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:

Pre-Clinical Studies

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 Transplantation volume 39, pages 637–645 (2007)Cite this article

Abstract

Recent data suggest that adult mesenchymal stem cells (MSCs) might enhance allogeneic hematopoietic engraftment and prevent graft-versus-host disease (GVHD) owing to their immunosuppressive nature. Using a murine model of acute GVHD, this study examined whether or not the immunosuppressive properties of MSCs could reduce the severity of experimental GVHD. The early injection of MSCs after transplant did not attenuate the severity of acute GVHD. Therefore, this study investigated whether or not the use of IL-10-transduced MSCs (IL-10 MSCs) could reduce the severity of acute GVHD. Lethally irradiated recipients were transplanted and injected with IL-10 MSCs, the MSC-expressing vector alone (vector MSCs), or the diluent (controls), respectively, on day +1. Compared with the vector MSCs or controls, there was a significantly lower mortality in the recipients of the IL-10 MSCs at day 50 after the transplant (percent survival, 0 or 10 vs 70%, P=0.0004 or 0.0064, respectively). The decrease in mortality was confirmed by the semi-quantitative GVHD score (P<0.05), and was associated with decreased serum levels of the pro-inflammatory cytokines, IFN-γ, on day +7 (P=0.015). Therefore, beneficial effects on GVHD were observed when MSCs were engineered to express the anti-inflammatory cytokine, IL-10.

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
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  1. Hill GR, Ferrara JL . 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.

    CAS  PubMed  Google Scholar 

  2. 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 

  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 non responders receiving anti-thymocyte globulin. Blood 2006; 107: 4177–4181.

    Article  CAS  Google Scholar 

  4. Ferrara JL, Deeg HJ . Graft-versus-host disease. N Engl J Med 1991; 324: 667–674.

    Article  CAS  Google Scholar 

  5. Marmont AM, Horowitz MM, Gale RP, Sobocinski K, Ash RC, van Bekkum DW et al. depletion of HLA-identical transplants in leukemia. Blood 1991; 78: 2120–2130.

    CAS  PubMed  Google Scholar 

  6. De Ugarte DA, Morizono K, Elbarbary A, Alfonso Z, Zuk PA, Zhu M et al. Comparison of multi-lineage cells from human adipose tissue and bone marrow. Cells Tissues Organs 2003; 174: 101–109.

    Article  Google Scholar 

  7. 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 

  8. Di Nicola M, Carlo-Stella C, Magni M, Milanesi M, Longoni PD, Matteucci P et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 2002; 99: 3838–3843.

    Article  CAS  Google Scholar 

  9. Le Blanc K, Tammik L, Sundberg B, Haynesworth SE, Ringden O . 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.

    Article  CAS  Google Scholar 

  10. Tse WT, Pendleton JD, Beyer WM, Egalka MC, Guinan EC . Suppression of allogeneic T cellproliferation by human marrow stromal cells: implications in transplantation. Transplantation 2003; 75: 389–397.

    Article  CAS  Google Scholar 

  11. 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 

  12. 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 

  13. 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 

  14. Le Blanc K, Frassoni F, Ball L, Uzunel M, Lanini E, Sundberg B et al. Mesenchymal stem cells for treatment of severe acute and extensive chronic graft-versus-host disease. Blood 2005; 106: 1439–1441.

    Google Scholar 

  15. 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 

  16. Min CK, Maeda Y, Lowler K, Liu C, Clouthier S, Lofthus D et al. Paradoxical effects of interleukin-18 on the severity of acute graft-versus-host disease mediated by CD4+ and CD8+ T cellsubsets after experimental allogeneic bone marrow transplantation. Blood 2004; 104: 3393–3399.

    Article  CAS  Google Scholar 

  17. Asai O, Longo DL, Tian ZG, Hornung RL, Taub DD, Ruscetti FW et al. Suppression of graft-versus-host disease and amplification of graft-versus-tumor effects by activated natural killer cells after allogeneic bone marrow transplantation. J Clin Invest 1998; 101: 1835–1842.

    Article  CAS  Google Scholar 

  18. Cooke KR, Kobzik L, Martin TR, Brewer J, Delmonte Jr J, Crawford JM et al. An experimental model of idiopathic pneumonia syndrome after bone marrow transplantation: I. The roles of minor H antigens and endotoxin. Blood 1996; 88: 3230–3239.

    CAS  PubMed  Google Scholar 

  19. Reddy P, Teshima T, Kukuruga M, Ordemann R, Liu C, Lowler K et al. Interleukin-18 regulates acute graft-versus-host disease by enhancing Fas-mediated donor T cell apoptosis. J Exp Med 2001; 194: 1433–1440.

    Article  CAS  Google Scholar 

  20. Djouad F, Plence P, Bony C, Tropel P, Apparailly F, Sany J et al. Immunosuppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals. Blood 2003; 102: 3837–3844.

    Article  CAS  Google Scholar 

  21. Oh IH, Kang YJ, Cho B . IL-10 is a novel ligand for hematopoietic stem cell transplantation. Blood 2004; 104: 2164.

    Google Scholar 

  22. Apparailly F, Verwaerde C, Jacquet C, Auriault C, Sany J, Jorgensen C . Adenovirus-mediated transfer of viral IL-10 gene inhibits murine collagen-induced arthritis. J Immunol 1998; 160: 5213–5220.

    CAS  PubMed  Google Scholar 

  23. Zhang Y, Louboutin JP, Zhu J, Rivera AJ, Emerson SG . Preterminal host dendritic cells in irradiated mice prime CD8+ T cell-mediated acute graft-versus-host disease. J Clin Invest 2002; 109: 1335–1344.

    Article  CAS  Google Scholar 

  24. Holler E . Cytokines, viruses, and graft-versus-host disease. Curr Opin Hematol 2002; 9: 479–484.

    Article  Google Scholar 

  25. Le Blanc K, Ringden O . Immunobiology of human mesenchymal stem cells and future use in hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2005; 11: 321–334.

    Article  CAS  Google Scholar 

  26. Aggarwal S, Pittenger MF . Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 2005; 105: 1815–1822.

    Article  CAS  Google Scholar 

  27. Rasmusson I, Ringden O, Sundberg B, Le Blanc K . Mesenchymal stem cells inhibit lymphocyte proliferation by mitogens and alloantigens by different mechanisms. Exp Cell Res 2005; 305: 33–41.

    Article  CAS  Google Scholar 

  28. Beyth S, Borovsky Z, Mevorach D, Liebergall M, Gazit Z, Aslan H et al. Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T cellunresponsiveness. Blood 2005; 105: 2214–2219.

    Article  CAS  Google Scholar 

  29. Javazon EH, Beggs KJ, Flake AW . Mesenchymal stem cells: paradoxes of passaging. Exp Hematol 2004; 32: 414–425.

    Article  CAS  Google Scholar 

  30. Studeny M, Marini FC, Champlin RE, Zompetta C, Fidler IJ, Andreeff M . Bone marrow-derived mesenchymal stem cells as vehicles for interferon-beta delivery into tumors. Cancer Res 2002; 62: 3603–3608.

    CAS  PubMed  Google Scholar 

  31. de Waal Malefyt R, Yssel H, de Vries JE . Direct effects of IL-10 on subsets of human CD4+ T cell clones and resting T cells. Specific inhibition of IL-2 production and proliferation. J Immunol 1993; 150: 4754–4765.

    CAS  PubMed  Google Scholar 

  32. Bogdan C, Vodovotz Y, Nathan C . Macrophage deactivation by interleukin 10. J Exp Med 1991; 174: 1549–1555.

    Article  CAS  Google Scholar 

  33. Allen RD, Staley TA, Sidman CL . Differential cytokine expression in acute and chronic murine graft-versus-host disease. Eur J Immunol 1993; 23: 333–337.

    Article  CAS  Google Scholar 

  34. Murphy WJ, Welniak LA, Taub DD, Wiltrout RH, Taylor PA, Vallera DA et al. Differential effects of the absence of interferon-gamma and IL-4 in acute graft-versus-host disease after allogeneic bone marrow transplantation in mice. J Clin Invest 1998; 102: 1742–1748.

    Article  CAS  Google Scholar 

  35. Hirayama M, Azuma E, Kumamoto T, Iwamoto S, Nashida Y, Araki M et al. Discrimination of acute graft-versus-host disease from infections by enumeration of peripheral blood interferon-gamma spot-forming cells. Transplantation 2006; 81: 632–635.

    Article  Google Scholar 

  36. Go NF, Castle BE, Barrett R, Kastelein R, Dang W, Mosmann TR et al. Interleukin 10, a novel B cell stimulatory factor: unresponsiveness of X chromosome-linked immunodeficiency B cells. J Exp Med 1990; 172: 1625–1631.

    Article  CAS  Google Scholar 

  37. MacNeil IA, Suda T, Moore KW, Mosmann TR, Zlotnik A . IL-10, a novel growth cofactor for mature and immature T cells. J Immunol 1990; 145: 4167–4173.

    CAS  PubMed  Google Scholar 

  38. Chen WF, Zlotnik A . IL-10: a novel cytotoxic T cell differentiation factor. J Immunol 1991; 147: 528–534.

    CAS  PubMed  Google Scholar 

  39. Blazar BR, Taylor PA, Smith S, Vallera DA . Interleukin-10 administration decreases survival in murine recipients of major histocompatibility complex disparate donor bone marrow grafts. Blood 1995; 85: 842–851.

    CAS  PubMed  Google Scholar 

  40. Blazar BR, Taylor PA, Panoskaltsis-Mortari A, Narula SK, Smith SR, Roncarolo MG et al. Interleukin-10 dose-dependent regulation of CD4+ and CD8+ T cell-mediated graft-versus-host disease. Transplantation 1998; 66: 1220–1229.

    Article  CAS  Google Scholar 

  41. Storb R . Bone marrow transplantation. Transplant Proc 1995; 27: 2649–2652.

    CAS  PubMed  Google Scholar 

  42. Horowitz MM, Gale RP, Sondel PM, Goldman JM, Kersey J, Kolb HJ et al. Graft-versus-leukemia reactions after bone marrow transplantation. Blood 1990; 75: 555–562.

    CAS  PubMed  Google Scholar 

  43. Barrett AJ . Mechanisms of the graft-versus-leukemia reaction. Stem Cells 1997; 15: 248–258.

    Article  CAS  Google Scholar 

  44. Yang YG, Qi J, Wang MG, Sykes M . Donor-derived interferon gamma separates graft-versus-leukemia effects and graft-versus-host disease induced by donor CD8 T cells. Blood 2002; 99: 4207–4215.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by a grant from the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (0420130-2). A grant of high-performance cell therapy R&D project (0405-DB01-0104-0006) by the Ministry of Health & Welfare partly supported this work.

Author information

Authors and Affiliations

  1. Catholic Hemapoietic Stem Cell Transplantation Center, St Mary's Hospital, The Catholic University of Korea, Seoul, Korea

    C-K Min, B-G Kim & Bin Cho

  2. Department of Hematology, St Mary's Hospital, The Catholic University of Korea, Seoul, Korea

    C-K Min & B-G Kim

  3. Department of Clinical Pathology, St Mary's Hospital, The Catholic University of Korea, Seoul, Korea

    G Park

  4. Department of Pediatrics, St Mary's Hospital, The Catholic University of Korea, Seoul, Korea

    Bin Cho

  5. High Performance Cell Therapy Center, The Catholic University of Korea, Seoul, Korea

    I-H Oh

Authors
  1. C-K Min
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. B-G Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. G Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bin Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. I-H Oh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C-K Min.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Min, CK., Kim, BG., Park, G. et al. 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, 637–645 (2007). https://doi.org/10.1038/sj.bmt.1705644

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.bmt.1705644

Keywords

This article is cited by

Search

Advanced search

Quick links