间充质干细胞防治移植物抗宿主病的研究进展
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摘要
移植物抗宿主病(GVHD)是异基因造血干细胞移植(allo-HSCT)后常见的严重并发症,严重影响移植的疗效及广泛应用。间充质干细胞(MSC)因其独特的免疫调节及组织修复能力成为allo-HSCT过程中GVHD预防及治疗的理想选择。本文就MSC防治GVHD的最新研究进展,MSC是否增加allo-HSCT后肿瘤复发及感染,影响MSC疗效的因素,MSC来源细胞外微囊对GVHD的防治作用等若干问题作一综述。
Objective: Graft-versus-host disease(GVHD) is a frequently encountered serious complication after allogeneic hematopoietic stem cell transplantation(allo-HSCT), it limits the success and widespread use of allo-HSCT. Mesenchymal stem cells(MSCs) are selected as ideal prophylactic and treatment means for GVHD during allo-HSCT due to their unique immunomodulatory and regenerative properties. Herein, the recent research progress about the prevantive and therapeutic effects of MSCs on GVHD and several issues related with the applications of MSC, including whether MSCs increasing risk of primary disease relapse and infection, impact of several clinical parameters on the clinical response to MSCs, and the prevantive and therapeutic effect of MSC-derived extracellular vesicles on GVHD are systematically reviewed.
Objective: Graft-versus-host disease(GVHD) is a frequently encountered serious complication after allogeneic hematopoietic stem cell transplantation(allo-HSCT), it limits the success and widespread use of allo-HSCT. Mesenchymal stem cells(MSCs) are selected as ideal prophylactic and treatment means for GVHD during allo-HSCT due to their unique immunomodulatory and regenerative properties. Herein, the recent research progress about the prevantive and therapeutic effects of MSCs on GVHD and several issues related with the applications of MSC, including whether MSCs increasing risk of primary disease relapse and infection, impact of several clinical parameters on the clinical response to MSCs, and the prevantive and therapeutic effect of MSC-derived extracellular vesicles on GVHD are systematically reviewed.
引文
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2 Kallekleiv M,Larun L,Bruserud O,et al.Co-transplantation of multipotent mesenchymal stromal cells in allogeneic hematopoietic stem cell transplantation:A systematic review and meta-analysis.Cytotherapy,2016;18(2):172-185.
3 Dotoli GM,De Santis GC,Orellana MD,et al.Mesenchymal stromal cell infusion to treat steroid-refractory acute GvHD III/IV after hematopoietic stem cell transplantation.Bone Marrow Transplant,2017;52(6):859-862.
4 von Dalowski F,Kramer M,Wermke M,et al.Mesenchymal stromal cells for treatment of acute steroid-refractory graft versus host disease:clinical responses and long-term outcome.Stem Cells,2016;34(2):357-366.
5 Muroi K,Miyamura K,Okada M,et al.Bone marrow-derived mesenchymal stem cells(JR-031)for steroid-refractory grade IIIor IV acute graft-versus-host disease:a phase II/III study.Int JHematol,2016;103(2):243-250.
6 Kuci Z,Bonig H,Kreyenberg H,et al.Mesenchymal stromal cells from pooled mononuclear cells of multiple bone marrow donors as rescue therapy in pediatric severe steroid-refractory graft-versushost disease:a multicenter survey.Haematologica,2016;101(8):985-994.
7 Chen X,Wang C,Yin J,et al.Efficacy of mesenchymal stem cell therapy for steroid-refractory acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation:Asystematic review and meta-analysis.PLoS One,2015;10(8):e0136991.
8 Hashmi S,Ahmed M,Murad MH,et al.Survival after mesenchymal stromal cell therapy in steroid-refractory acute graft-versus-host disease:systematic review and meta-analysis.Lancet Haematol,2016;3(1):e45-52.
9 Jurado M,De La Mata C,Ruiz-Garcia A,et al.Adipose tissuederived mesenchymal stromal cells as part of therapy for chronic graft-versus-host disease:a phase I/II study.Cytotherapy,2017;19(8):927-936.
10 Peng Y,Chen X,Liu Q,et al.Mesenchymal stromal cells infusions improve refractory chronic graft versus host disease through an increase of CD5+regulatory B cells producing interleukin 10.Leukemia,2015;29(3):636-646.
11张玲,张祥忠,李晓青,等.脐带间充质干细胞治疗难治性慢性移植物抗宿主病的疗效观察.器官移植,2016;7(6):459-462+483.
12 Lim JY,Ryu DB,Lee SE,et al.Mesenchymal stem cells(MSCs)attenuate cutaneous sclerodermatous graft-versus-host disease(SclGVHD)through inhibition of immune cell infiltration in a mouse model.J Invest Dermatol,2017;137(9):1895-1904.
13康慧珠,郑晓丽,王志东,等.单倍体相合造血干细胞移植联合脐带间充质干细胞输注治疗儿童恶性血液病的临床研究.中国实验血液学杂志,2017;25(4):1151-1157.
14 Gao L,Zhang Y,Hu B,et al.Phase II multicenter,randomized,double-blind controlled study of efficacy and safety of umbilical cord-derived mesenchymal stromal cells in the prophylaxis of chronic graft-versus-host disease after HLA-haploidentical stem-cell transplantation.J Clin Oncol,2016;34(24):2843-2850.
15 Liu Z,Zhang Y,Xiao H,et al.Cotransplantation of bone marrowderived mesenchymal stem cells in haploidentical hematopoietic stem cell transplantation in patients with severe aplastic anemia:an interim summary for a multicenter phase II trial results.Bone Marrow Transplant,2017;52(5):704-710.
16 Kuzmina LA,Petinati NA,Shipounova IN,et al.Analysis of multipotent mesenchymal stromal cells used for acute graft-versushost disease prophylaxis.Eur J Haematol,2016;96(4):425-434.
17乔淑凯,郭晓楠,张雅丽,等.异基因骨密质来源间充质干细胞对小鼠急性GVHD的防治作用及其机制研究.中国免疫学杂志,2016;32(11):1672-1677.
18王利,谷振阳,赵小利,等.间充质干细胞对移植物抗宿主病预防作用的Meta分析.中国实验血液学杂志,2015;23(4):1125-1132.
19 Stoma I,Karpov I,Krivenko S,et al.Mesenchymal stem cells transplantation in hematological patients with acute graft-versushost disease:characteristics and risk factors for infectious complications.Ann Hematol,2018;97(5):885-891.
20 Baygan A,Aronsson-Kurttila W,Moretti G,et al.Safety and side effects of using placenta-derived decidual stromal cells for graftversus-host disease and hemorrhagic cystitis.Front Immunol,2017;8:795.
21 Blennow O,Remberger M,Torlen J,et al.Risk factors for invasive mold infections and implications for choice of prophylaxis after allogeneic stem cell transplantation.Biol Blood Marrow Transplant,2016;22(9):1684-1689.
22 Schmidt S,Tramsen L,Schneider A,et al.Impact of human mesenchymal stromal cells on antifungal host response against Aspergillus fumigatus.Oncotarget,2017;8(56):95495-95503.
23 Rizk M,Monaghan M,Shorr R,et al.Heterogeneity in studies of mesenchymal stromal cells to treat or prevent graft-versus-host disease:A scoping review of the evidence.Biol Blood Marrow Transplant,2016;22(8):1416-1423.
24 Wang L,Zhang H,Guan L,et al.Mesenchymal stem cells provide prophylaxis against acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation:A meta-analysis of animal models.Oncotarget,2016;7(38):61764-61774.
25 Rani S,Ryan AE,Griffin MD,et al.Mesenchymal stem cell-derived extracellular vesicles:toward cell-free therapeutic applications.Mol Ther,2015;23(5):812-823.
26王利,赵莎莎,赵小利,等.间充质干细胞微泡的组织修复及其机制的研究进展.中华危重病急救医学,2014;26(11):845-848.
27 Kordelas L,Rebmann V,Ludwig AK,et al.MSC-derived exosomes:a novel tool to treat therapy-refractory graft-versus-host disease.Leukemia,2014;28(4):970-973.
28 Amarnath S,Foley JE,Farthing DE,et al.Bone marrow-derived mesenchymal stromal cells harness purinergenic signaling to tolerize human Th1 cells in vivo.Stem Cells,2015;33(4):1200-1212.
29 Wang L,Gu Z,Zhao X,et al.Extracellular vesicles released from human umbilical cord-derived mesenchymal stromal cells prevent life-threatening acute graft-versus-host disease in a mouse model of allogeneic hematopoietic stem cell transplantation.Stem Cells Dev,2016;25(24):1874-1883.
30 Fujii S,Miura Y,Fujishiro A,et al.Graft-versus-host disease amelioration by human bone marrow mesenchymal stromal/stem cell-derived extracellular vesicles is associated with peripheral preservation of naive T cell populations.Stem Cells,2018;36(3):434-445.
2 Kallekleiv M,Larun L,Bruserud O,et al.Co-transplantation of multipotent mesenchymal stromal cells in allogeneic hematopoietic stem cell transplantation:A systematic review and meta-analysis.Cytotherapy,2016;18(2):172-185.
3 Dotoli GM,De Santis GC,Orellana MD,et al.Mesenchymal stromal cell infusion to treat steroid-refractory acute GvHD III/IV after hematopoietic stem cell transplantation.Bone Marrow Transplant,2017;52(6):859-862.
4 von Dalowski F,Kramer M,Wermke M,et al.Mesenchymal stromal cells for treatment of acute steroid-refractory graft versus host disease:clinical responses and long-term outcome.Stem Cells,2016;34(2):357-366.
5 Muroi K,Miyamura K,Okada M,et al.Bone marrow-derived mesenchymal stem cells(JR-031)for steroid-refractory grade IIIor IV acute graft-versus-host disease:a phase II/III study.Int JHematol,2016;103(2):243-250.
6 Kuci Z,Bonig H,Kreyenberg H,et al.Mesenchymal stromal cells from pooled mononuclear cells of multiple bone marrow donors as rescue therapy in pediatric severe steroid-refractory graft-versushost disease:a multicenter survey.Haematologica,2016;101(8):985-994.
7 Chen X,Wang C,Yin J,et al.Efficacy of mesenchymal stem cell therapy for steroid-refractory acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation:Asystematic review and meta-analysis.PLoS One,2015;10(8):e0136991.
8 Hashmi S,Ahmed M,Murad MH,et al.Survival after mesenchymal stromal cell therapy in steroid-refractory acute graft-versus-host disease:systematic review and meta-analysis.Lancet Haematol,2016;3(1):e45-52.
9 Jurado M,De La Mata C,Ruiz-Garcia A,et al.Adipose tissuederived mesenchymal stromal cells as part of therapy for chronic graft-versus-host disease:a phase I/II study.Cytotherapy,2017;19(8):927-936.
10 Peng Y,Chen X,Liu Q,et al.Mesenchymal stromal cells infusions improve refractory chronic graft versus host disease through an increase of CD5+regulatory B cells producing interleukin 10.Leukemia,2015;29(3):636-646.
11张玲,张祥忠,李晓青,等.脐带间充质干细胞治疗难治性慢性移植物抗宿主病的疗效观察.器官移植,2016;7(6):459-462+483.
12 Lim JY,Ryu DB,Lee SE,et al.Mesenchymal stem cells(MSCs)attenuate cutaneous sclerodermatous graft-versus-host disease(SclGVHD)through inhibition of immune cell infiltration in a mouse model.J Invest Dermatol,2017;137(9):1895-1904.
13康慧珠,郑晓丽,王志东,等.单倍体相合造血干细胞移植联合脐带间充质干细胞输注治疗儿童恶性血液病的临床研究.中国实验血液学杂志,2017;25(4):1151-1157.
14 Gao L,Zhang Y,Hu B,et al.Phase II multicenter,randomized,double-blind controlled study of efficacy and safety of umbilical cord-derived mesenchymal stromal cells in the prophylaxis of chronic graft-versus-host disease after HLA-haploidentical stem-cell transplantation.J Clin Oncol,2016;34(24):2843-2850.
15 Liu Z,Zhang Y,Xiao H,et al.Cotransplantation of bone marrowderived mesenchymal stem cells in haploidentical hematopoietic stem cell transplantation in patients with severe aplastic anemia:an interim summary for a multicenter phase II trial results.Bone Marrow Transplant,2017;52(5):704-710.
16 Kuzmina LA,Petinati NA,Shipounova IN,et al.Analysis of multipotent mesenchymal stromal cells used for acute graft-versushost disease prophylaxis.Eur J Haematol,2016;96(4):425-434.
17乔淑凯,郭晓楠,张雅丽,等.异基因骨密质来源间充质干细胞对小鼠急性GVHD的防治作用及其机制研究.中国免疫学杂志,2016;32(11):1672-1677.
18王利,谷振阳,赵小利,等.间充质干细胞对移植物抗宿主病预防作用的Meta分析.中国实验血液学杂志,2015;23(4):1125-1132.
19 Stoma I,Karpov I,Krivenko S,et al.Mesenchymal stem cells transplantation in hematological patients with acute graft-versushost disease:characteristics and risk factors for infectious complications.Ann Hematol,2018;97(5):885-891.
20 Baygan A,Aronsson-Kurttila W,Moretti G,et al.Safety and side effects of using placenta-derived decidual stromal cells for graftversus-host disease and hemorrhagic cystitis.Front Immunol,2017;8:795.
21 Blennow O,Remberger M,Torlen J,et al.Risk factors for invasive mold infections and implications for choice of prophylaxis after allogeneic stem cell transplantation.Biol Blood Marrow Transplant,2016;22(9):1684-1689.
22 Schmidt S,Tramsen L,Schneider A,et al.Impact of human mesenchymal stromal cells on antifungal host response against Aspergillus fumigatus.Oncotarget,2017;8(56):95495-95503.
23 Rizk M,Monaghan M,Shorr R,et al.Heterogeneity in studies of mesenchymal stromal cells to treat or prevent graft-versus-host disease:A scoping review of the evidence.Biol Blood Marrow Transplant,2016;22(8):1416-1423.
24 Wang L,Zhang H,Guan L,et al.Mesenchymal stem cells provide prophylaxis against acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation:A meta-analysis of animal models.Oncotarget,2016;7(38):61764-61774.
25 Rani S,Ryan AE,Griffin MD,et al.Mesenchymal stem cell-derived extracellular vesicles:toward cell-free therapeutic applications.Mol Ther,2015;23(5):812-823.
26王利,赵莎莎,赵小利,等.间充质干细胞微泡的组织修复及其机制的研究进展.中华危重病急救医学,2014;26(11):845-848.
27 Kordelas L,Rebmann V,Ludwig AK,et al.MSC-derived exosomes:a novel tool to treat therapy-refractory graft-versus-host disease.Leukemia,2014;28(4):970-973.
28 Amarnath S,Foley JE,Farthing DE,et al.Bone marrow-derived mesenchymal stromal cells harness purinergenic signaling to tolerize human Th1 cells in vivo.Stem Cells,2015;33(4):1200-1212.
29 Wang L,Gu Z,Zhao X,et al.Extracellular vesicles released from human umbilical cord-derived mesenchymal stromal cells prevent life-threatening acute graft-versus-host disease in a mouse model of allogeneic hematopoietic stem cell transplantation.Stem Cells Dev,2016;25(24):1874-1883.
30 Fujii S,Miura Y,Fujishiro A,et al.Graft-versus-host disease amelioration by human bone marrow mesenchymal stromal/stem cell-derived extracellular vesicles is associated with peripheral preservation of naive T cell populations.Stem Cells,2018;36(3):434-445.