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Mesenchymal stem cells for the treatment and prevention of graft-versus-host disease: experiments and practice

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Abstract

Mesenchymal stem cells (MSCs) have emerged as a therapeutic approach in a range of medical fields, including regenerative medicine, cancer, autoimmune diseases, and inflammatory diseases, because of their unique properties of tissue repair and major histocompatibility complex-unmatched immunosuppression. Because both in vitro and in vivo findings demonstrate that MSCs possess potent immunoregulatory functions, there has been increasing interest in the role of MSCs in allogeneic hematopoietic stem cell transplantation, especially in the prevention and treatment of graft-versus-host disease (GVHD). GVHD is a major cause of transplantation-related mortality, and conventional immunosuppressants frequently fail to treat patients suffering from GVHD. Following Ringden’s pilot study that used third-party MSCs to treat a steroid-refractory GVHD patient, MSCs have created growing interest as a therapeutic agent for GVHD. There have been further studies which demonstrated the potentials of MSC treatment in steroid-refractory GVHD, de novo GVHD, and also GVHD prevention. However, MSCs still present limitations. The need for MSCs to be “licensed” in a pro-inflammatory environment, especially in the presence of interferon gamma, allows only a narrow window for their administration. Thus, their effects have been less clear as a preventive measure before the inflammatory environment of GVHD is established and also when administered during a chronic setting where MSCs may be alternatively licensed. In this review, we focus on the immunomodulatory properties of MSCs and their effects in relation to GVHD. Given the efficacy of MSCs in murine models of GVHD and their safety in clinical trials, it is crucial that larger clinical trials are conducted and further modifications are investigated.

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Abbreviations

aGVHD:

Acute graft-versus-host disease

CFU-F:

Colony-forming unit fibroblast

cGVHD:

Chronic graft-versus-host disease

CIA:

Collagen-induced arthritis

DC:

Dendritic cell

EGFP:

Enhanced green fluorescent protein

GVHD:

Graft-versus-host disease

GVL:

Graft-versus-leukemia

HSCT:

Allogeneic hematopoietic stem cell transplantation

IL-10:

Interleukin-10

MSC:

Mesenchymal stem cell

MHC:

Major histocompatibility complex

NK:

Natural killer

RFP:

Red fluorescent protein

Treg:

Regulatory T cell

References

  1. Dexter TM, Spooncer E, Schofield R, Lord BI, Simmons P (1984) Haemopoietic stem cells and the problem of self-renewal. Blood Cells 10(2–3):315–339

    CAS  PubMed  Google Scholar 

  2. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284(5411):143–147

    Article  CAS  PubMed  Google Scholar 

  3. Sanchez-Ramos J, Song S, Cardozo-Pelaez F, Hazzi C, Stedeford T, Willing A, Freeman TB, Saporta S, Janssen W, Patel N, Cooper DR, Sanberg PR (2000) Adult bone marrow stromal cells differentiate into neural cells in vitro. Exp Neurol 164(2):247–256. doi:10.1006/exnr.2000.7389

    Article  CAS  PubMed  Google Scholar 

  4. Toma C, Pittenger MF, Cahill KS, Byrne BJ, Kessler PD (2002) Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart. Circulation 105(1):93–98

    Article  PubMed  Google Scholar 

  5. Friedenstein AJ, Chailakhjan RK, Lalykina KS (1970) The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell Tissue Kinet 3(4):393–403

    CAS  PubMed  Google Scholar 

  6. Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop D, Horwitz E (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8(4):315–317. doi:10.1080/14653240600855905

    Article  CAS  PubMed  Google Scholar 

  7. Ringdén O, Nilsson B (1985) Death by graft-versus-host disease associated with HLA mismatch, high recipient age, low marrow cell dose, and splenectomy. Transplantation 40(1):39–44

    Article  PubMed  Google Scholar 

  8. Le Blanc K, Rasmusson I, Sundberg B, Gotherstrom C, Hassan M, Uzunel M, Ringden O (2004) Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 363(9419):1439–1441. doi:10.1016/s0140-6736(04)16104-7

    Article  PubMed  Google Scholar 

  9. English K, Ryan JM, Tobin L, Murphy MJ, Barry FP, Mahon BP (2009) Cell contact, prostaglandin E(2) and transforming growth factor beta 1 play non-redundant roles in human mesenchymal stem cell induction of CD4 + CD25 (high) forkhead box P3+ regulatory T cells. Clin Exp Immunol 156(1):149–160. doi:10.1111/j.1365-2249.2009.03874.x

    Article  CAS  PubMed  Google Scholar 

  10. Glennie S, Soeiro I, Dyson PJ, Lam EW, Dazzi F (2005) Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells. Blood 105(7):2821–2827. doi:10.1182/blood-2004-09-3696

    Article  CAS  PubMed  Google Scholar 

  11. Di Nicola M, Carlo-Stella C, Magni M, Milanesi M, Longoni PD, Matteucci P, Grisanti S, Gianni AM (2002) Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 99(10):3838–3843

    Article  PubMed  Google Scholar 

  12. Stagg J, Pommey S, Eliopoulos N, Galipeau J (2006) Interferon-gamma-stimulated marrow stromal cells: a new type of nonhematopoietic antigen-presenting cell. Blood 107(6):2570–2577. doi:10.1182/blood-2005-07-2793

    Article  CAS  PubMed  Google Scholar 

  13. Corcione A, Benvenuto F, Ferretti E, Giunti D, Cappiello V, Cazzanti F, Risso M, Gualandi F, Mancardi GL, Pistoia V, Uccelli A (2006) Human mesenchymal stem cells modulate B-cell functions. Blood 107(1):367–372. doi:10.1182/blood-2005-07-2657

    Article  CAS  PubMed  Google Scholar 

  14. Augello A, Tasso R, Negrini SM, Amateis A, Indiveri F, Cancedda R, Pennesi G (2005) Bone marrow mesenchymal progenitor cells inhibit lymphocyte proliferation by activation of the programmed death 1 pathway. Eur J Immunol 35(5):1482–1490. doi:10.1002/eji.200425405

    Article  CAS  PubMed  Google Scholar 

  15. Spaggiari GM, Capobianco A, Abdelrazik H, Becchetti F, Mingari MC, Moretta L (2008) Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production: role of indoleamine 2,3-dioxygenase and prostaglandin E2. Blood 111(3):1327–1333. doi:10.1182/blood-2007-02-074997

    Article  CAS  PubMed  Google Scholar 

  16. Krampera M, Cosmi L, Angeli R, Pasini A, Liotta F, Andreini A, Santarlasci V, Mazzinghi B, Pizzolo G, Vinante F, Romagnani P, Maggi E, Romagnani S, Annunziato F (2006) Role for interferon-γ in the immunomodulatory activity of human bone marrow mesenchymal stem cells. Stem Cells 24(2):386–398. doi:10.1634/stemcells.2005-0008

    Article  CAS  PubMed  Google Scholar 

  17. Sotiropoulou PA, Perez SA, Gritzapis AD, Baxevanis CN, Papamichail M (2006) Interactions between human mesenchymal stem cells and natural killer cells. Stem Cells 24(1):74–85. doi:10.1634/stemcells.2004-0359

    Article  PubMed  Google Scholar 

  18. Jiang XX, Zhang Y, Liu B, Zhang SX, Wu Y, Yu XD, Mao N (2005) Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells. Blood 105(10):4120–4126. doi:10.1182/blood-2004-02-0586

    Article  CAS  PubMed  Google Scholar 

  19. Aggarwal S, Pittenger MF (2005) Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 105(4):1815–1822. doi:10.1182/blood-2004-04-1559

    Article  CAS  PubMed  Google Scholar 

  20. Maccario R, Podesta M, Moretta A, Cometa A, Comoli P, Montagna D, Daudt L, Ibatici A, Piaggio G, Pozzi S, Frassoni F, Locatelli F (2005) Interaction of human mesenchymal stem cells with cells involved in alloantigen-specific immune response favors the differentiation of CD4+ T-cell subsets expressing a regulatory/suppressive phenotype. Haematologica 90(4):516–525

    CAS  PubMed  Google Scholar 

  21. Groh ME, Maitra B, Szekely E, Koc ON (2005) Human mesenchymal stem cells require monocyte-mediated activation to suppress alloreactive T cells. Exp Hematol 33(8):928–934. doi:10.1016/j.exphem.2005.05.002

    Article  CAS  PubMed  Google Scholar 

  22. Beyth S, Borovsky Z, Mevorach D, Liebergall M, Gazit Z, Aslan H, Galun E, Rachmilewitz J (2005) Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness. Blood 105(5):2214–2219. doi:10.1182/blood-2004-07-2921

    Article  CAS  PubMed  Google Scholar 

  23. Zhang W, Ge W, Li C, You S, Liao L, Han Q, Deng W, Zhao RC (2004) Effects of mesenchymal stem cells on differentiation, maturation, and function of human monocyte-derived dendritic cells. Stem Cells Dev 13(3):263–271. doi:10.1089/154732804323099190

    Article  CAS  PubMed  Google Scholar 

  24. Ramasamy R, Fazekasova H, Lam EW, Soeiro I, Lombardi G, Dazzi F (2007) Mesenchymal stem cells inhibit dendritic cell differentiation and function by preventing entry into the cell cycle. Transplantation 83(1):71–76. doi:10.1097/01.tp.0000244572.24780.54

    Article  PubMed  Google Scholar 

  25. Nauta AJ, Kruisselbrink AB, Lurvink E, Willemze R, Fibbe WE (2006) Mesenchymal stem cells inhibit generation and function of both CD34+-derived and monocyte-derived dendritic cells. J Immunol 177(4):2080–2087

    CAS  PubMed  Google Scholar 

  26. Krampera M, Glennie S, Dyson J, Scott D, Laylor R, Simpson E, Dazzi F (2003) Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide. Blood 101(9):3722–3729. doi:10.1182/blood-2002-07-2104

    Article  CAS  PubMed  Google Scholar 

  27. Keating A (2008) How do mesenchymal stromal cells suppress T cells? Cell Stem Cell 2(2):106–108. doi:10.1016/j.stem.2008.01.007

    Article  CAS  PubMed  Google Scholar 

  28. Ren G, Zhang L, Zhao X, Xu G, Zhang Y, Roberts AI, Zhao RC, Shi Y (2008) Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell 2(2):141–150. doi:10.1016/j.stem.2007.11.014

    Article  CAS  PubMed  Google Scholar 

  29. Nasef A, Ashammakhi N, Fouillard L (2008) Immunomodulatory effect of mesenchymal stromal cells: possible mechanisms. Regen Med 3(4):531–546. doi:10.2217/17460751.3.4.531

    Article  CAS  PubMed  Google Scholar 

  30. Meisel R, Zibert A, Laryea M, Gobel U, Daubener W, Dilloo D (2004) Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation. Blood 103(12):4619–4621. doi:10.1182/blood-2003-11-3909

    Article  CAS  PubMed  Google Scholar 

  31. Ye Z, Wang Y, Xie HY, Zheng SS (2008) Immunosuppressive effects of rat mesenchymal stem cells: involvement of CD4 + CD25+ regulatory T cells. Hepatobiliary Pancreat Dis Int 7(6):608–614

    PubMed  Google Scholar 

  32. Di Ianni M, Del Papa B, De Ioanni M, Moretti L, Bonifacio E, Cecchini D, Sportoletti P, Falzetti F, Tabilio A (2008) Mesenchymal cells recruit and regulate T regulatory cells. Exp Hematol 36(3):309–318. doi:10.1016/j.exphem.2007.11.007

    Article  PubMed  CAS  Google Scholar 

  33. Joo SY, Cho KA, Jung YJ, Kim HS, Park SY, Choi YB, Hong KM, Woo SY, Seoh JY, Cho SJ, Ryu KH (2010) Mesenchymal stromal cells inhibit graft-versus-host disease of mice in a dose-dependent manner. Cytotherapy 12(3):361–370. doi:10.3109/14653240903502712

    Article  CAS  PubMed  Google Scholar 

  34. Zappia E, Casazza S, Pedemonte E, Benvenuto F, Bonanni I, Gerdoni E, Giunti D, Ceravolo A, Cazzanti F, Frassoni F, Mancardi G, Uccelli A (2005) Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Blood 106(5):1755–1761. doi:10.1182/blood-2005-04-1496

    Article  CAS  PubMed  Google Scholar 

  35. Gonzalez MA, Gonzalez-Rey E, Rico L, Buscher D, Delgado M (2009) Treatment of experimental arthritis by inducing immune tolerance with human adipose-derived mesenchymal stem cells. Arthritis Rheum 60(4):1006–1019. doi:10.1002/art.24405

    Article  CAS  PubMed  Google Scholar 

  36. Patel SA, Meyer JR, Greco SJ, Corcoran KE, Bryan M, Rameshwar P (2010) Mesenchymal stem cells protect breast cancer cells through regulatory T cells: role of mesenchymal stem cell-derived TGF-beta. J Immunol 184(10):5885–5894. doi:10.4049/jimmunol.0903143

    Article  CAS  PubMed  Google Scholar 

  37. Nemeth K, Keane-Myers A, Brown JM, Metcalfe DD, Gorham JD, Bundoc VG, Hodges MG, Jelinek I, Madala S, Karpati S, Mezey E (2010) Bone marrow stromal cells use TGF-beta to suppress allergic responses in a mouse model of ragweed-induced asthma. Proc Natl Acad Sci U S A 107(12):5652–5657. doi:10.1073/pnas.0910720107

    Article  CAS  PubMed  Google Scholar 

  38. Madec AM, Mallone R, Afonso G, Abou Mrad E, Mesnier A, Eljaafari A, Thivolet C (2009) Mesenchymal stem cells protect NOD mice from diabetes by inducing regulatory T cells. Diabetologia 52(7):1391–1399. doi:10.1007/s00125-009-1374-z

    Article  CAS  PubMed  Google Scholar 

  39. Choi YS, Jeong JA, Lim DS (2012) Mesenchymal stem cell-mediated immature dendritic cells induce regulatory T cell-based immunosuppressive effect. Immunol Invest 41(2):214–229. doi:10.3109/08820139.2011.619022

    Article  CAS  PubMed  Google Scholar 

  40. Maccario R, Podestà M, Moretta A, Cometa A, Comoli P, Montagna D, Daudt L, Ibatici A, Piaggio G, Pozzi S, Frassoni F, Locatelli F (2005) Interaction of human mesenchymal stem cells with cells involved in alloantigen-specific immune response favors the differentiation of CD4+ T-cell subsets expressing a regulatory/suppressive phenotype. Haematologica 90(4):516–525

    CAS  PubMed  Google Scholar 

  41. Marigo IDF (2011) The immunomodulatory properties of mesenchymal stem cells. Semin Immunopathol 33:593–602

    Article  PubMed  Google Scholar 

  42. Dazzi F, Marelli-Berg FM (2008) Mesenchymal stem cells for graft-versus-host disease: close encounters with T cells. Eur J Immunol 38(6):1479–1482. doi:10.1002/eji.200838433

    Article  CAS  PubMed  Google Scholar 

  43. Hoogduijn MJ, Popp F, Verbeek R, Masoodi M, Nicolaou A, Baan C, Dahlke MH (2010) The immunomodulatory properties of mesenchymal stem cells and their use for immunotherapy. Int Immunopharmacol 10(12):1496–1500. doi:10.1016/j.intimp.2010.06.019

    Article  CAS  PubMed  Google Scholar 

  44. Sudres M, Norol F, Trenado A, Gregoire S, Charlotte F, Levacher B, Lataillade JJ, Bourin P, Holy X, Vernant JP, Klatzmann D, Cohen JL (2006) Bone marrow mesenchymal stem cells suppress lymphocyte proliferation in vitro but fail to prevent graft-versus-host disease in mice. J Immunol 176(12):7761–7767

    CAS  PubMed  Google Scholar 

  45. Tisato V, Naresh K, Girdlestone J, Navarrete C, Dazzi F (2007) Mesenchymal stem cells of cord blood origin are effective at preventing but not treating graft-versus-host disease. Leuk: Off J Leuk Soc Am Leuk Res Fund UK 21(9):1992–1999. doi:10.1038/sj.leu.2404847

    Article  CAS  Google Scholar 

  46. Polchert D, Sobinsky J, Douglas G, Kidd M, Moadsiri A, Reina E, Genrich K, Mehrotra S, Setty S, Smith B, Bartholomew A (2008) IFN-gamma activation of mesenchymal stem cells for treatment and prevention of graft versus host disease. Eur J Immunol 38(6):1745–1755

    Article  CAS  PubMed  Google Scholar 

  47. Li H, Guo Z, Jiang X, Zhu H, Li X, Mao N (2008) Mesenchymal stem cells alter migratory property of T and dendritic cells to delay the development of murine lethal acute graft-versus-host disease. Stem Cells 26(10):2531–2541. doi:10.1634/stemcells.2008-0146

    Article  CAS  PubMed  Google Scholar 

  48. Chapel A, Bertho JM, Bensidhoum M, Fouillard L, Young RG, Frick J, Demarquay C, Cuvelier F, Mathieu E, Trompier F, Dudoignon N, Germain C, Mazurier C, Aigueperse J, Borneman J, Gorin NC, Gourmelon P, Thierry D (2003) Mesenchymal stem cells home to injured tissues when co-infused with hematopoietic cells to treat a radiation-induced multi-organ failure syndrome. J Gene Med 5(12):1028–1038. doi:10.1002/jgm.452

    Article  PubMed  Google Scholar 

  49. Joo SY, Cho KA, Jung YJ, Kim HS, Park SY, Choi YB, Hong KM, Woo SY, Seoh JY, Ryu KH (2011) Bioimaging for the monitoring of the in vivo distribution of infused mesenchymal stem cells in a mouse model of the graft-versus-host reaction. Cell Biol Int 35(4):417–421. doi:10.1042/CBI20100563

    Article  PubMed  Google Scholar 

  50. Chu YW, Gress RE (2008) Murine models of chronic graft-versus-host disease: insights and unresolved issues. Biol Blood Marrow Transplant 14(4):365–378. doi:10.1016/j.bbmt.2007.12.002

    Article  CAS  PubMed  Google Scholar 

  51. Ma Z, Chen F, Madaio MP, Cohen PL, Eisenberg RA (2006) Modulation of autoimmunity by TLR9 in the chronic graft-vs-host model of systemic lupus erythematosus. J Immunol 177(10):7444–7450

    CAS  PubMed  Google Scholar 

  52. Tschetter JR, Mozes E, Shearer GM (2000) Progression from acute to chronic disease in a murine parent-into-F1 model of graft-versus-host disease. J Immunol 165(10):5987–5994

    CAS  PubMed  Google Scholar 

  53. Kim J, Choi WS, La S, Suh JH, Kim BS, Cho HR, Kwon BS, Kwon B (2005) Stimulation with 4-1BB (CD137) inhibits chronic graft-versus-host disease by inducing activation-induced cell death of donor CD4+ T cells. Blood 105(5):2206–2213. doi:10.1182/blood-2004-06-2080

    Article  CAS  PubMed  Google Scholar 

  54. Levy S, Nagler A, Okon S, Marmary Y (2000) Parotid salivary gland dysfunction in chronic graft-versus-host disease (cGVHD): a longitudinal study in a mouse model. Bone Marrow Transplant 25(10):1073–1078. doi:10.1038/sj.bmt.1702383

    Article  CAS  PubMed  Google Scholar 

  55. Fang B, Song YP, Liao LM, Han Q, Zhao RC (2006) Treatment of severe therapy-resistant acute graft-versus-host disease with human adipose tissue-derived mesenchymal stem cells. Bone Marrow Transplant 38(5):389–390. doi:10.1038/sj.bmt.1705457

    Article  CAS  PubMed  Google Scholar 

  56. Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I, Lanino E, Sundberg B, Bernardo ME, Remberger M, Dini G, Egeler RM, Bacigalupo A, Fibbe W, Ringden O (2008) Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet 371(9624):1579–1586. doi:10.1016/s0140-6736(08)60690-x

    Article  PubMed  CAS  Google Scholar 

  57. Lucchini G, Introna M, Dander E, Rovelli A, Balduzzi A, Bonanomi S, Salvade A, Capelli C, Belotti D, Gaipa G, Perseghin P, Vinci P, Lanino E, Chiusolo P, Orofino MG, Marktel S, Golay J, Rambaldi A, Biondi A, D’Amico G, Biagi E (2010) Platelet-lysate-expanded mesenchymal stromal cells as a salvage therapy for severe resistant graft-versus-host disease in a pediatric population. Biol Blood Marrow Transplant 16(9):1293–1301. doi:10.1016/j.bbmt.2010.03.017

    Article  PubMed  Google Scholar 

  58. Müller I, Kordowich S, Holzwarth C, Isensee G, Lang P, Neunhoeffer F, Dominici M, Greil J, Handgretinger R (2008) Application of multipotent mesenchymal stromal cells in pediatric patients following allogeneic stem cell transplantation. Blood Cells Mol Dis 40(1):25–32. doi:10.1016/j.bcmd.2007.06.021

    Article  PubMed  Google Scholar 

  59. Prasad VK, Lucas KG, Kleiner GI, Talano JA, Jacobsohn D, Broadwater G, Monroy R, Kurtzberg J (2011) Efficacy and safety of ex vivo cultured adult human mesenchymal stem cells (Prochymal) in pediatric patients with severe refractory acute graft-versus-host disease in a compassionate use study. Biol Blood Marrow Transplant 17(4):534–541. doi:10.1016/j.bbmt.2010.04.014

    Article  CAS  PubMed  Google Scholar 

  60. Ringdén O, Uzunel M, Rasmusson I, Remberger M, Sundberg B, Lonnies H, Marschall HU, Dlugosz A, Szakos A, Hassan Z, Omazic B, Aschan J, Barkholt L, Le Blanc K (2006) Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease. Transplantation 81(10):1390–1397. doi:10.1097/01.tp.0000214462.63943.14

    Article  PubMed  Google Scholar 

  61. von Bonin M, Stölzel F, Goedecke A, Richter K, Wuschek N, Holig K, Platzbecker U, Illmer T, Schaich M, Schetelig J, Kiani A, Ordemann R, Ehninger G, Schmitz M, Bornhauser M (2009) Treatment of refractory acute GVHD with third-party MSC expanded in platelet lysate-containing medium. Bone Marrow Transplant 43(3):245–251. doi:10.1038/bmt.2008.316

    Article  CAS  Google Scholar 

  62. Wu KH, Chan CK, Tsai C, Chang YH, Sieber M, Chiu TH, Ho M, Peng CT, Wu HP, Huang JL (2011) Effective treatment of severe steroid-resistant acute graft-versus-host disease with umbilical cord-derived mesenchymal stem cells. Transplantation 91(12):1412–1416. doi:10.1097/TP.0b013e31821aba18

    Article  PubMed  Google Scholar 

  63. Tse WT, Pendleton JD, Beyer WM, Egalka MC, Guinan EC (2003) Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation. Transplantation 75(3):389–397. doi:10.1097/01.TP.0000045055.63901.A9

    Article  CAS  PubMed  Google Scholar 

  64. Osiris Therapeutics Inc. (2012) Osiris Therapeutics Inc. Products. Osiris Therapeutics, Inc. http://www.osiris.com/therapeutics.php. Accessed 7 Sept 2012

  65. Kebriaei P, Isola L, Bahceci E, Holland K, Rowley S, McGuirk J, Devetten M, Jansen J, Herzig R, Schuster M, Monroy R, Uberti J (2009) Adult human mesenchymal stem cells added to corticosteroid therapy for the treatment of acute graft-versus-host disease. Biol Blood Marrow Transplant 15(7):804–811. doi:10.1016/j.bbmt.2008.03.012

    Article  CAS  PubMed  Google Scholar 

  66. Zhou H, Guo M, Bian C, Sun Z, Yang Z, Zeng Y, Ai H, Zhao RC (2010) Efficacy of bone marrow-derived mesenchymal stem cells in the treatment of sclerodermatous chronic graft-versus-host disease: clinical report. Biol Blood Marrow Transplant 16(3):403–412. doi:10.1016/j.bbmt.2009.11.006

    Article  CAS  PubMed  Google Scholar 

  67. Weng JY, Du X, Geng SX, Peng YW, Wang Z, Lu ZS, Wu SJ, Luo CW, Guo R, Ling W, Deng CX, Liao PJ, Xiang AP (2010) Mesenchymal stem cell as salvage treatment for refractory chronic GVHD. Bone Marrow Transplant 45(12):1732–1740. doi:10.1038/bmt.2010.195

    Article  CAS  PubMed  Google Scholar 

  68. Badillo AT, Peranteau WH, Heaton TE, Quinn C, Flake AW (2008) Murine bone marrow derived stromal progenitor cells fail to prevent or treat acute graft-versus-host disease. Br J Haematol 141(2):224–234. doi:10.1111/j.1365-2141.2008.07040.x

    Article  PubMed  Google Scholar 

  69. Prigozhina TB, Khitrin S, Elkin G, Eizik O, Morecki S, Slavin S (2008) Mesenchymal stromal cells lose their immunosuppressive potential after allotransplantation. Exp Hematol 36(10):1370–1376. doi:10.1016/j.exphem.2008.04.022

    Article  CAS  PubMed  Google Scholar 

  70. Chung NG, Jeong DC, Park SJ, Choi BO, Cho B, Kim HK, Chun CS, Won JH, Han CW (2004) Cotransplantation of marrow stromal cells may prevent lethal graft-versus-host disease in major histocompatibility complex mismatched murine hematopoietic stem cell transplantation. Int J Hematol 80(4):370–376

    Article  PubMed  Google Scholar 

  71. Baron F, Lechanteur C, Willems E, Bruck F, Baudoux E, Seidel L, Vanbellinghen JF, Hafraoui K, Lejeune M, Gothot A, Fillet G, Beguin Y (2010) Cotransplantation of mesenchymal stem cells might prevent death from graft-versus-host disease (GVHD) without abrogating graft-versus-tumor effects after HLA-mismatched allogeneic transplantation following nonmyeloablative conditioning. Biol Blood Marrow Transplant 16(6):838–847

    Article  PubMed  Google Scholar 

  72. Lazarus HM, Koc ON, Devine SM, Curtin P, Maziarz RT, Holland HK, Shpall EJ, McCarthy P, Atkinson K, Cooper BW, Gerson SL, Laughlin MJ, Loberiza FR Jr, Moseley AB, Bacigalupo A (2005) Cotransplantation of HLA-identical sibling culture-expanded mesenchymal stem cells and hematopoietic stem cells in hematologic malignancy patients. Biol Blood Marrow Transplant 11(5):389–398. doi:10.1016/j.bbmt.2005.02.001

    Article  PubMed  Google Scholar 

  73. Ning H, Yang F, Jiang M, Hu L, Feng K, Zhang J, Yu Z, Li B, Xu C, Li Y, Wang J, Hu J, Lou X, Chen H (2008) The correlation between cotransplantation of mesenchymal stem cells and higher recurrence rate in hematologic malignancy patients: outcome of a pilot clinical study. Leuk: Off J Leuk Soc Am Leuk Res Fund UK 22(3):593–599. doi:10.1038/sj.leu.2405090

    Article  CAS  Google Scholar 

  74. Kuzmina LA, Petinati NA, Parovichnikova EN, Lubimova LS, Gribanova EO, Gaponova TV, Shipounova IN, Zhironkina OA, Bigildeev AE, Svinareva DA, Drize NJ, Savchenko VG (2012) Multipotent mesenchymal stromal cells for the prophylaxis of acute graft-versus-host disease-a phase II study. Stem Cells Int 2012:968213. doi:10.1155/2012/968213

    PubMed  Google Scholar 

  75. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, Thomas ED (1995) 1994 consensus conference on acute GVHD grading. Bone Marrow Transplant 15(6):825–828

    CAS  PubMed  Google Scholar 

  76. Dignan FL, Clark A, Amrolia P, Cornish J, Jackson G, Mahendra P, Scarisbrick JJ, Taylor PC, Hadzic N, Shaw BE, Potter MN (2012) Diagnosis and management of acute graft-versus-host disease. Br J Haematol 158(1):30–45. doi:10.1111/j.1365-2141.2012.09129.x

    Article  CAS  PubMed  Google Scholar 

  77. Osiris Therapeutics, Inc (2009) Osiris Therapeutics announces preliminary results for prochymal phase III GvHD Trials. Business Wire. http://investor.osiris.com/releasedetail.cfm?releaseid=407404. Accessed 7 Sept 2012

  78. Djouad F, Plence P, Bony C, Tropel P, Apparailly F, Sany J, Noel D, Jorgensen C (2003) Immunosuppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals. Blood 102(10):3837–3844. doi:10.1182/blood-2003-04-1193

    Article  CAS  PubMed  Google Scholar 

  79. Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW, Richardson AL, Polyak K, Tubo R, Weinberg RA (2007) Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 449(7162):557–563. doi:10.1038/nature06188

    Article  CAS  PubMed  Google Scholar 

  80. Zhu W, Xu W, Jiang R, Qian H, Chen M, Hu J, Cao W, Han C, Chen Y (2006) Mesenchymal stem cells derived from bone marrow favor tumor cell growth in vivo. Exp Mol Pathol 80(3):267–274. doi:10.1016/j.yexmp.2005.07.004

    Article  CAS  PubMed  Google Scholar 

  81. Tolar J, Nauta AJ, Osborn MJ, Panoskaltsis Mortari A, McElmurry RT, Bell S, Xia L, Zhou N, Riddle M, Schroeder TM, Westendorf JJ, McIvor RS, Hogendoorn PC, Szuhai K, Oseth L, Hirsch B, Yant SR, Kay MA, Peister A, Prockop DJ, Fibbe WE, Blazar BR (2007) Sarcoma derived from cultured mesenchymal stem cells. Stem Cells 25(2):371–379. doi:10.1634/stemcells.2005-0620

    Article  CAS  PubMed  Google Scholar 

  82. Lepperdinger G, Brunauer R, Jamnig A, Laschober G, Kassem M (2008) Controversial issue: is it safe to employ mesenchymal stem cells in cell-based therapies? Exp Gerontol 43(11):1018–1023. doi:10.1016/j.exger.2008.07.004

    Article  CAS  PubMed  Google Scholar 

  83. Bernardo ME, Zaffaroni N, Novara F, Cometa AM, Avanzini MA, Moretta A, Montagna D, Maccario R, Villa R, Daidone MG, Zuffardi O, Locatelli F (2007) Human bone marrow derived mesenchymal stem cells do not undergo transformation after long-term in vitro culture and do not exhibit telomere maintenance mechanisms. Cancer Res 67(19):9142–9149. doi:10.1158/0008-5472.CAN-06-4690

    Article  CAS  PubMed  Google Scholar 

  84. Wang Y, Huso DL, Harrington J, Kellner J, Jeong DK, Turney J, McNiece IK (2005) Outgrowth of a transformed cell population derived from normal human BM mesenchymal stem cell culture. Cytotherapy 7(6):509–519. doi:10.1080/14653240500363216

    Article  CAS  PubMed  Google Scholar 

  85. Peister A, Mellad JA, Larson BL, Hall BM, Gibson LF, Prockop DJ (2004) Adult stem cells from bone marrow (MSCs) isolated from different strains of inbred mice vary in surface epitopes, rates of proliferation, and differentiation potential. Blood 103(5):1662–1668. doi:10.1182/blood-2003-09-3070

    Article  CAS  PubMed  Google Scholar 

  86. Teshima T (2011) Th1 and Th17 join forces for acute GVHD. Blood 118(18):4765–4767. doi:10.1182/blood-2011-09-377325

    Article  CAS  PubMed  Google Scholar 

  87. Yu YWD, Liu C, Kaosaard K, Semple K, Anasetti C, Yu XZ (2011) Prevention of GVHD while sparing GVL effect by targeting Th1 and Th17 transcription factor T-bet and RORγt in mice. Blood 118(18):5011–5020

    Article  CAS  PubMed  Google Scholar 

  88. Chen B, Hu J, Liao L, Sun Z, Han Q, Song Z, Zhao RC (2010) Flk-1+ mesenchymal stem cells aggravate collagen-induced arthritis by up-regulating interleukin-6. Clin Exp Immunol 159(3):292–302. doi:10.1111/j.1365-2249.2009.04069.x

    Article  CAS  PubMed  Google Scholar 

  89. Schurgers E, Kelchtermans H, Mitera T, Geboes L, Matthys P (2010) Discrepancy between the in vitro and in vivo effects of murine mesenchymal stem cells on T-cell proliferation and collagen-induced arthritis. Arthritis Res Ther 12(1):R31. doi:10.1186/ar2939

    Article  PubMed  CAS  Google Scholar 

  90. Park MJ, Park HS, Cho ML, Oh HJ, Cho YG, Min SY, Chung BH, Lee JW, Kim HY, Cho SG (2011) Transforming growth factor beta-transduced mesenchymal stem cells ameliorate experimental autoimmune arthritis through reciprocal regulation of Treg/Th17 cells and osteoclastogenesis. Arthritis Rheum 63(6):1668–1680. doi:10.1002/art.30326

    Article  CAS  PubMed  Google Scholar 

  91. Eljaafari A, Tartelin ML, Aissaoui H, Chevrel G, Osta B, Lavocat F, Miossec P (2012) Bone marrow-derived and synovium-derived mesenchymal cells promote Th17 cell expansion and activation through caspase 1 activation: contribution to the chronicity of rheumatoid arthritis. Arthritis Rheum 64(7):2147–2157. doi:10.1002/art.34391

    Article  CAS  PubMed  Google Scholar 

  92. Guo Z, Zheng C, Chen Z, Gu D, Du W, Ge J, Han Z, Yang R (2009) Fetal BM-derived mesenchymal stem cells promote the expansion of human Th17 cells, but inhibit the production of Th1 cells. Eur J Immunol 39(10):2840–2849. doi:10.1002/eji.200839070

    Article  CAS  PubMed  Google Scholar 

  93. Svobodova E, Krulova M, Zajicova A, Pokorna K, Prochazkova J, Trosan P, Holan V (2012) The role of mouse mesenchymal stem cells in differentiation of naive T-cells into anti-inflammatory regulatory T-cell or proinflammatory helper T-cell 17 population. Stem Cells Dev 21(6):901–910. doi:10.1089/scd.2011.0157

    Article  CAS  PubMed  Google Scholar 

  94. Chavakis E, Urbich C, Dimmeler S (2008) Homing and engraftment of progenitor cells: a prerequisite for cell therapy. J Mol Cell Cardiol 45(4):514–522. doi:10.1016/j.yjmcc.2008.01.004

    Article  CAS  PubMed  Google Scholar 

  95. Karp JM, Leng Teo GS (2009) Mesenchymal stem cell homing: the devil is in the details. Cell Stem Cell 4(3):206–216. doi:10.1016/j.stem.2009.02.001

    Article  CAS  PubMed  Google Scholar 

  96. Min CK, Kim BG, Park G, Cho B, Oh IH (2007) IL-10-transduced bone marrow mesenchymal stem cells can attenuate the severity of acute graft-versus-host disease after experimental allogeneic stem cell transplantation. Bone Marrow Transplant 39(10):637–645. doi:10.1038/sj.bmt.1705644

    Article  CAS  PubMed  Google Scholar 

  97. Payne NL, Dantanarayana A, Sun G, Moussa L, Caine S, McDonald C, Herszfeld D, Bernard CC, Siatskas C (2012) Early intervention with gene-modified mesenchymal stem cells overexpressing interleukin-4 enhances anti-inflammatory responses and functional recovery in experimental autoimmune demyelination. Cell Adh Migr 6(3):179–189. doi:10.4161/cam.20341

    Article  PubMed  Google Scholar 

  98. Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez XR, Reyes M, Lenvik T, Lund T, Blackstad M, Du J, Aldrich S, Lisberg A, Low WC, Largaespada DA, Verfaillie CM (2002) Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 418(6893):41–49. doi:10.1038/nature00870

    Article  CAS  PubMed  Google Scholar 

  99. Roobrouck VD, Clavel C, Jacobs SA, Ulloa-Montoya F, Crippa S, Sohni A, Roberts SJ, Luyten FP, Van Gool SW, Sampaolesi M, Delforge M, Luttun A, Verfaillie CM (2011) Differentiation potential of human postnatal mesenchymal stem cells, mesoangioblasts, and multipotent adult progenitor cells reflected in their transcriptome and partially influenced by the culture conditions. Stem Cells 29(5):871–882. doi:10.1002/stem.633

    Article  CAS  PubMed  Google Scholar 

  100. Jacobs SA, Roobrouck VD, Verfaillie CM, Van Gool SW (2013) Immunological characteristics of human mesenchymal stem cells and multipotent adult progenitor cells. Immunol Cell Biol 91(1):32–39. doi:10.1038/icb.2012.64

    Article  CAS  PubMed  Google Scholar 

  101. Jacobs SA, Pinxteren J, Roobrouck VD, Luyckx A, Van’t Hof W, Deans R, Verfaillie CM, Waer M, Billiau AD, Van Gool SW (2012) Human multipotent adult progenitor cells are non-immunogenic and exert potent immunomodulatory effects on alloreactive T cell responses. Cell Transplant. doi:10.3727/096368912X657369

    PubMed  Google Scholar 

  102. Athersys I MultiStem: a novel stem cell therapy. Athersys, Inc. http://www.athersys.com/. Accessed 21 Jan

  103. Boozer S, Lehman N, Lakshmipathy U, Love B, Raber A, Maitra A, Deans R, Rao MS, Ting AE (2009) Global characterization and genomic stability of human multistem, a multipotent adult progenitor cell. J Stem Cells 4(1):17–28

    PubMed  Google Scholar 

  104. Kovacsovics-Bankowski M, Mauch K, Raber A, Streeter PR, Deans RJ, Maziarz RT, Van’t Hof W (2008) Pre-clinical safety testing supporting clinical use of allogeneic multipotent adult progenitor cells. Cytotherapy 10(7):730–742. doi:10.1080/14653240802320245

    Article  CAS  PubMed  Google Scholar 

  105. Vaes B, Van’t Hof W, Deans R, Pinxteren J (2012) Application of MultiStem((R)) allogeneic cells for immunomodulatory therapy: clinical progress and pre-clinical challenges in prophylaxis for graft versus host disease. Front Immunol 3:345. doi:10.3389/fimmu.2012.00345

    Article  PubMed  Google Scholar 

  106. Kovacsovics-Bankowski M, Streeter PR, Mauch KA, Frey MR, Raber A, van’t Hof W, Deans R, Maziarz RT (2009) Clinical scale expanded adult pluripotent stem cells prevent graft-versus-host disease. Cell Immunol 255(1–2):55–60. doi:10.1016/j.cellimm.2008.10.004

    Article  CAS  PubMed  Google Scholar 

  107. Highfill SL, Kelly RM, O’Shaughnessy MJ, Zhou Q, Xia LL, Panoskaltsis-Mortari A, Taylor PA, Tolar J, Blazar BR (2009) Multipotent adult progenitor cells can suppress graft-versus-host disease via prostaglandin E(2) synthesis and only if localized to sites of allopriming. Blood 114(3):693–701. doi:10.1182/blood-2009-03-213850

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by a grant from the Korean Health Technology R&D Project, Ministry for Health & Welfare, Republic of Korea (A092258).

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Authors and Affiliations

  1. Laboratory of Immune Regulation, Convergent Research Consortium for Immunologic Disease, The Catholic University of Korea College of Medicine, Seoul, South Korea

    Nayoun Kim, Keon-Il Im, Jung-Yeon Lim, Eun-Joo Jeon, Eun-Jung Kim & Seok-Goo Cho

  2. Department of Biology, KyungHee University, Seoul, South Korea

    Young-Sun Nam

  3. Department of Hematology, Catholic Blood and Marrow Transplantation Center, Seoul St. Mary’s Hospital, 222, Banpo-daero, Seocho-gu, Seoul, 137-701, Korea

    Seok-Goo Cho

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  1. Nayoun Kim
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Kim, N., Im, KI., Lim, JY. et al. Mesenchymal stem cells for the treatment and prevention of graft-versus-host disease: experiments and practice. Ann Hematol 92, 1295–1308 (2013). https://doi.org/10.1007/s00277-013-1796-z

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