症肌无力的随访研究
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摘要
目的：观察与研究自体外周血造血干细胞移植(APBSCT)治疗重症肌无力(MG)的安全性及近,远期疗效的。
方法：MG患者四例,移植前血浆置换3-4次,胸腺局部照射20-25Gy,若合并胸腺瘤者行手术切除。后联用环磷酰胺(CTX)和粒细胞集落刺激因子(G-CSF)动员自体外周血造血干细胞(APBSCs),并经血细胞分离仪分离和采集后4℃保存(72h内)。经环磷酰胺+马法兰方案预处理后,经锁骨下静脉回输APBSCs。回输后用抗淋巴细胞球蛋白(ALG)体内去除T细胞,并用G-CSF提升白细胞。当中性粒细胞>0.5×109/L、血小板>50×109/L时,提示造血功能重建,移植成功。移植后通过观察移植前后患者临床症状、体征及实验室指标的改变评价疗效。
结果：例1经APBSCT后肌无力症状、体征逐渐缓解,T淋巴细胞亚群和神经电生理均有不同程度的恢复,2年后临床症状体征完全缓解消失,电生理恢复正常,停用抗胆碱酯酶药,能正常工作及生活,2005年至2007年无复发,,至08年后同前无力症状再发,靠激素和抗胆碱酯酶药维持治至今。
例2行APBSCT后5个月,临床症状和体征完全缓解,神经电生理恢复正常,随访至今9年无复发。
例3行移植后仅2个月,肌无力症状、体征明显好转,神经电生理明显改善,但仍有两侧软腭上提力差,闭眼无力,鼓腮无力等无力症状,3年后上述无力症状体征完全缓解,电生理恢复正常,随访至今8年无复发。
例4移植后约1月开始起效,5个月后明显好转,全身肌力改善,以四肢改善明显,肌力5—级,可以适当下地劳动,无呼吸乏力,眼肌和面肌恢复稍慢。1年2个月后复查,上睑下垂四肢乏力等症状体征较移植前明显改善,但出现四肢腱反射亢进,以双下肢明显,呈(++++),双踝阵挛亦较前明显,呈持续性,并出现双侧病理征明显阳性,远期疗效仍有待进一步观察。
结论：APBSCT治疗MG安全、有效,远期疗效肯定,但不排除存在复发风险；MG患者APBSCT前神经低频重复电刺激检查可在一定程度上预测移植后肌力的恢复情况；.出现越早,越重的症状恢复越慢,出现越迟,越轻的恢复越快；临床症状恢复较实验指标恢复快；临床恢复与抗乙酰胆碱受体抗体指标呈不一致性。
To explore the clinical effect and safty of treatment of Refractory Myasthenia Gravis by autologous peripheral blood stem cell transplantationin, four MG patients were chosen to deal with the method.Methods:autologous peripheral blood stem cells (APBSCs) were mobilized with cyclophosphamide (CTX) and granulocytecolony-stimulating factor (G-CSF).The CD34+cells harvesting was performed by continuous flow leukapheresis using a CS-3000plus blood separator, then APBSCs were collected and preserved at4℃in refrigerator.then the patients were conditioned by CTX (60mg/kg/d, for2days)+maphalan(120mg/m2/d, for1day)+thymus radiotherapy+plasma exchange. To clear away T cell, antilymphocyteglobulin was used (10mg/kg/d, for2days)after APBSCs had been reinfused.Granulocyte recovery was stimulated by G-CSF. The four patients' clinical manifestations and immunologic markers were compared before and after transplantation.Results:1,The first MG patients got an excellent clinical remission after transplantation in2～8months,and The patients' clinical manifestations and immunologic markers were completely remission after about two years. But she took the disease again two years latter. Then she had to take back hormone and anticholinesterase drugs to keep her physical strength.2.the second MG patient were completely remission after five months. there was no relapse by nine years observed results.3.The third patient got an excellent clinical remission after transplantation in about2months, too. Then completely remission afte about3years. There was no relapse by8years observed results.4.The forth MG patient felt batter after the transplantation in about5months,and he can do some housework as normal.lyear and2months latter, he got an excellent clinical remission,too. Conclussions:APBSCT is effective and safe for MG, and the long-term effect is sure. But there may be some risk of relapse. The repetitive nerve stimulation test before transplantation is helpful in predicting the recovery of MG after APBSCT to some extent.The earlier and heavier the symptom is, the later it would disappear. The clinical symptoms recover faster than The index. The Clinical recovery donot stay the same with the high-low lines Of AchRab index.
方法：MG患者四例,移植前血浆置换3-4次,胸腺局部照射20-25Gy,若合并胸腺瘤者行手术切除。后联用环磷酰胺(CTX)和粒细胞集落刺激因子(G-CSF)动员自体外周血造血干细胞(APBSCs),并经血细胞分离仪分离和采集后4℃保存(72h内)。经环磷酰胺+马法兰方案预处理后,经锁骨下静脉回输APBSCs。回输后用抗淋巴细胞球蛋白(ALG)体内去除T细胞,并用G-CSF提升白细胞。当中性粒细胞>0.5×109/L、血小板>50×109/L时,提示造血功能重建,移植成功。移植后通过观察移植前后患者临床症状、体征及实验室指标的改变评价疗效。
结果：例1经APBSCT后肌无力症状、体征逐渐缓解,T淋巴细胞亚群和神经电生理均有不同程度的恢复,2年后临床症状体征完全缓解消失,电生理恢复正常,停用抗胆碱酯酶药,能正常工作及生活,2005年至2007年无复发,,至08年后同前无力症状再发,靠激素和抗胆碱酯酶药维持治至今。
例2行APBSCT后5个月,临床症状和体征完全缓解,神经电生理恢复正常,随访至今9年无复发。
例3行移植后仅2个月,肌无力症状、体征明显好转,神经电生理明显改善,但仍有两侧软腭上提力差,闭眼无力,鼓腮无力等无力症状,3年后上述无力症状体征完全缓解,电生理恢复正常,随访至今8年无复发。
例4移植后约1月开始起效,5个月后明显好转,全身肌力改善,以四肢改善明显,肌力5—级,可以适当下地劳动,无呼吸乏力,眼肌和面肌恢复稍慢。1年2个月后复查,上睑下垂四肢乏力等症状体征较移植前明显改善,但出现四肢腱反射亢进,以双下肢明显,呈(++++),双踝阵挛亦较前明显,呈持续性,并出现双侧病理征明显阳性,远期疗效仍有待进一步观察。
结论：APBSCT治疗MG安全、有效,远期疗效肯定,但不排除存在复发风险；MG患者APBSCT前神经低频重复电刺激检查可在一定程度上预测移植后肌力的恢复情况；.出现越早,越重的症状恢复越慢,出现越迟,越轻的恢复越快；临床症状恢复较实验指标恢复快；临床恢复与抗乙酰胆碱受体抗体指标呈不一致性。
To explore the clinical effect and safty of treatment of Refractory Myasthenia Gravis by autologous peripheral blood stem cell transplantationin, four MG patients were chosen to deal with the method.Methods:autologous peripheral blood stem cells (APBSCs) were mobilized with cyclophosphamide (CTX) and granulocytecolony-stimulating factor (G-CSF).The CD34+cells harvesting was performed by continuous flow leukapheresis using a CS-3000plus blood separator, then APBSCs were collected and preserved at4℃in refrigerator.then the patients were conditioned by CTX (60mg/kg/d, for2days)+maphalan(120mg/m2/d, for1day)+thymus radiotherapy+plasma exchange. To clear away T cell, antilymphocyteglobulin was used (10mg/kg/d, for2days)after APBSCs had been reinfused.Granulocyte recovery was stimulated by G-CSF. The four patients' clinical manifestations and immunologic markers were compared before and after transplantation.Results:1,The first MG patients got an excellent clinical remission after transplantation in2～8months,and The patients' clinical manifestations and immunologic markers were completely remission after about two years. But she took the disease again two years latter. Then she had to take back hormone and anticholinesterase drugs to keep her physical strength.2.the second MG patient were completely remission after five months. there was no relapse by nine years observed results.3.The third patient got an excellent clinical remission after transplantation in about2months, too. Then completely remission afte about3years. There was no relapse by8years observed results.4.The forth MG patient felt batter after the transplantation in about5months,and he can do some housework as normal.lyear and2months latter, he got an excellent clinical remission,too. Conclussions:APBSCT is effective and safe for MG, and the long-term effect is sure. But there may be some risk of relapse. The repetitive nerve stimulation test before transplantation is helpful in predicting the recovery of MG after APBSCT to some extent.The earlier and heavier the symptom is, the later it would disappear. The clinical symptoms recover faster than The index. The Clinical recovery donot stay the same with the high-low lines Of AchRab index.
引文
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2 Euler HH, Marnont AM, Bacigalupo A, et al. Early recurrence or persistence ofautoimmune diseases after unmanipulated autologous stem cell transplantation. Blood,1996,88(9):3621-3625
3 Yoshinobu Iwasaki, Shuji Ohsugi, YoshizumiTakemura, et al. Multidisciplinarytherapy including high-dose chemotherapy followed by peripheral blood stemcell transplantation for invasive thymoma. Chest,2002,122:2249-2252
4陈虎.外周血造血干细胞的采集与处理.见：达万明主编,自体造血干细胞移植.北京：人民卫生出版社,2000,91-103
5 Fruehauf S, HaasR, Conrdt C, et al. Peripheral blood progenitor cell (PBPC)counts during steady-state hematopoiesis allow to estimate the yield of mobilized PBPC after filgrastim (R-metHuG-CSF)-supported cytotoxic chemotherapy. Blood,1995,85(9):2619-2626
6 Husson B, Ravoet C, Dehon M, et al. Predictive value of the steady-stateperipheral blood progenitor cell (PBPC) counts for the yield of PBPC collectedby leukapheresis after mobilization by granulocyte colony-stimulating factor(G-CSF) alone or chemotherapy and G-CSF. Blood,1996,87(8):3526-3528
7 Fruehauf S, HaasR, Conrdt C, et al. Peripheral blood progenitor cell (PBPC)counts during steady-state hematopoiesis allow to estimate the yield of mobilizedPBPC after filgrastim (R-metHuG-CSF)-supported cytotoxic chemotherapy. Blood,1995,85(9):2619-2626
8耿良权,刘慧兰,汤宝林等.自体外周血造血干细胞移植治疗重症肌无力2例,中国组织工程研究与临床康复第12卷第43期2008-10-21出版
9高雁婷,叶宝东,周郁鸿等.炙马钱子胶囊联合白体外周血干细胞移植治疗难治性重症肌无力远期疗效观察,现代中西医结合杂志,2010-5-19
10李亚红,王黎明,田丁军等,自体干细胞移植治疗重症肌无力一例报告,中华神经科杂志,2005-4
11王秀云,许贤豪,孙宏,等.重症肌无力病人的临床绝对评分法和相对评分法.中华神经科杂志,1997,30(2)：87-90
12陈虎.外周血造血干细胞的采集与处理.见：达万明主编,自体造血干细胞移植.北京：人民卫生出版社,2000,91-103
13 Bensinger W, Appelbaum F, Rowley S, et al. Factors that influence collection andengraftment of autologous peripheral-blood stem cells. J Clin Oncol,1995,13(10):2547-2555
14袁长红,刘永梅。重症肌无力危象75例临床分析。中国现代医药杂志,2011,4：
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19欧阳建,倪秀石,陈兵,等.自体造血干细胞移植治疗进展型多发性硬化的临床研究.中华内科杂志,2001,8：550-552
20王金铠,张金巧,邢莉民,等.外周血干细胞移植治疗难治性系统性红斑狼疮.临床内科杂志,2002,19：459-461
21欧阳建,孙凌云,杨永功,等.自身骨髓造血干细胞移植治疗系统性红斑狼疮初探.中华内科杂志,2001,4：229-231
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23 Schmitz N, Linch D, Dreger P, et al. Randomised trial of filgrastim-mobilisedperipheral blood progenitor cell transplantation versus autologous bone-marrow transplantation in lymphoma patients. Lancet,1996,347:353-357
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27刘源,达万明.自体造血干细胞移植后的造血与免疫功能重建.见：达万明主编,自体造血干细胞移植.兰州：甘肃科学技术出版社1995,162-168
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30刘源,达万明.自体造血干细胞移植后的造血与免疫功能重建.见：达万明主编,自体造血干细胞移植.兰州：甘肃科学技术出版社,1995,162-168
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8 Tyndall A, Gratwohl A. Blood and marrow stem cell transplants in auto-immune disease:a consensus report written on behalf of the European Leagueagainst Rheumatism (EULAR) and the European Group for Blood and MarrowTransplantation (EBMT). Bone marrow transplantation,1997,19 (7):643-645
9陈虎.外周血造血干细胞的采集与处理.见：达万明主编,自体造血干细胞移植.北京：人民卫生出版社,2000,91-103
10 Fruehauf S, Haas R, Conrdt C, et al. Peripheral blood progenitor cell (PBPC)counts during steady-state hematopoiesis allow to estimate the yield ofmobilized PBPC after filgrastim (R-metHuG-CSF)-supported cytotoxicchemotherapy. Blood,1995,85(9):2619-2626
11 Husson B, Ravoet C, Dehon M, et al. Predictive value of the steady-state57
12 Tyndall A, Gratwohl A. Blood and marrow stem cell transplants in auto-immune disease:a consensus report written on behalf of the European Leagueagainst Rheumatism (EULAR) and the European Group for Blood and MarrowTransplantation (EBMT). Bone marrow transplantation,1997,19 (7):643-645
13王金铠,张金巧,邢莉民,等.外周血干细胞移植治疗难治性系 统性红斑狼疮.临床内科杂志,2002,19：459-461
14欧阳建,孙凌云,杨永功,等.自身骨髓造血干细胞移植治疗系统性红斑狼疮初探.中华内科杂志,2001,4：229-231
15欧阳建,陈兵,李翠萍,等.纯化的CD34+细胞移植治疗移植后复发的系统性红斑狼疮.中华医学杂志,2003,83(1)：55-56
16欧阳建,倪秀石,陈兵,等.自体造血干细胞移植治疗多发性硬化的临床研究.中华内科杂志,2001,8：550-552
17 Burt RK, Traynor AE, Pope R, et al. Treatment of autoimmune disease by intense immunosuppressive conditioning and autologous hematopoietic stemcell transplantation. Blood,1998,92 (10):3505-3514
19 Tyndall A, Gratwohl A. Blood and marrow stem cell transplants in auto-immune disease:a consensus report written on behalf of the European Leagueagainst Rheumatism (EULAR) and the European Group for Blood and MarrowTransplantation (EBMT). Bone marrow transplantation,1997,19(7):643-645
20 Ziegler BL, Buhing HJ, Scheding S, et al. Cytokine responses of hematopoieticprogentior cells. In:Educational program book. 98 ISH-EHA combined hema-tology congress. Amsterdam,1998, 51-57
21达万明.外周血干/祖细胞的特性.见：达万明主编,外周血干细 胞移植.北京：人民卫生出版社,2000,30-44
22耿良权,刘慧兰,汤宝林等.自体外周血造血干细胞移植治疗重症肌无力2例,中国组织工程研究与临床康复第12卷第43期2008-10-21出版
23高雁婷,叶宝东,周郁鸿等.炙马钱子胶囊联合自体外周血干细胞移植治疗难治性重症肌无力远期疗效观察,现代中西医结合杂志,2010-5-19
24李亚红,王黎明,田丁军等,自体干细胞移植治疗重症肌无力—例报告,中华神经科杂志,2005-4
2 Euler HH, Marnont AM, Bacigalupo A, et al. Early recurrence or persistence ofautoimmune diseases after unmanipulated autologous stem cell transplantation. Blood,1996,88(9):3621-3625
3 Yoshinobu Iwasaki, Shuji Ohsugi, YoshizumiTakemura, et al. Multidisciplinarytherapy including high-dose chemotherapy followed by peripheral blood stemcell transplantation for invasive thymoma. Chest,2002,122:2249-2252
4陈虎.外周血造血干细胞的采集与处理.见：达万明主编,自体造血干细胞移植.北京：人民卫生出版社,2000,91-103
5 Fruehauf S, HaasR, Conrdt C, et al. Peripheral blood progenitor cell (PBPC)counts during steady-state hematopoiesis allow to estimate the yield of mobilized PBPC after filgrastim (R-metHuG-CSF)-supported cytotoxic chemotherapy. Blood,1995,85(9):2619-2626
6 Husson B, Ravoet C, Dehon M, et al. Predictive value of the steady-stateperipheral blood progenitor cell (PBPC) counts for the yield of PBPC collectedby leukapheresis after mobilization by granulocyte colony-stimulating factor(G-CSF) alone or chemotherapy and G-CSF. Blood,1996,87(8):3526-3528
7 Fruehauf S, HaasR, Conrdt C, et al. Peripheral blood progenitor cell (PBPC)counts during steady-state hematopoiesis allow to estimate the yield of mobilizedPBPC after filgrastim (R-metHuG-CSF)-supported cytotoxic chemotherapy. Blood,1995,85(9):2619-2626
8耿良权,刘慧兰,汤宝林等.自体外周血造血干细胞移植治疗重症肌无力2例,中国组织工程研究与临床康复第12卷第43期2008-10-21出版
9高雁婷,叶宝东,周郁鸿等.炙马钱子胶囊联合白体外周血干细胞移植治疗难治性重症肌无力远期疗效观察,现代中西医结合杂志,2010-5-19
10李亚红,王黎明,田丁军等,自体干细胞移植治疗重症肌无力一例报告,中华神经科杂志,2005-4
11王秀云,许贤豪,孙宏,等.重症肌无力病人的临床绝对评分法和相对评分法.中华神经科杂志,1997,30(2)：87-90
12陈虎.外周血造血干细胞的采集与处理.见：达万明主编,自体造血干细胞移植.北京：人民卫生出版社,2000,91-103
13 Bensinger W, Appelbaum F, Rowley S, et al. Factors that influence collection andengraftment of autologous peripheral-blood stem cells. J Clin Oncol,1995,13(10):2547-2555
14袁长红,刘永梅。重症肌无力危象75例临床分析。中国现代医药杂志,2011,4：
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