Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Stem Cells

Mesenchymal stem cells of cord blood origin are effective at preventing but not treating graft-versus-host disease

Leukemia volume 21, pages 1992–1999 (2007)Cite this article

Abstract

The immunosuppressive properties of mesenchymal stem cells (MSC) make them particularly attractive to manipulate graft-versus-host disease (GVHD). So far, the experience of using MSC to treat GVHD is limited to a few cases, controversial results come from preclinical models and several issues remain to be clarified. The present studies were designed to address these questions in a xenogenic model testing the ability of umbilical cord blood-derived MSC (UCB-MSC) to prevent and/or treat GVHD. Sublethally irradiatiated non-obese diabetic/severe combined immunodeficiency NOD/SCID mice transplanted with human peripheral blood mononuclear cells (huPBMC) showed extensive human T-cell proliferation in the peripheral blood, lymphoid and non-lymphoid tissues, which evolved in extensive GVHD (wasting, ruffled hair and hunched back). The mice treated with a single dose of UCB-MSC did not behave differently form the controls. However, when UCB-MSC were given at weekly intervals, there was a marked decrease in human T-cell proliferation and none of the mice developed GVHD. No therapeutic effect was obtained if UCB-MSC were administered at onset of GVHD. This work supports the clinical use of MSC in stem cell transplantation as a prophylaxis rather than treatment of GVHD.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Antin JH, Chen AR, Couriel DR, Ho VT, Nash RA, Weisdorf D . Novel approaches to the therapy of steroid-resistant acute graft-versus-host disease. Biol Blood Marrow Transplant 2004; 10: 655–668.

    Article  CAS  Google Scholar 

  2. Khoury H, Kashyap A, Adkins DR, Brown RA, Miller G, Vij R et al. Treatment of steroid-resistant acute graft-versus-host disease with anti-thymocyte globulin. Bone Marrow Transplant 2001; 27: 1059–1064.

    Article  CAS  Google Scholar 

  3. Van Lint MT, Milone G, Leotta S, Uderzo C, Scime R, Dallorso 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.

    Article  CAS  Google Scholar 

  4. Deeg HJ, Blazar BR, Bolwell BJ, Long GD, Schuening F, Cunningham J et al. Treatment of steroid-refractory acute graft-versus-host disease with anti-CD147 monoclonal antibody ABX-CBL. Blood 2001; 98: 2052–2058.

    Article  CAS  Google Scholar 

  5. Ji SQ, Chen HR, Yan HM, Wang HX, Liu J, Zhu PY et al. Anti-CD25 monoclonal antibody (basiliximab) for prevention of graft-versus-host disease after haploidentical bone marrow transplantation for hematological malignancies. Bone Marrow Transplant 2005; 36: 349–354.

    Article  CAS  Google Scholar 

  6. Subramaniam DS, Fowler DH, Pavletic SZ . Chronic graft-versus-host disease in the era of reduced-intensity conditioning. Leukemia 2007; 21: 853–859.

    Article  CAS  Google Scholar 

  7. Bacigalupo A, Lamparelli T, Gualandi F, Bregante S, Raiola AM, Di Grazia C et al. Prophylactic antithymocyte globulin reduces the risk of chronic graft-versus-host disease in alternative-donor bone marrow transplants. Biol Blood Marrow Transplant 2002; 8: 656–661.

    Article  CAS  Google Scholar 

  8. Anjos-Afonso F, Bonnet D . Nonhematopoietic/endothelial SSEA-1+ cells define the most primitive progenitors in the adult murine bone marrow mesenchymal compartment. Blood 2007; 109: 1298–1306.

    Article  CAS  Google Scholar 

  9. Martinez C, Hofmann TJ, Marino R, Dominici M, Horwitz EM . Human bone marrow mesenchymal stromal cells express the neural ganglioside GD2: a novel surface marker for the identification of MSCs. Blood 2007; 109: 4245–4248.

    Article  CAS  Google Scholar 

  10. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999; 284: 143–147.

    Article  CAS  Google Scholar 

  11. Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006; 8: 315–317.

    Article  CAS  Google Scholar 

  12. Le Blanc K, Pittenger M . Mesenchymal stem cells: progress toward promise. Cytotherapy 2005; 7: 36–45.

    Article  CAS  Google Scholar 

  13. Campagnoli C, Roberts IA, Kumar S, Bennett PR, Bellantuono I, Fisk NM . Identification of mesenchymal stem/progenitor cells in human first-trimester fetal blood, liver, and bone marrow. Blood 2001; 98: 2396–2402.

    Article  CAS  Google Scholar 

  14. in ‘t Anker PS, Noort WA, Scherjon SA, Kleijburg-van der Keur C, Kruisselbrink AB, van Bezooijen RL et al. Mesenchymal stem cells in human second-trimester bone marrow, liver, lung, and spleen exhibit a similar immunophenotype but a heterogeneous multilineage differentiation potential. Haematologica 2003; 88: 845–852.

    Google Scholar 

  15. Igura K, Zhang X, Takahashi K, Mitsuru A, Yamaguchi S, Takashi TA . Isolation and characterization of mesenchymal progenitor cells from chorionic villi of human placenta. Cytotherapy 2004; 6: 543–553.

    Article  CAS  Google Scholar 

  16. Tsai MS, Lee JL, Chang YJ, Hwang SM . Isolation of human multipotent mesenchymal stem cells from second-trimester amniotic fluid using a novel two-stage culture protocol. Hum Reprod 2004; 19: 1450–1456.

    Article  Google Scholar 

  17. Kern S, Eichler H, Stoeve J, Kluter H, Bieback K . Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem Cells 2006; 24: 1294–1301.

    Article  CAS  Google Scholar 

  18. Erices A, Conget P, Minguell JJ . Mesenchymal progenitor cells in human umbilical cord blood. Br J Haematol 2000; 109: 235–242.

    Article  CAS  Google Scholar 

  19. Glennie S, Soeiro I, Dyson PJ, Lam EW, Dazzi F . Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells. Blood 2005; 105: 2821–2827.

    Article  CAS  Google Scholar 

  20. Krampera M, Glennie S, Dyson J, Scott D, Laylor R, Simpson E et al. Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide. Blood 2003; 101: 3722–3729.

    Article  CAS  Google Scholar 

  21. Ramasamy R, Lam EW, Soeiro I, Tisato V, Bonnet D, Dazzi F . Mesenchymal stem cells inhibit proliferation and apoptosis of tumor cells: impact on in vivo tumor growth. Leukemia 2007; 21: 304–310.

    Article  CAS  Google Scholar 

  22. Lazarus HM, Koc ON, Devine SM, Curtin P, Maziarz RT, Holland HK et al. Cotransplantation of HLA-identical sibling culture-expanded mesenchymal stem cells and hematopoietic stem cells in hematologic malignancy patients. Biol Blood Marrow Transplant 2005; 11: 389–398.

    Article  Google Scholar 

  23. Ringden O, Uzunel M, Rasmusson I, Remberger M, Sundberg B, Lonnies H et al. Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease. Transplantation 2006; 81: 1390–1397.

    Article  Google Scholar 

  24. Le Blanc K, Rasmusson I, Sundberg B, Gotherstrom C, Hassan M, Uzunel M et al. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 2004; 363: 1439–1441.

    Article  Google Scholar 

  25. Zappia E, Casazza S, Pedemonte E, Benvenuto F, Bonanni I, Gerdoni E et al. Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Blood 2005; 106: 1755–1761.

    Article  CAS  Google Scholar 

  26. Djouad F, Fritz V, Apparailly F, Louis-Plence P, Bony C, Sany J et al. Reversal of the immunosuppressive properties of mesenchymal stem cells by tumor necrosis factor alpha in collagen-induced arthritis. Arthritis Rheum 2005; 52: 1595–1603.

    Article  CAS  Google Scholar 

  27. Ninichuk V, Gross O, Segerer S, Hoffmann R, Radomska E, Buchstaller A et al. Multipotent mesenchymal stem cells reduce interstitial fibrosis but do not delay progression of chronic kidney disease in collagen4A3-deficient mice. Kidney Int 2006; 70: 121–129.

    Article  CAS  Google Scholar 

  28. Follenzi A, Sabatino G, Lombardo A, Boccaccio C, Naldini L . Efficient gene delivery and targeted expression to hepatocytes in vivo by improved lentiviral vectors. Hum Gene Ther 2002; 13: 243–260.

    Article  CAS  Google Scholar 

  29. Hill GR, Crawford JM, Cooke KR, Brinson YS, Pan L, Ferrara JL . Total body irradiation and acute graft-versus-host disease: the role of gastrointestinal damage and inflammatory cytokines. Blood 1997; 90: 3204–3213.

    CAS  Google Scholar 

  30. Sandhu JS, Gorczynski R, Shpitz B, Gallinger S, Nguyen HP, Hozumi N . A human model of xenogeneic graft-versus-host disease in SCID mice engrafted with human peripheral blood lymphocytes. Transplantation 1995; 60: 179–184.

    Article  CAS  Google Scholar 

  31. van Rijn RS, Simonetti ER, Hagenbeek A, Hogenes MC, de Weger RA, Canninga-van Dijk MR et al. A new xenograft model for graft-versus-host disease by intravenous transfer of human peripheral blood mononuclear cells in RAG2−/− gammac−/− double-mutant mice. Blood 2003; 102: 2522–2531.

    Article  CAS  Google Scholar 

  32. Dazzi F, Capelli D, Hasserjian R, Cotter F, Corbo M, Poletti A et al. The kinetics and extent of engraftment of chronic myelogenous leukemia cells in non-obese diabetic/severe combined immunodeficiency mice reflect the phase of the donor’s disease: an in vivo model of chronic myelogenous leukemia biology. Blood 1998; 92: 1390–1396.

    CAS  Google Scholar 

  33. Laylor R, Dewchand H, Simpson E, Dazzi F . Engraftment of allogeneic hematopoietic stem cells requires both inhibition of host-versus-graft responses and ‘space’ for homeostatic expansion. Transplantation 2005; 79: 1484–1491.

    Article  Google Scholar 

  34. Hauger O, Frost EE, van Heeswijk R, Deminiere C, Xue R, Delmas Y et al. MR evaluation of the glomerular homing of magnetically labeled mesenchymal stem cells in a rat model of nephropathy. Radiology 2006; 238: 200–210.

    Article  Google Scholar 

  35. Wu GD, Nolta JA, Jin YS, Barr ML, Yu H, Starnes VA et al. Migration of mesenchymal stem cells to heart allografts during chronic rejection. Transplantation 2003; 75: 679–685.

    Article  Google Scholar 

  36. Bartholomew A, Sturgeon C, Siatskas M, Ferrer K, McIntosh K, Patil S et al. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol 2002; 30: 42–48.

    Article  Google Scholar 

  37. Augello A, Tasso R, Negrini SM, Cancedda R, Pennesi G . Cell therapy using allogeneic bone marrow mesenchymal stem cells prevents tissue damage in collagen-induced arthritis. Arthritis Rheum 2007; 56: 1175–1186.

    Article  CAS  Google Scholar 

  38. Sudres M, Norol F, Trenado A, Gregoire S, Charlotte F, Levacher B et al. Bone marrow mesenchymal stem cells suppress lymphocyte proliferation in vitro but fail to prevent graft-versus-host disease in mice. J Immunol 2006; 176: 7761–7767.

    Article  CAS  Google Scholar 

  39. Nauta AJ, Westerhuis G, Kruisselbrink AB, Lurvink EG, Willemze R, Fibbe WE . Donor-derived mesenchymal stem cells are immunogenic in an allogeneic host and stimulate donor graft rejection in a nonmyeloablative setting. Blood 2006; 108: 2114–2120.

    Article  CAS  Google Scholar 

  40. Eliopoulos N, Stagg J, Lejeune L, Pommey S, Galipeau J . Allogeneic marrow stromal cells are immune rejected by MHC class I- and class II-mismatched recipient mice. Blood 2005; 106: 4057–4065.

    Article  CAS  Google Scholar 

  41. Chung NG, Jeong DC, Park SJ, Choi BO, Cho B, Kim HK et al. 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 2004; 80: 370–376.

    Article  Google Scholar 

  42. Mutis T, Gillespie G, Schrama E, Falkenburg JH, Moss P, Goulmy E . Tetrameric HLA class I-minor histocompatibility antigen peptide complexes demonstrate minor histocompatibility antigen-specific cytotoxic T lymphocytes in patients with graft-versus-host disease. Nat Med 1999; 5: 839–842.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by Leukaemia Research Fund.

Author information

Authors and Affiliations

  1. Stem Cell Biology Section, Kennedy Institute of Rheumatology, Imperial College, London, UK

    V Tisato & F Dazzi

  2. Department of Histopathology, Hammersmith Hospital, Imperial College, London, UK

    K Naresh

  3. H&I Research Department, Histocompatibility and Immunogenetics Research Group, Colindale Centre National Health Service Blood and Transplant, Colindale, UK

    J Girdlestone & C Navarrete

Authors
  1. V Tisato
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K Naresh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J Girdlestone
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C Navarrete
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. F Dazzi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to F Dazzi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tisato, V., Naresh, K., Girdlestone, J. et al. Mesenchymal stem cells of cord blood origin are effective at preventing but not treating graft-versus-host disease. Leukemia 21, 1992–1999 (2007). https://doi.org/10.1038/sj.leu.2404847

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2404847

Keywords

This article is cited by

Search

Advanced search

Quick links