Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease:: a phase II study
Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease:: a phase II study
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DOI：
10.1016/s0140-6736(08)60690-x
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发表时间：
2008-05-10
期刊：
影响因子：
168.9
通讯作者：
Ringden, Olle
中科院分区：
文献类型：
--
作者：
LeBlanc, Katarina;Frassoni, Francesco;Ringden, Olle
背景：严重移植物抗宿主病（GVHD）是同种异体造血干细胞移植后危及生命的并发症。间充质干细胞在体外和体内调节免疫反应。我们的目的是评估造血干细胞移植后间充质干细胞是否可以改善GVHD。方法在一项多中心II期实验研究中，使用来自欧洲血液和骨髓移植组织体外扩增程序的间充质干细胞治疗激素抵抗的严重急性GVHD患者。我们记录了细胞输注后长达60个月的反应、移植相关死亡和其他不良事件。结果：2001年10月至2007年1月，55例患者接受治疗。骨髓间充质干细胞的中位剂量为1.4 × 10(6)（最小-最大范围为0.4-9x10(6)）个细胞/ kg体重。27名患者接受了一剂，22名接受了两剂，6名患者接受了3至5剂的细胞，这些细胞来自hla相同的兄弟姐妹供者（n=5）、单倍相同的供者（n=18）和第三方hla不匹配的供者（n=69）。30例患者完全缓解，9例改善。没有患者在输注间充质干细胞期间或输注后立即出现副作用。反应率与供体hla匹配无关。3例恶性肿瘤复发，1例急性髓性白血病复发。输注后1年，完全缓解者的移植相关死亡率低于部分缓解或无缓解者（30例中有11例[37%]vs 25例中有18例[72%]；p=0.002），造血干细胞移植后2年的总生存率更高(30例中有16例[53%]vs 25例中有4例[16%]；p=0。018)。输注体外扩增的间充质干细胞，无论供体如何，可能是治疗类固醇抵抗性急性GVHD患者的有效方法。资助瑞典癌症协会儿童癌症基金会，瑞典研究委员会，斯德哥尔摩癌症协会，卡罗林斯卡癌症和过敏基金会。欧盟卫生高等学院，伦巴第大区，CARIPLO基金会，意大利癌症防治协会，圣保罗都灵公司，CARIGE Cellule Staminali项目，欧盟委员会，Ricerca科学技术大学部长，Ricerca Finalizzata区域利古里亚2005年荷兰组织工程援助计划。
Background Severe graft-versus-host disease (GVHD) is a life-threatening complication after allogeneic transplantation with haemopoietic stem cells. Mesenchymal stem cells modulate immune responses in vitro and in vivo. We aimed to assess whether mesenchymal stem cells could ameliorate GVHD after haemopoietic-stem-cell transplantation.Methods Patients with steroid-resistant, severe, acute GVHD were treated with mesenchymal stem cells, derived with the European Group for Blood and Marrow Transplantation ex-vivo expansion procedure, in a multicentre, phase II experimental study. We recorded response, transplantation-related deaths, and other adverse events for up to 60 months' follow-up from infusion of the cells.Findings Between October, 2001, and January, 2007, 55 patients were treated. The median dose of bone-marrow derived mesenchymal stem cells was 1.4x10(6) (Min-max range 0.4-9x10(6)) cells per kg bodyweight. 27 patients received one dose, 22 received two doses, and six three to five doses of cells obtained from HLA-identical sibling donors (n=5), haploidentical donors (n=18), and third-party HLA-mismatched donors (n=69). 30 patients had a complete response and nine showed improvement. No patients had side-effects during or immediately after infusions of mesenchymal stem cells. Response rate was not related to donor HLA-match. Three patients had recurrent malignant disease and one developed de-novo acute myeloid leukaemia of recipient origin. Complete responders had lower transplantation-related mortality 1 year after infusion than did patients with partial or no response (11 [37%] of 30 vs 18 [72%] of 25; p=0.002) and higher overall survival 2 years after haemopoietic-stem-cell transplantation (16 [53%] of 30 vs four [16%] of 25; p=0 . 018).Interpretation Infusion of mesenchymal stem cells expanded in vitro, irrespective of the donor, might be an effective therapy for patients with steroid-resistant, acute GVHD.Funding Swedish Cancer Society Children's Cancer Foundation, Swedish Research Council, Cancer Society in Stockholm, Cancer and Allergy Foundation, Karolinska. Institutet, Istituto Superiore di Sanita, European Union, Regione Lombardia, Fondazione CARIPLO, Associazione Italiana Ricerca contro il Cancro, Compagnia di San Paolo Torino, Progetto CARIGE Cellule Staminali, European Commission, Ministero dell'Universita e della Ricerca Scientifica e Tecnologica, Ricerca Finalizzata Regione Liguria 2005 Assistenza Domiciliare, Dutch Programme for Tissue Engineering.