International Journal of Hematology

, Volume 80, Issue 4, pp 370–376 | Cite as

Cotransplantation of Marrow Stromal Cells May Prevent Lethal Graft-versus-Host Disease in Major Histocompatibility Complex Mismatched Murine Hematopoietic Stem Cell Transplantation

  • Nak Gyun Chung
  • Dae Chul Jeong
  • Soo Jeong Park
  • Byung Ock Choi
  • Bin Cho
  • Hack Ki Kim
  • Chung Sik Chun
  • Jong Ho Won
  • Chi Wha Han


Marrow stromal cells (MSC) produce a microenvironment supporting hematopoiesis and may contribute immune tolerance because of low immunogenicity and the suppressive effect of alloreactivity. We investigated whether cotransplantation of MSC could prevent lethal graft-versus-host disease (GVHD) in major histocompatibility complex mismatched allogeneic murine hematopoietic stem cell transplantation (HSCT) using female BALB/c (H-2d, recipient) and C3H/He (H-2k, donor) mice. MSC were obtained from C3H/He bone marrow cells (BMC). MSC and irradiated BALB/c splenocytes (SP) were cocultured with C3H/He SP or BMC. Nonirradiated MSC did not inhibit the proliferation of alloantigen-stimulated BMC and SP. However, irradiated MSC suppressed the proliferation of alloantigen-stimulated SP at a level comparable with that of immunosuppressive agents, and the suppression by MSC was reversed to a significant degree by interleukin 2. Lethally irradiated BALB/c mice received transplants of donor cells according to the following experimental groups (group A, BMC only; group B, BMC and SP; group C, BMC, SP, and MSC; group D, BMC and MSC). The survival rate in group D was higher than in the other groups (P =.0057), and the clinical GVHD scores and serum levels of interferon-γ were low in group D. Our results suggest that cotransplantation of MSC in HSCT prevents lethal GVHD, possibly by immune modulation.

Key words

Marrow stromal cell Allogeneic hematopoietic stem cell transplantation Cell proliferation assay Interferon-γ 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Martin PJ, Hansen JA, Storb R,Thomas ED. Human marrow transplantation: an immunological perspective. Adv Immunol. 1987;40:379–438.CrossRefGoogle Scholar
  2. 2.
    Beatty PG, Hansen JA, Longton GM, et al. Marrow transplantation from HLA-matched unrelated donors for treatment of hematologic malignancies. Transplantation. 1991;51:443–447.CrossRefGoogle Scholar
  3. 3.
    Ikehara S. A new concept of stem cell disorders and their new therapy. J Hematother Stem Cell Res. 2003;12:643–653.CrossRefGoogle Scholar
  4. 4.
    Starzl TE, Murase N, Thomson AW, Trucco M, Rao A. Immunity and tolerance are related, and governed by antigen migration and localization. Transplant Proc. 1999;31:1406–1411.CrossRefPubMedCentralPubMedGoogle Scholar
  5. 5.
    Nikolic B, Sykes M. Bone marrow chimerism and transplantation tolerance. Curr Opin Immunol. 1997;9:634–640.CrossRefGoogle Scholar
  6. 6.
    Prockop DJ. Marrow stromal cells as stem cells for nonhematopoietic tissues. Science. 1997;276:71–74.CrossRefGoogle Scholar
  7. 7.
    Almeida-Porada G, Flake AW, Glimp HA, Zanjani ED. Cotrans- plantation of stroma results in enhancement of engraftment and early expression of donor hematopoietic stem cells in utero. Exp Hematol. 1999;27:1569–1575.CrossRefGoogle Scholar
  8. 8.
    Majumdar MK, Thiede MA, Mosca JD, Moorman M, Gerson SL. Phenotypic and functional comparison of cultures of marrow- derived mesenchymal stem cell (MSCs) and stromal cells. J Cell Physiol. 1998;176:57–66.CrossRefGoogle Scholar
  9. 9.
    Noveli EM, Buyaner D, Chopra RK, et al. Human mesenchymal stem cells can enhance human CD34+ cell repopulating of NOD/ SCID mice [abstract]. Blood. 1998;92:117a.Google Scholar
  10. 10.
    Peled A, Petit I, Kollet O, et al. Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4. Science. 1999;283:845–848.CrossRefPubMedCentralGoogle Scholar
  11. 11.
    Horwitz EM, Gordon PL, Koo WK, et al. Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: implications for cell therapy of bone. Proc Natl Acad Sci USA. 2002;99:8932–8937.CrossRefPubMedCentralGoogle Scholar
  12. 12.
    Pereira RF, Halford KW, O’Hara MD, et al. Cultured adherent cells from marrow can serve as long-lasting precursor cells for bone, cartilage, and lung in irradiated mice. Proc Natl Acad Sci USA.1995;92:4857–4861.CrossRefPubMedCentralPubMedGoogle Scholar
  13. 13.
    Di Nicola M, Carlo-Stella C, Magni M, et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood. 2002;99:3838–3843.CrossRefGoogle Scholar
  14. 14.
    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.CrossRefGoogle Scholar
  15. 15.
    Jeong DC, Han CW, Jin JY, et al. Effectiveness of rotor off fraction in allogeneic murine bone marrow transplantation with complete disparity of major histocompatibility. Exp Hematol. 1999;27:1219–1225.CrossRefGoogle Scholar
  16. 16.
    Cooke KR, Kobzik L, Martin TR, 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.PubMedGoogle Scholar
  17. 17.
    Krampera M, Glennie S, Dyson J, 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.CrossRefGoogle Scholar
  18. 18.
    Tse WT, Pendleton JD, Beyer WM, Egalka MC, Guinan EC. Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation. Transplantation. 2003;75:389–397.CrossRefGoogle Scholar
  19. 19.
    Le Blanc K,Tammik L, Sundberg B, Haynesworth SE, Ringdén 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.CrossRefGoogle Scholar
  20. 20.
    Fan TX, Hisha H, Jin TN, et al. Successful allogeneic bone marrow transplantation (BMT) by injection of bone marrow cells via portal vein: stromal cells as BMT-facilitating cells. Stem Cells. 2001;19:144–150.CrossRefGoogle Scholar
  21. 21.
    Gurevitch O, Prigozhina TB, Pugatsch T, Slavin S. Transplantation of allogeneic or xenogeneic bone marrow within the donor stromal microenvironment. Transplantation. 1999;68:1362–1368.CrossRefGoogle Scholar
  22. 22.
    Meisel R, Zibert A, Laryea M, et al. Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxy- genase-mediated tryptophan degradation. Blood. 2004;103:4619–4621.CrossRefGoogle Scholar
  23. 23.
    Goker H, Haznedaroglu IC, Chao NJ. Acute graft-vs-host disease: pathobiology and management. Exp Hematol. 2001;29:259–277.CrossRefGoogle Scholar
  24. 24.
    Lazarus H, Curtin P, Devine S, et al. Role of mesenchymal stem cells (MSC) in allogeneic transplantation: early phase I clinical results [abstract]. Blood. 1998;96:392a.Google Scholar
  25. 25.
    Frassoni F, Labopin M, Bacigalupo A, et al. Expanded mesenchymal stem cells (MSC), co-infused with HLA identical hemopoietic stem cell transplants, reduce acute and chronic graft-versus-host disease: a matched pair analysis [abstract]. Bone Marrow Transplant. 2002;29:S2.Google Scholar
  26. 26.
    Le Blanc K, Rasmusson I, Sundberg B, et al. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet. 2004;363:1439–1441.CrossRefGoogle Scholar
  27. 27.
    Imamura M, Hashino S, Kobayashi H, et al. Serum cytokine levels in bone marrow transplantation: synergistic interaction of interleukin-6, interferon-gamma, and tumor necrosis factor-alpha in graft-versus-host disease. Bone Marrow Transplant. 1994;13:745–751.PubMedGoogle Scholar
  28. 28.
    Ferrara JL, Cooke KR, Pan L, Krenger W. The immunopathophysiology of acute graft-versus-host-disease. Stem Cells. 1996;14:473–489.CrossRefGoogle Scholar
  29. 29.
    van der Meer A, Wissink WM, Schattenberg AV, Joosten I. Interferon-γ- based mixed lymphocyte culture as a selection tool for allogeneic bone marrow donors other than identical siblings. Br J Haematol. 1999;105:340–348.CrossRefGoogle Scholar
  30. 30.
    Djouad F, Plence P, Bony C, et al. Immunosuppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals. Blood. 2003;102:3837–3844.CrossRefGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2004

Authors and Affiliations

  • Nak Gyun Chung
    • 1
  • Dae Chul Jeong
    • 1
  • Soo Jeong Park
    • 2
  • Byung Ock Choi
    • 3
  • Bin Cho
    • 1
  • Hack Ki Kim
    • 1
  • Chung Sik Chun
    • 1
  • Jong Ho Won
    • 4
  • Chi Wha Han
    • 2
  1. 1.Department of PediatricsOur Lady of Mercy HospitalInchonRepublic of Korea
  2. 2.Internal MedicineThe Catholic University of Korea College of MedicineKorea
  3. 3.Radiation OncologyThe Catholic University of Korea College of MedicineKorea
  4. 4.Department of Internal MedicineSoonchunhyang University Medical CollegeSeoulKorea

Personalised recommendations