Therapeutic effects of mesenchymal stem cell transfusion on different damaged organs in graft-versus-host disease

doi:10.3969/j.issn.2095-4344.2014.23.012

Abstract

Abstract:

BACKGROUND: Because of their immunological properties, bone marrow mesenchymal stem cells transfusion is developed as a new treatment for refractory graft-versus-host disease.

OBJECTIVE: To analyze the safety and curative effect of bone marrow mesenchymal stem cells transfusion on treating different organ damages in graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.

METHODS: Eight patients with malignant hematologic disease were included in this study. The patients developed severe steroid-resistant graft-versus-host disease after allogeneic hematopoietic stem cell transplantation and received transfusion of mesenchymal stme cell (1×10⁶/kg) together with the primary therapy of immunosuppressive agent.

RESULTS AND CONCLUSION: For the totally eight patients, six got response (two cases of complete remission, and four cases of partial remission) and two showed no remission. Four of five cutaneous damages were ameliorated and one showed no effect. For three cases of oral graft-versus-host disease, two acquired complete remission and one showed partial remission. Two cases of liver graft-versus-host disease and two cases of astro-intestinal graft-versus-host disease obtained complete remission. No response was displayed to three cases of ocular graft-versus-host disease, one case of bronchiolitis obliterans, and one case of urinary graft-versus-host disease. In the median follow-up of 28 months (7-62 months), three patients developed posttransplant lymphoproliferative disorders within 3 months after mesenchymal stem cells transfusion. Administration of mesenchymal stem cells is safe for treatment of severe graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Mesenchymal stem cells transfusion may be a promising therapy for refractory cutaneous , astro-intestinal, liver and oral graft-versus-host disease but not for pulmonary, ocular and urinary graft-versus-host disease. Whether mesenchymal stem cells transfusion is associated with posttransplant lymphoproliferative disorders needs more case data.

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

全文链接：

Key words: stem cells, mesenchymal stem cells, graft vs host disease

CLC Number:

R394.2

Lu Ying, Zhang Xiang-zhong, Liu Xiang-fu, Li Fang, Lin Dong-jun. Therapeutic effects of mesenchymal stem cell transfusion on different damaged organs in graft-versus-host disease[J]. Chinese Journal of Tissue Engineering Research, 2014, 18(23): 3676-3681.

Figures/Tables 1

2.1 参与者数量分析纳入患者8例，治疗过程无脱落，均进入结果分析。 2.2 移植物抗宿主病的累及器官 8例移植物抗宿主病患者中，2例为急性移植物抗宿主病； 6例为慢性移植物抗宿主病，其中2例(病例4，病例6)由急性移植物抗宿主病演变而来。8例移植物抗宿主病患者的病变累及多个器官，其中皮肤5例，口腔3例，眼睛3例，肝脏2例，胃肠道2例，肺脏1例，膀胱1例。 2.3 间充质干细胞的治疗效果所有患者均在原有免疫抑制剂治疗的基础上接受间充质干细胞治疗。1例输注1次，5例输注2次，1例输注3次，1例输注4次。输注期间所有患者均未出现输液相关不良反应。8例患者中6例经间充质干细胞治疗有效(2例完全缓解，4例部分缓解)，2例无效。各受损靶器官治疗反应见表1。5例皮肤病变中4例均得到改善，1例无效，1例在移植后21个月出现硬皮病样慢性移植物抗宿主病，用雷帕鸣治疗后有所改善，1个月后因急性阑尾炎行阑尾切除术，术后切口一直无法愈合，在输注间充质干细胞2次后伤口痊愈。3例口腔病变中2例得到完全缓解，1例部分缓解。2例肝脏病变以及2例胃肠道病变均获得完全缓解。3例眼睛病变用间充质干细胞治疗无效。 2.4 间充质干细胞输注治疗移植物抗宿主病综合评价见表1。 2.5 间充质干细胞对闭塞性系支气管炎的治疗效果病例6在移植后11个月出现胸闷、气促，肺部CT提示双肺炎症，左肺下叶不张，右肺上叶、中叶、左肺上叶肺气肿。纤维支气管镜取右肺背段组织病理检查提示：肺泡间隔增厚伴淋巴细胞浸润。诊断为闭塞性细支气管炎，用抗生素以及大剂量甲基强的松龙治疗后气促逐渐好转，但是患者需要依赖氧疗生活，在输注间充质干细胞2个疗程后患者可以脱离吸氧。2个月后患者又出现严重气促，再次输注间充质干细胞2个疗程后无效果。 2.6 间充质干细胞对膀胱移植物抗宿主病的治疗效果病例7在移植后25 d出现出血性膀胱炎，检测血以及尿巨细胞病毒DNA均为阳性，在持续膀胱冲洗的基础上，先后予更昔洛韦以及膦甲酸钠治疗后巨细胞病毒DNA转为阴性，但是患者仍有出血性膀胱炎。考虑膀胱移植物抗宿主病的可能性，先后予甲强龙、他克莫司的免疫抑制治疗，患者出血性膀胱炎症状仍有反复。于输注间充质干细胞2次后症状无改善。最后患者行膀胱镜+膀胱黏膜电切活检术，膀胱黏膜病理：送检少许变性纤维组织，表面未见确切披覆上皮，可见少量血块，间质小血管丰富，呈慢性炎症改变。 2.7 临床转归截止至2013年12月31日，随访中位时间28(7-62)个月。2例完全缓解患者中，病例6在移植后13个月(输注间充质干细胞后7个月)因疾病复发死亡，病例8在移植后4个月(输注间充质干细胞后1个月)因并发中枢神经系统移植后淋巴增殖性疾病而死亡。4例部分缓解患者中，病例3因急性髓细胞白血病复发导致的中枢神经系统白血病，于移植后30个月(输注间充质干细胞后23个月)死亡；其他3例患者随访中位时间41 (26-59)个月，目前已经停用免疫抑制剂；病例4移植后11个月(输注间充质干细胞后3个月)出现外周移植后淋巴增殖性疾病，经美罗华治疗后缓解。2例无效患者均死亡，病例5因闭塞性细支气管炎于移植后23个月(输注间充质干细胞后10个月)死于呼吸功能衰竭；病例7因并发严重感染以及移植后淋巴增殖性疾病死亡。 2.8 不良反应 8例患者总共输注间充质干细胞18次，所有患者均未出现输液相关不良反应。"

References

[1] Shlomchik WD. Antigen presentation in graft-vs-host disease. Exp Hematol.2003;31(12):1187-1197.
[2] Csencsits KL, Bishop DK. Contrasting alloreactive CD4+ and CD8+ T cells: there’s more to it than MHC restriction. Am J Transplant.2003;3(2):107-115.
[3] Iwasaki T. Recent advances in the treatment of graft-versus-host disease. Clin Med Res.2004;2(4):243-252.
[4] Sarantopoulos S,Stevenson KE, Kim HT, et al. High levels of B-cell activating factor in patients with active chronic graft-versus-host disease.Clin Cancer Res. 2007;13(20): 6107-6106.
[5] Bacigalupo A. Management of acute graft - versus – host disease. Br J Haematol. 2007;137(2): 87-98.
[6] Keyser KA, Beagles KE, Kiem HP. Comparison of mesenchymal stem cells from different tissues to suppress T-cell activation. Cell Transplant. 2007;16(5): 555-562.
[7] Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses.Blood. 2005; 105(4):1815-1822.
[8] Spaggiari GM, Capobianco A, Becchetti S, et al.Mesenchymal stem cell-natural killer cell interactions:evidence that activated NK cells are capable of killing MSCs, whereas MSCs can inhibit IL-2-induced NK-cellproliferation. Blood. 2006; 107(4): 1484-1490.
[9] Corcione A, Benvenuto F, Ferretti E, et al. Human mesenchymal stem cells modulate B-cell functions.Blood. 2006;107(1): 367-372.
[10] Le Blanc K,Rasmusson I,Sundberg B,et al.Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet.2004; 363(9419): 1439-1441.
[11] Zhao K, Huang F, Peng YW, Clinical observation of mesenchymal stem cell as salvage treatment for refractory acute graft-versus-host disease. Zhonghua Xue Ye Xue Za Zhi. 2013;34(2):122-126.
[12] Introna M, Lucchini G, Dander E, et al.Treatment of Graft versus Host Disease with Mesenchymal Stromal Cells: A Phase I Study on 40 Adult and Pediatric Patients. Biol Blood Marrow Transplant. 2014 ;20(3):375-381.
[13] 张乐施,刘启发,黄科.问充质干细胞治疗糖皮质激素耐药性慢性移植物抗宿主病临床疗效观察[J].中华内科杂志,2009,48(7): 542-546.
[14] Martino R, Romero P, Subirá M,et al. Comparison of the classic Glucksberg criteria and the IBMTR Severity Index for grading acute graft-versus-host disease following HLA-identical sibling stem cell transplantation. International Bone Marrow Transplant Registry. Bone Marrow Transplant. 1999;24(3):283-287.
[15] Filipovieh AH, Weisdorf D, Pavletie S, et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-vel'Bus-Host Disease: I. Diagnosis and Staging Working Group Report. Biol Blood Marrow Transplant.2005;1l: 945-955．
[16] Gronthos S,Franklin DM,Leddy HA,et al.Surface protein characterization of human adipose tissue derived stromalcells.J Cell Physiol.2001;189(1):54-63.
[17] Campaagnoli C,Roberts IA, Kumar S, et al. Identifiction of mesenchymal stem/ progenitor cells in human first-trimester fetal blood,liver,and bone marrow. Blood.2001;98(8): 2396-2402.
[18] Igura K,ZhangX,Takahashi K,et al.Isolation and characterization of mesenchymal progenitor cells from chorionic villi of human placenta. Cytotherapy.2004; 6(6):543-553.
[19] Resnick IB, Barkats C, Shapira MY, et al.Treatment of severe steroid resistant acute GVHD with mesenchymal stromal cells (MSC). Am J Blood Res.2013;3(3):225-238.
[20] Ball LM, Bernardo ME, Roelofs H, et al.Multiple infusions of mesenchymal stromal cells induce sustained remission in children with steroid-refractory, grade III-IV acute graft-versus- host disease. Br J Haematol. 2013;163(4):501-509.
[21] Sato K, Ozaki K, Mori M, et al.Mesenchymal stromal cells for graft-versus-host disease: basic aspects and clinical outcomes.J Clin Exp Hematop. 2010;50(2):79-89.
[22] Inamoto Y,Flowers ME. Treatment of chronic graft-versus- host disease in 2011. Curr Opin Hematol.2011;18(6):414- 420.
[23] Saliba RM,de Lima M,Giralt S,et al. Hyperacute GVHD: risk factors,outcomes,and clinical implications. Blood.2007;109 (7):2751-2758.
[24] Peas PF,Fernández-Herrera J,García-Diez A. Dermatologic treatment of cutaneous graft versus host disease. Am J Clin Dermatol.2004;5 (6):403 -416.
[25] Wu PA, Cowen EW.Cutaneous graft-versus-host disease--clinical considerations and management. Curr Probl Dermatol.2012;43:101-115.
[26] Schnitzler M, Hasskarl J, Egger M,et al. Successful treatment of severe acute intestinal graft-versus-host resistant to systemic and topical steroids with alemtuzumab. Biol Blood Marrow Transplant.2009;15(8):910-918.
[27] Schub N, Günther A, Schrauder A.Therapy of steroid-refractory acute GVHD with CD52 antibody alemtuzumab is effective. Bone Marrow Transplant. 2011;46 (1):143-147.
[28] Soubani AO, Uberti JP. Bronchiolitis obliterans following haematopoietic stem cell transplantation. Eur Respir J.2007; 29(5): 1007-1019.
[29] Bergeron A, Godet C, Chevret S,et al.Bronchiolitis obliterans syndrome after allogeneic hematopoietic SCT: phenotypes and prognosis. Bone Marrow Transplant. 2013;48(6): 819-824.
[30] Fraile P, Vazquez L, Caballero D, et al.Chronic graft-versus-host disease of the kidney in patients with allogenic hematopoietic stem cell transplant. Eur J Haematol. 2013;91(2):129-134
[31] Cutis RE,Travis LB,Rowlings PA,et al. Risk of lymphoproliferative disorders after bone marrow transplantation: a multi-institutional study. Blood.1999;94(7)：2208-2216.
[32] Seçkin D, Barete S, Euvrard S, et al.Primary cutaneous posttransplant lymphoproliferative disorders in solid organ transplant recipients: a multicenter European case series. Am J Transplant. 2013;13(8):2146-2153.
[33] Weinstock DM,Ambrossi GC,Brennan C, et al.preempitive diagnosis and treatment of Epstein-Barr virus-associated posttransplant lymphoproliferative disorder after hematopoietic stem cell transplant: an approach in development.Bone Marrow Transplant. 2006;37(6):539-546.
[34] Liu XD, Fan ZP, Peng YW, et al. The outcome and safety of mesenchymal stem cells from bone marrow of a third party donor in treatment of secondary poor graft function following allogeneic hematopoietic stem cell transplantation.Zhonghua Xue Ye Xue Za Zhi.2012;33(2):98-102.