Skip to main content
SpringerLink
Log in

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

  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Martin PJ, Hansen JA, Storb R,Thomas ED. Human marrow transplantation: an immunological perspective. Adv Immunol. 1987;40:379–438.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  3. Ikehara S. A new concept of stem cell disorders and their new therapy. J Hematother Stem Cell Res. 2003;12:643–653.

    Article  Google Scholar 

  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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Nikolic B, Sykes M. Bone marrow chimerism and transplantation tolerance. Curr Opin Immunol. 1997;9:634–640.

    Article  CAS  Google Scholar 

  6. Prockop DJ. Marrow stromal cells as stem cells for nonhematopoietic tissues. Science. 1997;276:71–74.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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. 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.

    Article  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  23. Goker H, Haznedaroglu IC, Chao NJ. Acute graft-vs-host disease: pathobiology and management. Exp Hematol. 2001;29:259–277.

    Article  CAS  Google Scholar 

  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. 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. 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.

    Article  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  28. Ferrara JL, Cooke KR, Pan L, Krenger W. The immunopathophysiology of acute graft-versus-host-disease. Stem Cells. 1996;14:473–489.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pediatrics, Our Lady of Mercy Hospital, #665, Pupyung-6-Dong, Pupyung Gu, 403-720, Inchon, Republic of Korea

    Nak Gyun Chung, Dae Chul Jeong, Bin Cho, Hack Ki Kim & Chung Sik Chun

  2. Internal Medicine, The Catholic University of Korea College of Medicine, Korea

    Soo Jeong Park & Chi Wha Han

  3. Radiation Oncology, The Catholic University of Korea College of Medicine, Korea

    Byung Ock Choi

  4. Department of Internal Medicine, Soonchunhyang University Medical College, Seoul, Korea

    Jong Ho Won

Authors
  1. Nak Gyun Chung
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dae Chul Jeong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Soo Jeong Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Byung Ock Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bin Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hack Ki Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Chung Sik Chun
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jong Ho Won
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Chi Wha Han
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dae Chul Jeong.

About this article

Cite this article

Chung, N.G., Jeong, D.C., Park, S.J. 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 80, 370–376 (2004). https://doi.org/10.1532/IJH97.A30409

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1532/IJH97.A30409

Key words

Search

Navigation