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Mesenchymal stem cells targeting the GVHD

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Abstract

Acute graft-versus-host disease (GVHD) occurs after allogeneic hematopoietic stem cell transplant and is a reaction of donor immune cells against host tissues. About 35%–50% of hematopoietic stem cell transplant (HSCT) recipients will develop acute GVHD. It is associated with considerable morbidity and mortality, particularly in patients who do not respond to primary therapy, which usually consists of glucocorticoids(steroids). Most of the available second-line and third-line treatments for steroid-refractory acute GVHD induce severe immunodeficiency, which is commonly accompanied by lethal infectious complications. Mesenchymal stem cells (MSCs) have been shown to mediate immunomodulatory effects. The recently elucidated immunosuppressive potential of mesenchymal stem cells has set the stage for their clinical testing as cellular immunosuppressants, MSCs have been used in patients with steroid-refractory acute GVHD, and encouraging responses have been obtained in many studies. The utility of MSCs for the treatment of GVHD is becoming clear.

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References

  1. Lorenz E, Uphoff D, Reid T R, et al. Modification of irradiation injury in mice and guinea pigs by bone marrow injections. J Natl Cancer Inst, 1951, 12: 197–201, 14874130, 1:STN:280:DyaG38%2FgsVansg%3D%3D

    PubMed  CAS  Google Scholar 

  2. van Bekkum D W, de Vries M J. The production of radiation chimaeras. In: Radiation Chimaeras. London, United Kingdom: Logos Press Limited, 1967. 20–78

    Google Scholar 

  3. Billingham R E. The biology of graft-versus-host reactions. In: The Harvey Lectures. New York: Academic Press, 1966. 21–78

    Google Scholar 

  4. Deeg H J. How I treat refractory acute GVHD. Blood, 2007, 109: 4119–4126, 17234737, 10.1182/blood-2006-12-041889, 1:CAS:528:DC%2BD2sXls1anurg%3D

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  5. Larghero J, Vija L, Lecourt S, et al. Mesenchymal stem cells and immunomodulation: toward new immunosuppressive strategies for the treatment of autoimmune diseases? Rev Med Interne, 2009, 30: 287–299, 18930338, 10.1016/j.revmed.2008.08.019, 1:STN:280:DC%2BD1M7mslyhsA%3D%3D

    Article  PubMed  CAS  Google Scholar 

  6. Aggarwal S, Pittenger M F. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood, 2005, 105: 1815–1822, 15494428, 10.1182/blood-2004-04-1559, 1:CAS:528:DC%2BD2MXhsVGjt7Y%3D

    Article  PubMed  CAS  Google Scholar 

  7. Le Blanc K, Ringdén O. Immunomodulation by mesenchymal stem cells and clinical experience. J InternMed, 2007, 262: 509–525, 10.1111/j.1365-2796.2007.01844.x, 1:CAS:528:DC%2BD2sXhtlOhtLrI

    Google Scholar 

  8. Müller I, Kordowich S, Holzwarth C, et al. Application of multipotent mesenchymal stromal cells in pediatric patients following allogeneic stem cell transplantation. Blood Cells Mol Dis, 2008, 40: 25–32, 17869550, 10.1016/j.bcmd.2007.06.021

    Article  PubMed  Google Scholar 

  9. Hill G R, Ferrara J L M. The primacy of the gastrointestinal tract as a target organ of acute graft-versus-host disease: Rationale for the use of cytokine shields in allogeneic bone marrow transplantation. Blood 2000, 95: 2754–2759, 10779417, 1:CAS:528:DC%2BD3cXivVarurw%3D

    PubMed  CAS  Google Scholar 

  10. Ball L M, Egeler R M. EBMT Paediatric Working Party. Acute GvHD: pathogenesis and classification. Bone Marrow Transplant, 2008, 41: S58–64, 18545246, 10.1038/bmt.2008.56, 1:CAS:528:DC%2BD1cXntVCnu7s%3D

    Article  PubMed  CAS  Google Scholar 

  11. David A Jacobsohn, Georgia B Vogelsang. Acute graft versus host disease. Orphanet J Rare Dis, 2007, 2: 35, 17784964, 10.1186/1750-1172-2-35

    Article  PubMed  PubMed Central  Google Scholar 

  12. Messina C, Faraci M, de Fazio V, et al. Prevention and treatment of acute GvHD. Bone Marrow Transplant, 2008, 41: S65–70, 18545247, 10.1038/bmt.2008.57, 1:CAS:528:DC%2BD1cXntVCnu7k%3D

    Article  PubMed  CAS  Google Scholar 

  13. MacMillan M L, Weisdorf D J, Wagner J E. Response of 443 patients to steroids as primary therapy for acute GvHD: Comparison of grading system. Biol Blood Marrow Transplant, 2002, 47: 387–394, 10.1053/bbmt.2002.v8.pm12171485

    Article  Google Scholar 

  14. van Lint M T, Uderzo C, Locasciulli A, et al. Early treatment of acute graft-versus-host disease with high- or low-dose 6-methylpredniso-lone: A multicenter randomized trial from the Italian Group for Bone Marrow Transplantation. Blood, 1998, 92: 2288–2293, 9746766

    PubMed  Google Scholar 

  15. Cragg L, Blazar B R, Defor T, et al. A randomized trial comparing prednisone with antithymocyte globulin/prednisone as an initial systemic therapy for moderately severe acute graft-versus-host disease. Biol Blood Marrow Transplant, 2000, 6: 441–447, 10975513, 10.1016/S1083-8791(00)70036-X, 1:CAS:528:DC%2BD3cXmsFajs70%3D

    Article  PubMed  CAS  Google Scholar 

  16. van Lint M T, Milone G, Leotta S, et al. Treatment of acute graft-versus-host disease with prednisolone: Significant survival advantage for day +5 responders and no advantage for nonresponders receiving anti-thymocyte globulin. Blood, 2006, 107: 4177–4181, 16449522, 10.1182/blood-2005-12-4851, 1:CAS:528:DC%2BD28XkvFWgsL8%3D

    Article  PubMed  Google Scholar 

  17. Antin J H, Chen A R, Couriel D R, et al. Novel approaches to the therapy of steroid resistant acute graft versus host disease. Biol Blood Marrow Transplant, 2004, 10: 655–668, 15389432, 10.1016/j.bbmt.2004.07.007, 1:CAS:528:DC%2BD2cXpsl2gtbs%3D

    Article  PubMed  CAS  Google Scholar 

  18. Antin J H. Approaches to graft-vs-host disease. Paediatr Transplant, 2005, 9: 71–75, 10.1111/j.1399-3046.2005.00441.x, 1:CAS:528:DC%2BD2MXhtlGitb7E

    Article  CAS  Google Scholar 

  19. Doney K, Martin P, Storb R, et al. A randomized trial of antihuman thymocyte globulin versus murine monoclonal antihuman T-cell antibodies as immunosuppressive therapy for aplastic anemia. Exp Hematol, 1985, 13: 520–524, 3873345, 1:STN:280:DyaL2M3gsVWntw%3D%3D

    PubMed  CAS  Google Scholar 

  20. Curtis R E, Travis L B, Rowlings P A, et al. Risk of lymphoproliferative disorders after bone marrow transplantation: A multi-institutional study. Blood, 1999, 94: 2208–2216, 10498590, 1:CAS:528:DyaK1MXmsVCis7Y%3D

    PubMed  CAS  Google Scholar 

  21. Deeg H J, Blazar B R, Bolwell B J, et al. Treatment of steroid-refractory acute graft-verus-host-disease with anti-CD147 monoclonal antibody ABX-CBL. Blood, 2001, 98: 2052–2058, 11567989, 10.1182/blood.V98.7.2052, 1:CAS:528:DC%2BD3MXnsVChsb8%3D

    Article  PubMed  CAS  Google Scholar 

  22. Carpenter P A, Appelbaum F R, Corey L, et al. A humanized non-FcR-bindinganti-CD3 antibody, visilizumab, for treatment of steroid-refractory acute graft-versus-host disease. Blood, 2002, 99: 2712–2719, 11929757, 10.1182/blood.V99.8.2712, 1:CAS:528:DC%2BD38XivVyqur0%3D

    Article  PubMed  CAS  Google Scholar 

  23. Jacobsohn D A, Vogelsang G B. Novel pharmacotherapeutic approaches to prevention and treatment of GvHD. Drugs, 2001, 62: 879–889, 10.2165/00003495-200262060-00002

    Article  Google Scholar 

  24. Benito A I, Furlong T, Martin P J, et al. Sirolimus (rapamycin) for the treatment of steroid-refractory acute graft-versus-host disease. Transplantation, 2001, 72: 1924–1929, 11773890, 10.1097/00007890-200112270-00010, 1:CAS:528:DC%2BD38XnsV2nug%3D%3D

    Article  PubMed  CAS  Google Scholar 

  25. Bolanos-Meade J, Jacobsohn D A, Margolis J, et al. Pentostatin in steroid-refractory acute graft-versus-host disease. J Clin Oncol, 2005, 20: 2661–2668

    Google Scholar 

  26. Tyndall A, Uccelli A. Multipotent mesenchymal stromal cells for autoimmune diseases: Teaching new dogs old tricks. Bone Marrow Transplant, 2009, 43: 821–828, 19308035, 10.1038/bmt.2009.63, 1:CAS:528:DC%2BD1MXntF2iu7s%3D

    Article  PubMed  CAS  Google Scholar 

  27. Nauta A J, Fibbe W E. Immunomodulatory properties of mesenchymal stromal cells. Blood, 2007, 110: 3499–506, 17664353, 10.1182/blood-2007-02-069716, 1:CAS:528:DC%2BD2sXhtlarurzE

    Article  PubMed  CAS  Google Scholar 

  28. Gonzalo-Daganzo R, Regidor C, Martín-Donaire T, et al. Results of a pilot study on the use of third-party donor mesenchymal stromal cells in cord blood transplantation in adults. Cytotherapy, 2009, 11: 278–288, 19308773, 10.1080/14653240902807018, 1:CAS:528:DC%2BD1MXlt1Kms7o%3D

    Article  PubMed  CAS  Google Scholar 

  29. Noort W A, Kruisselbrink A B, in’t Anker P S, et al. Mesenchymal stem cells promote engraftment of human umbilical cord blood-derived CD34(+) cells in NOD/SCID mice. Exp Hematol, 2002, 30: 870–878, 12160838, 10.1016/S0301-472X(02)00820-2

    Article  PubMed  Google Scholar 

  30. Klyushnenkova E, Mosca J D, Zernetkina V, et al. T cell responses to allogeneic human mesenchymal stem cells: Immunogenicity, tolerance, and suppression. J Biomed Sci, 2005, 12: 47–57, 15864738, 10.1007/s11373-004-8183-7, 1:CAS:528:DC%2BD2MXhtlWkur3F

    Article  PubMed  CAS  Google Scholar 

  31. Selmani Z, Naji A, Zidi I, et al. Human leukocyte antigen-G5 secretion by human mesenchymal stem cells is required to suppress T lymphocyte and natural killer function and to induce CD4+CD25 high FOXP3+ regulatory T cells. Stem Cells, 2008, 26: 212–222, 17932417, 10.1634/stemcells.2007-0554, 1:CAS:528:DC%2BD1cXhvVCktb0%3D

    Article  PubMed  CAS  Google Scholar 

  32. Edinger M, Hoffmann P, Ermann J, et al. CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation. Nat Med, 2003, 9: 1144–1150, 12925844, 10.1038/nm915, 1:CAS:528:DC%2BD3sXmvVWnsrs%3D

    Article  PubMed  CAS  Google Scholar 

  33. Wolf D, Wolf A M, Fong D, et al. Regulatory T-cells in the graft and the risk of acute graft-versus-host disease after allogeneic stem cell transplantation. Transplantation, 2007, 83: 1107–1113, 17452902, 10.1097/01.tp.0000260140.04815.77

    Article  PubMed  Google Scholar 

  34. Le Blanc K, Tammik C, Rosendahl K, et al. HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. Exp Hematol, 2003, 31: 890–896, 14550804, 10.1016/S0301-472X(03)00110-3, 1:CAS:528:DC%2BD3sXnvVOlsrk%3D

    Article  PubMed  Google Scholar 

  35. Le Blanc K, Tammik L, Sundberg B, et al. Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex. Scand J Immunol, 2003, 57: 11–20, 12542793, 10.1046/j.1365-3083.2003.01176.x

    Article  PubMed  Google Scholar 

  36. Bartholomew A, Sturgeon C, Siatskas M, et al. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol, 2002, 30: 42–48, 11823036, 10.1016/S0301-472X(01)00769-X

    Article  PubMed  Google Scholar 

  37. von Bonin M, Stölzel F, Goedecke A, et al. Treatment of refractory acute GVHD with third-party MSC expanded in platelet lysate-containing medium. Bone Marrow Transplant, 2009, 43: 245–251, 10.1038/bmt.2008.316, 1:CAS:528:DC%2BD1MXhslSgtLk%3D

    Article  Google Scholar 

  38. Zappia E, Casazza S, Pedemonte E, et al. Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Blood, 2005, 106: 1755–1761, 15905186, 10.1182/blood-2005-04-1496, 1:CAS:528:DC%2BD2MXps1Ogtrk%3D

    Article  PubMed  CAS  Google Scholar 

  39. Glennie S, Soeiro I, Dyson P J, et al. Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells. Blood, 2005, 105: 2821–2827, 15591115, 10.1182/blood-2004-09-3696, 1:CAS:528:DC%2BD2MXivFGmt7k%3D

    Article  PubMed  CAS  Google Scholar 

  40. Le Blanc K, Rasmusson I, Gotherstrom C, et al. Mesenchymal stem cells inhibit the expression of CD25 (interleukin-2 receptor) and CD38 on phytohaemagglutinin-activated lymphocytes. Scand J Immunol, 2004, 60: 307–315, 15320889, 10.1111/j.0300-9475.2004.01483.x

    Article  PubMed  Google Scholar 

  41. Bacigalupo A, Valle M, Podesta M, et al. T-cell suppression mediated by mesenchymal stem cells is deficient in patients with severe aplastic anemia. Exp Hematol, 2005, 33: 819–827, 15963858, 10.1016/j.exphem.2005.05.006, 1:CAS:528:DC%2BD2MXlt1Kis7w%3D

    Article  PubMed  CAS  Google Scholar 

  42. Han Q, Sun Z, Liu L, et al. Impairment in immuno-modulatory function of Flk1(+)CD31(−)CD34(−) MSCss from MDS-RA patients. Leuk Res, 2007, 31: 1469–1478, 17360037, 10.1016/j.leukres.2006.12.016, 1:CAS:528:DC%2BD2sXht1amsrrE

    Article  PubMed  CAS  Google Scholar 

  43. English K, Barry F P, Mahon B P. Murine mesenchymal stem cells suppress dendritic cell migration, maturation and antigen presentation. Immunol Lett, 2008, 115: 50–58, 18022251, 10.1016/j.imlet.2007.10.002, 1:CAS:528:DC%2BD1cXhtlejsQ%3D%3D

    Article  PubMed  CAS  Google Scholar 

  44. Zhang W, Ge W, Li C H, et al. Inhibition effect of bone marrow mesenchymal stem cells on T-lymphocyte proliferation through up-regulation of CD8+CD28 T cells. Zhongguo Shi Yan Xue Ye Xue Za Zhi, 2004, 12: 666–669, 15498131

    PubMed  Google Scholar 

  45. Jiang X X, Zhang Y, Liu B, et al. Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells. Blood, 2005, 105: 4120–4126, 15692068, 10.1182/blood-2004-02-0586, 1:CAS:528:DC%2BD2MXktlSrt7k%3D

    Article  PubMed  CAS  Google Scholar 

  46. Nauta A J, Kruisselbrink A B, Lurvink E, et al. Mesenchymal stem cells inhibit generation and function of both CD34+-derived and monocyte-derived dendritic cells. J Immunol, 2006, 177: 2080–2087, 16887966, 1:CAS:528:DC%2BD28Xns1Kht7o%3D

    Article  PubMed  CAS  Google Scholar 

  47. Zhang B, Liu R, Shi D, et al. Mesenchymal stem cells induce mature dendritic cells into a novel Jagged-2 dependent regulatory dendritic cell population. Blood, 2009, 113: 46–57, 18832657, 10.1182/blood-2008-04-154138, 1:CAS:528:DC%2BD1MXmtFSktw%3D%3D

    Article  PubMed  CAS  Google Scholar 

  48. Chen L, Zhang W, Yue H, et al. Effects of human mesenchymal stem cells on the differentiation of dendritic cells from CD34+ cells. Stem Cells Dev, 2007, 16: 719–731, 17999594, 10.1089/scd.2007.0065, 1:CAS:528:DC%2BD2sXht1ykurjP

    Article  PubMed  CAS  Google Scholar 

  49. Corcione A, Benvenuto F, Ferretti E, et al. Human mesenchymal stem cells modulate B-cell functions. Blood, 2006, 107: 367–372, 16141348, 10.1182/blood-2005-07-2657, 1:CAS:528:DC%2BD28XhsVGksQ%3D%3D

    Article  PubMed  CAS  Google Scholar 

  50. Sotiropoulou P A, Perez S A, Gritzapis A D, et al. Interactions between human mesenchymal stem cells and natural killer cells. Stem Cells, 2006, 24: 74–85, 16099998, 10.1634/stemcells.2004-0359

    Article  PubMed  Google Scholar 

  51. Spaggiari G M, Capobianco A, Becchetti S, et al. Mesenchymal stem cell-natural killer cell interactions: Evidence that activated NK cells are capable of killing MSCss, whereas MSCss can inhibit IL-2-induced NK-cell proliferation. Blood, 2006, 107: 1484–1490, 16239427, 10.1182/blood-2005-07-2775, 1:CAS:528:DC%2BD28XhsFemtrg%3D

    Article  PubMed  CAS  Google Scholar 

  52. Le Blanc K, Frassoni F, Ball L, et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet, 2008, 371: 1579–1586, 18468541, 10.1016/S0140-6736(08)60690-X, 1:CAS:528:DC%2BD1cXlslWhsbk%3D

    Article  PubMed  Google Scholar 

  53. von Bonin M, Stölzel F, Goedecke A, et al. Treatment of refractory acute GVHD with third-party MSC expanded in platelet lysate-containing medium. Biol Bone Marrow Transplant, 2008, 43: 1–7

    Google Scholar 

  54. Fang B, Song Y, Liao L, et al. Favorable response to human adipose tissue-derived mesenchymal stem cells in steroid-refractory acute graft-versus-host disease. Transplant Proc, 2007, 39: 3358–3362, 18089385, 10.1016/j.transproceed.2007.08.103, 1:STN:280:DC%2BD2sjlt1Sitw%3D%3D

    Article  PubMed  CAS  Google Scholar 

  55. Graul A I. Promoting, improving and accelerating the drug development and approval processes. Drug News Perspect, 2008, 22: 30–38, 10.1358/dnp.2009.22.1.1303816, 1:CAS:528:DC%2BD1MXktFGmtLY%3D

    Article  Google Scholar 

  56. Osiris Therapeutics, Inc. Osiris therapeutics reports positive Phase II results using PROCHYMAL(TM) for the treatment of acute graft vs. host disease. BALTIMORE, Nov 09, 2006 (BUSINESS WIRE) — Osiris Therapeutics, Inc.

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Wang, L., Zhao, R.C. Mesenchymal stem cells targeting the GVHD. SCI CHINA SER C 52, 603–609 (2009). https://doi.org/10.1007/s11427-009-0091-7

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