留言板

尊敬的读者、作者、审稿人, 关于本刊的投稿、审稿、编辑和出版的任何问题, 您可以本页添加留言。我们将尽快给您答复。谢谢您的支持!

姓名
邮箱
手机号码
标题
留言内容
验证码

间充质干细胞防治慢性移植物抗宿主病:进展与挑战

鲍颖颖, 陈小湧. 间充质干细胞防治慢性移植物抗宿主病:进展与挑战[J]. 器官移植, 2023, 14(3): 327-335. doi: 10.3969/j.issn.1674-7445.2023.03.002
引用本文: 鲍颖颖, 陈小湧. 间充质干细胞防治慢性移植物抗宿主病:进展与挑战[J]. 器官移植, 2023, 14(3): 327-335. doi: 10.3969/j.issn.1674-7445.2023.03.002
Bao Yingying, Chen Xiaoyong. Prevention and treatment of chronic graft-versus-host disease by mesenchymal stem cells: advances and challenges[J]. ORGAN TRANSPLANTATION, 2023, 14(3): 327-335. doi: 10.3969/j.issn.1674-7445.2023.03.002
Citation: Bao Yingying, Chen Xiaoyong. Prevention and treatment of chronic graft-versus-host disease by mesenchymal stem cells: advances and challenges[J]. ORGAN TRANSPLANTATION, 2023, 14(3): 327-335. doi: 10.3969/j.issn.1674-7445.2023.03.002

间充质干细胞防治慢性移植物抗宿主病:进展与挑战

doi: 10.3969/j.issn.1674-7445.2023.03.002
基金项目: 

国家自然科学基金 82270230

国家自然科学基金 81970109

国家重点研发计划 2022YFA1105000

广东省自然科学基金杰出青年项目 2023B1515020119

详细信息
    作者简介:
    通讯作者:

    陈小湧(ORCID:0000-0002-5973-4143),副教授,研究方向为间充质干细胞治疗的细胞与分子机制,Email:chenxiaoy@mail.sysu.edu.cn

  • 中图分类号: R617, R552

Prevention and treatment of chronic graft-versus-host disease by mesenchymal stem cells: advances and challenges

More Information
  • 摘要: 慢性移植物抗宿主病(cGVHD)是异基因造血干细胞移植后的主要并发症,也是导致非复发死亡的主要原因,因其病理生理过程复杂,常规糖皮质激素联合免疫抑制药的防治有效率不足50%。对于糖皮质激素抵抗的cGVHD患者需启动二线治疗,然而目前的二线治疗方法尚未形成共识,且治疗效果不佳。间充质干细胞(MSC)是最常见的成体干细胞之一,因其具有多维度、多靶点的免疫调控功能,已被广泛应用于cGVHD的预防及治疗,且大量研究证实了MSC治疗cGVHD的安全性和有效性,有望成为cGVHD防治的新策略。本文主要围绕MSC防治cGVHD的研究进展、作用机制及存在的问题等方面进行综述,以期为今后优化MSC治疗方案、提高cGVHD防治效果提供新思路。

     

  • 图  1  cGVHD主要发病环节

    注:→表示促进或进展,┥表示抑制,×表示阻断。GC为生发中心。

    Figure  1.  Overview of cGVHD pathogenesis

    表  1  MSC预防cGVHD的临床现状

    Table  1.   The clinical status of MSC in prevention of cGVHD

    研究者 年份(年) 患者类型 MSC组(n)/对照组(n) MSC来源 MSC剂量(×106/kg) 结论
    Liu, et al[10] 2011 成人、儿童 27/28 骨髓 0.30~0.50 两组间2年生存率及复发率差异无统计学意义;MSC组cGVHD发生率有所降低;血浆中SDF-1α、TPO、IL-11升高
    Gao, et al [13] 2016 成人、儿童 62/62 脐带 不详 MSC治疗组cGVHD累积发生率显著降低;2年生存率差异无统计学意义;Treg及CD27+记忆性B细胞数量增加
    Wang, et al [14] 2021 成人 17/0 骨髓 0.01~65.00 MSC治疗后5年生存率为64.7%,非复发性生存率为79.1%;2年cGVHD的发生率为63%,中度及重度cGVHD的发生率为17%
    Zhao, et al [15] 2022 成人、儿童 99/99 骨髓 1.00 MSC治疗组1年和2年cGVHD的累积发生率显著低于对照组
    Wang, et al [20] 2019 儿童 35/0 骨髓 1.00 MSC治疗后所有患者均实现造血重建,总生存率为85.71%,cGVHD的发生率为22.86%
    注:①SDF为基质细胞衍生因子。
    ②TPO为促血小板生成素。
    下载: 导出CSV

    表  2  MSC治疗cGVHD的临床现状

    Table  2.   The clinical status of MSC treatment for cGVHD

    研究者 年份(年) 患者类型 n MSC来源 MSC剂量(×106/kg) 结论
    Macías-Sánchez, et al [9] 2022 成人、儿童 16 骨髓,脂肪 0.52~2.10 MSC反应良好者2年生存率达70.00%,无应答者生存率为16.67%;18岁以下患者2年生存率更高
    Weng, et al[22] 2010 成人 19 骨髓 0.23~1.42 对MSC的治疗反应良好的患者达73.7%,2年生存率达到77.7%;MSC治疗组CD5+CD19+B细胞比例增加,CD8+CD28+T细胞比例降低
    Jurado, et al [23] 2017 成人 14 脂肪 1.00或3.00 完全缓解的患者达80.0%;未见基础疾病复发及感染造成的死亡;总生存率为71.4%
    Boberg, et al [24] 2020 成人 11 骨髓 1.30~3.00 6例患者严重的cGVHD症状得到持续改善;MSC反应良好者免疫抑制药减量或停用;MSC能够改善患者的胸腺功能,初始Treg比例增加
    Peng, et al [27] 2014 成人 38 骨髓 1.00 5例患者完全缓解,23例患者部分缓解;血浆BAFF水平降低;CD27+记忆B细胞增加
    Peng, et al [28] 2015 成人 23 骨髓 1.00 20例患者出现完全缓解或部分缓解;复发率和病死率与其他治疗间差异无统计学意义;MSC反应良好者CD5+IL-10+B细胞比例显著上升
    Stenger, et al [29] 2022 成人 7 骨髓 2.00 3个不同剂量MSC输注均耐受性良好;7例cGVHD中有5例部分缓解,外周血淋巴细胞亚群差异无统计学意义
    注:①BAFF为B细胞活化因子。
    下载: 导出CSV
  • [1] ARAI S, ARORA M, WANG T, et al. Increasing incidence of chronic graft-versus-host disease in allogeneic transplantation: a report from the Center for International Blood and Marrow Transplant Research[J]. Biol Blood Marrow Transplant, 2015, 21(2): 266-274. DOI: 10.1016/j.bbmt.2014.10.021.
    [2] PENACK O, MARCHETTI M, RUUTU T, et al. Prophylaxis and management of graft versus host disease after stem-cell transplantation for haematological malignancies: updated consensus recommendations of the European Society for Blood and Marrow Transplantation[J]. Lancet Haematol, 2020, 7(2): e157-e167. DOI: 10.1016/S2352-3026(19)30256-X.
    [3] JIANG H, FU D, BIDGOLI A, et al. T cell subsets in graft versus host disease and graft versus tumor[J]. Front Immunol, 2021, 12: 761448. DOI: 10.3389/fimmu.2021.761448.
    [4] HILL GR, BETTS BC, TKACHEV V, et al. Current concepts and advances in graft-versus-host disease immunology[J]. Annu Rev Immunol, 2021, 39: 19-49. DOI: 10.1146/annurev-immunol-102119-073227.
    [5] ZEISER R, BLAZAR BR. Pathophysiology of chronic graft-versus-host disease and therapeutic targets[J]. N Engl J Med, 2017, 377(26): 2565-2579. DOI: 10.1056/NEJMra1703472.
    [6] HU C, WU Z, LI L. Mesenchymal stromal cells promote liver regeneration through regulation of immune cells[J]. Int J Biol Sci, 2020, 16(5): 893-903. DOI: 10.7150/ijbs.39725.
    [7] SONG N, SCHOLTEMEIJER M, SHAH K. Mesenchymal stem cell immunomodulation: mechanisms and therapeutic potential[J]. Trends Pharmacol Sci, 2020, 41(9): 653-664. DOI: 10.1016/j.tips.2020.06.009.
    [8] LE BLANC K, RASMUSSON I, SUNDBERG B, et al. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells[J]. Lancet, 2004, 363(9419): 1439-1441. DOI: 10.1016/S0140-6736(04)16104-7.
    [9] MACÍAS-SÁNCHEZ MDM, MORATA-TARIFA C, CUENDE N, et al. Mesenchymal stromal cells for treating steroid-resistant acute and chronic graft versus host disease: a multicenter compassionate use experience[J]. Stem Cells Transl Med, 2022, 11(4): 343-355. DOI: 10.1093/stcltm/szac003.
    [10] LIU K, CHEN Y, ZENG Y, et al. Coinfusion of mesenchymal stromal cells facilitates platelet recovery without increasing leukemia recurrence in haploidentical hematopoietic stem cell transplantation: a randomized, controlled clinical study[J]. Stem Cells Dev, 2011, 20(10): 1679-1685. DOI: 10.1089/scd.2010.0447.
    [11] MACMILLAN ML, BLAZAR BR, DEFOR TE, et al. Transplantation of ex-vivo culture-expanded parental haploidentical mesenchymal stem cells to promote engraftment in pediatric recipients of unrelated donor umbilical cord blood: results of a phase I-Ⅱ clinical trial[J]. Bone Marrow Transplant, 2009, 43(6): 447-454. DOI: 10.1038/bmt.2008.348.
    [12] BERNARDO ME, BALL LM, COMETA AM, et al. Co-infusion of ex vivo-expanded, parental MSCs prevents life-threatening acute GVHD, but does not reduce the risk of graft failure in pediatric patients undergoing allogeneic umbilical cord blood transplantation[J]. Bone Marrow Transplant, 2011, 46(2): 200-207. DOI: 10.1038/bmt.2010.87.
    [13] 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]. J Clin Oncol, 2016, 34(24): 2843-2850. DOI: 10.1200/JCO.2015.65.3642.
    [14] WANG Q, XU N, WANG Y, et al. Allogeneic stem cell transplantation combined with transfusion of mesenchymal stem cells in primary myelofibrosis: a multicenter retrospective study[J]. Front Oncol, 2022, 11: 792142. DOI: 10.3389/fonc.2021.792142.
    [15] ZHAO K, LIN R, FAN Z, et al. Mesenchymal stromal cells plus basiliximab, calcineurin inhibitor as treatment of steroid-resistant acute graft-versus-host disease: a multicenter, randomized, phase 3, open-label trial[J]. J Hematol Oncol, 2022, 15(1): 22. DOI: 10.1186/s13045-022-01240-4.
    [16] WANG L, ZHU CY, MA DX, et al. Efficacy and safety of mesenchymal stromal cells for the prophylaxis of chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation: a meta-analysis of randomized controlled trials[J]. Ann Hematol, 2018, 97(10): 1941-1950. DOI: 10.1007/s00277-018-3384-8.
    [17] MORATA-TARIFA C, MACÍAS-SÁNCHEZ MDM, GUTIÉRREZ-PIZARRAYA A, et al. Mesenchymal stromal cells for the prophylaxis and treatment of graft-versus-host disease-a meta-analysis[J]. Stem Cell Res Ther, 2020, 11(1): 64. DOI: 10.1186/s13287-020-01592-z.
    [18] FISHER SA, CUTLER A, DOREE C, et al. Mesenchymal stromal cells as treatment or prophylaxis for acute or chronic graft-versus-host disease in haematopoietic stem cell transplant (HSCT) recipients with a haematological condition[J]. Cochrane Database Syst Rev, 2019, 1(1): CD009768. DOI: 10.1002/14651858.CD009768.pub2.
    [19] LI T, LUO C, ZHANG J, et al. Efficacy and safety of mesenchymal stem cells co-infusion in allogeneic hematopoietic stem cell transplantation: a systematic review and meta-analysis[J]. Stem Cell Res Ther, 2021, 12(1): 246. DOI: 10.1186/s13287-021-02304-x.
    [20] WANG Z, YU H, CAO F, et al. Donor-derived marrow mesenchymal stromal cell co-transplantation following a haploidentical hematopoietic stem cell transplantation trail to treat severe aplastic anemia in children[J]. Ann Hematol, 2019, 98(2): 473-479. DOI: 10.1007/s00277-018-3523-2.
    [21] MÜLLER I, KORDOWICH S, HOLZWARTH C, et al. Application of multipotent mesenchymal stromal cells in pediatric patients following allogeneic stem cell transplantation[J]. Blood Cells Mol Dis, 2008, 40(1): 25-32. DOI: 10.1016/j.bcmd.2007.06.021.
    [22] WENG JY, DU X, GENG SX, et al. Mesenchymal stem cell as salvage treatment for refractory chronic GVHD[J]. Bone Marrow Transplant, 2010, 45(12): 1732-1740. DOI: 10.1038/bmt.2010.195.
    [23] JURADO M, DE LA MATA C, RUIZ-GARCÍA A, et al. Adipose tissue-derived mesenchymal stromal cells as part of therapy for chronic graft-versus-host disease: a phase I/Ⅱ study[J]. Cytotherapy, 2017, 19(8): 927-936. DOI: 10.1016/j.jcyt.2017.05.002.
    [24] BOBERG E, VON BAHR L, AFRAM G, et al. Treatment of chronic GVHD with mesenchymal stromal cells induces durable responses: a phase Ⅱ study[J]. Stem Cells Transl Med, 2020, 9(10): 1190-1202. DOI: 10.1002/sctm.20-0099.
    [25] ZHOU T, HE C, LAI P, et al. miR-204-containing exosomes ameliorate GVHD-associated dry eye disease[J]. Sci Adv, 2022, 8(2): eabj9617. DOI: 10.1126/sciadv.abj9617.
    [26] CHEN S, ZHAO K, LIN R, et al. The efficacy of mesenchymal stem cells in bronchiolitis obliterans syndrome after allogeneic HSCT: a multicenter prospective cohort study[J]. EbioMedicine, 2019, 49: 213-222. DOI: 10.1016/j.ebiom.2019.09.039.
    [27] PENG Y, CHEN X, LIU Q, et al. Alteration of naïve and memory B-cell subset in chronic graft-versus-host disease patients after treatment with mesenchymal stromal cells[J]. Stem Cells Transl Med, 2014, 3(9): 1023-1031. DOI: 10.5966/sctm.2014-0001.
    [28] 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[J]. Leukemia, 2015, 29(3): 636-646. DOI: 10.1038/leu.2014.225.
    [29] STENGER E, GIVER CR, LANGSTON A, et al. Safety of autologous freshly expanded mesenchymal stromal cells for the treatment of graft-versus-host disease[J]. Front Immunol, 2022, 13: 959658. DOI: 10.3389/fimmu.2022.959658.
    [30] ZHANG X, ZHAO K, HE JB, et al. Mesenchymal stem cells improve the structure and function of the graft-versus-host disease receptor thymus: CCR9 plays an important role in its homing thymus[J]. Blood, 2019, 134(Suppl 1): 5599. DOI: 10.1182/blood-2019-125307.
    [31] LAI P, CHEN X, GUO L, et al. A potent immunomodulatory role of exosomes derived from mesenchymal stromal cells in preventing cGVHD[J]. J Hematol Oncol, 2018, 11(1): 135. DOI: 10.1186/s13045-018-0680-7.
    [32] ROZMUS J, KARIMINIA A, ABDOSSAMADI S, et al. Comprehensive B cell phenotyping profile for chronic graft-versus-host disease diagnosis[J]. Biol Blood Marrow Transplant, 2019, 25(3): 451-458. DOI: 10.1016/j.bbmt.2018.11.007.
    [33] YEHUDAI-OFIR D, HENIG I, ZUCKERMAN T. Aberrant B cells, autoimmunity and the benefit of targeting B cells in chronic graft-versus-host disease[J]. Autoimmun Rev, 2020, 19(4): 102493. DOI: 10.1016/j.autrev.2020.102493.
    [34] SARANTOPOULOS S, RITZ J. Aberrant B-cell homeostasis in chronic GVHD[J]. Blood, 2015, 125(11): 1703-1707. DOI: 10.1182/blood-2014-12-567834.
    [35] JIA W, POE JC, SU H, et al. BAFF promotes heightened BCR responsiveness and manifestations of chronic GVHD after allogeneic stem cell transplantation[J]. Blood, 2021, 137(18): 2544-2557. DOI: 10.1182/blood.2020008040.
    [36] ZHANG M, ZHANG S. T cells in fibrosis and fibrotic diseases[J]. Front Immunol, 2020, 11: 1142. DOI: 10.3389/fimmu.2020.01142.
    [37] GUO L, LAI P, WANG Y, et al. Extracellular vesicles derived from mesenchymal stem cells prevent skin fibrosis in the cGVHD mouse model by suppressing the activation of macrophages and B cells immune response[J]. Int Immunopharmacol, 2020, 84: 106541. DOI: 10.1016/j.intimp.2020.106541.
    [38] MACDONALD KP, HILL GR, BLAZAR BR. Chronic graft-versus-host disease: biological insights from preclinical and clinical studies[J]. Blood, 2017, 129(1): 13-21. DOI: 10.1182/blood-2016-06-686618.
    [39] LI Y, HAO J, HU Z, et al. Current status of clinical trials assessing mesenchymal stem cell therapy for graft versus host disease: a systematic review[J]. Stem Cell Res Ther, 2022, 13(1): 93. DOI: 10.1186/s13287-022-02751-0.
    [40] 孙旭燕, 张学娟, 赵江宁, 等. 性别差异对间充质干细胞生物学特性的影响[J/CD]. 中华细胞与干细胞杂志(电子版), 2021, 11(5): 317-320. DOI: 10.3877/cma.j.issn.2095-1221.2021.05.010.

    SUN XY, ZHANG XJ, ZHAO JN, et al. Effects of gender differences on biological characteristics of mesenchymal stem cells[J/CD]. Chin J Cell Stem Cell (Electr Edit), 2021, 11(5): 317-320. DOI: 10.3877/cma.j.issn.2095-1221.2021.05.010.
    [41] VAN DER WAGEN LE, MIRANDA-BEDATE A, JANSSEN A, et al. Efficacy of MSC for steroid-refractory acute GVHD associates with MSC donor age and a defined molecular profile[J]. Bone Marrow Transplant, 2020, 55(11): 2188-2192. DOI: 10.1038/s41409-020-0910-9.
    [42] TAGO Y, KOBAYASHI C, OGURA M, et al. Human amnion-derived mesenchymal stem cells attenuate xenogeneic graft-versus-host disease by preventing T cell activation and proliferation[J]. Sci Rep, 2021, 11(1): 2406. DOI: 10.1038/s41598-021-81916-y.
    [43] CHEN J, HUANG J, SHI J, et al. Nestin+ Peyer's patch resident MSCs enhance healing of inflammatory bowel disease through IL-22-mediated intestinal epithelial repair[J]. Cell Prolif, 2023, 56(2): e13363. DOI: 10.1111/cpr.13363.
    [44] BIKORIMANA JP, SAAD W, ABUSARAH J, et al. CD146 defines a mesenchymal stromal cell subpopulation with enhanced suppressive properties[J]. Cells, 2022, 11(15): 2263. DOI: 10.3390/cells11152263.
    [45] BOREGOWDA SV, KRISHNAPPA V, HAGA CL, et al. A clinical indications prediction scale based on twist1 for human mesenchymal stem cells[J]. EbioMedicine, 2015, 4: 62-73. DOI: 10.1016/j.ebiom.2015.12.020.
    [46] SHEN MZ, LIU XX, QIU ZY, et al. Efficacy and safety of mesenchymal stem cells treatment for multidrug-resistant graft-versus-host disease after haploidentical allogeneic hematopoietic stem cell transplantation[J]. Ther Adv Hematol, 2022, 13: 20406207211072838. DOI: 10.1177/20406207211072838.
    [47] SCHULTZ KR, KARIMINIA A, NG B, et al. Immune profile differences between chronic GVHD and late acute GVHD: results of the ABLE/PBMTC 1202 studies[J]. Blood, 2020, 135(15): 1287-1298. DOI: 10.1182/blood.2019003186.
    [48] MILOSEVIC E, BABIC A, IOVINO L, et al. Use of the NIH consensus criteria in cellular and soluble biomarker research in chronic graft-versus-host disease: a systematic review[J]. Front Immunol, 2022, 13: 1033263. DOI: 10.3389/fimmu.2022.1033263.
  • 加载中
图(2) / 表(2)
计量
  • 文章访问数:  496
  • HTML全文浏览量:  186
  • PDF下载量:  84
  • 被引次数: 0
出版历程
  • 收稿日期:  2023-01-16
  • 刊出日期:  2023-05-15

目录

    /

    返回文章
    返回