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:

Conditioning Regimens

Towards a myeloablative regimen with clinical potential: I. Treosulfan conditioning and bone marrow transplantation allow induction of donor-specific tolerance for skin grafts across full MHC barriers

Bone Marrow Transplantation volume 32, pages 15–22 (2003)Cite this article

Summary:

To investigate whether we could create a radiation-free conditioning regimen to induce permanent mixed and multilineage chimerism and donor-specific tolerance, we treated recipient mice with anti-T-cell antibodies, varying and fractionated doses of Treosulfan and fully MHC disparate bone marrow cells. Treosulfan is mainly used in the treatment of ovarian cancer. It is a structural analog of busulfan, but it does not induce severe hepatotoxicity or veno-occlusive disease at or above the maximum tolerated dose, lacks significant nonhematological toxicity and has limited organ toxicity. We report here the successful induction of permanent mixed multilineage chimerism and donor-specific tolerance as was proven by skin transplantation and IFN-γ ELISPOT. In conclusion, because of its lower nonhematological toxicity, compared with other myeloablative regimens (eg irradiation or busulfan admin- istration), Treosulfan could be a better candidate for conditioning to induce donor-specific allograft tolerance.

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. Glover MT, Deeks JJ, Raftery MJ et al. Immunosuppression and risk of non-melanoma skin cancer in renal transplant recipients. Lancet 1997; 349: 398.

    Article  CAS  PubMed  Google Scholar 

  2. Penn I . Occurrence of cancers in immunosuppressed organ transplant recipients. In: Cecka GM, Terosaki PI (eds) Clinical Transplants. Tissue Typing Laboratory, Los Angeles, Califorrnia, USA, 1998; 147–158.

    Google Scholar 

  3. Falkenhain ME, Cosio FG, Sedmak DD . Progressive histologic injury in kidneys from heart and liver transplant recipients receiving cyclosporine. Transplantation 1996; 62: 364–370.

    Article  CAS  PubMed  Google Scholar 

  4. de Vries-van der Zwan, Besseling AC, van der Pol MA et al. Specific tolerance induction and organ transplantation. Leukemia Lymphoma 1998; 31: 131–142.

    Article  Google Scholar 

  5. de Vries-van der Zwan, Besseling AC, de Waal LP et al. Specific tolerance induction and transplantation: a single-day protocol. Blood 1997; 89: 2596–2601.

    Google Scholar 

  6. Sharabi Y, Sachs DH . Mixed chimerism and permanent specific transplantation tolerance induced by a nonlethal preparative regimen. J Exp Med 1989; 169: 493–502.

    Article  CAS  PubMed  Google Scholar 

  7. Wekerle T, Sykes M . Mixed chimerism as an approach for the induction of transplantation tolerance. Transplantation 1999; 68: 459–467.

    Article  CAS  PubMed  Google Scholar 

  8. Jones TR, Ha J, Williams MA et al. The Role of the IL-2 pathway in costimulation blockade-resistant rejection of allografts. J Immunol 2002; 168: 1123–1130.

    Article  CAS  PubMed  Google Scholar 

  9. Maier S, Tertilt C, Chambron N et al. Inhibition of natural killer cells results in acceptance of cardiac allografts in CD28−/− mice. Nat Med 2001; 7: 557–562.

    Article  CAS  PubMed  Google Scholar 

  10. de Vries-van der Zwan, Besseling AC, Kievits F et al. Anti-CD3 treatment facilitates engraftment of full H-2-disparate donor bone marrow cells and subsequent skin allograft tolerance. Transplantation 1994; 58: 610–617.

    Article  Google Scholar 

  11. Hartley JA, O'Hare CC, Baumgart J . DNA alkylation and interstrand cross-linking by treosulfan. Br J Cancer 1999; 79: 264–266.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Scheulen ME, Hilger RA, Oberhoff C et al. Clinical phase I dose escalation and pharmacokinetic study of high-dose chemotherapy with treosulfan and autologous peripheral blood stem cell transplantation in patients with advanced malignancies. Clin Cancer Res 2000; 6: 4209–4216.

    CAS  PubMed  Google Scholar 

  13. Rigos D, Wechsel HW, Bichler KH . Treosulfan in the treatment of metastatic renal cell carcinoma. Anticancer Res 1999; 19: 1549–1552.

    CAS  PubMed  Google Scholar 

  14. Kopf-Maier P, Sass G . Antitumor activity of treosulfan in human lung carcinomas. Cancer Chemother Pharmacol 1996; 37: 211–221.

    Article  CAS  PubMed  Google Scholar 

  15. Gropp M, Meier W, Hepp H . Treosulfan as an effective second-line therapy in ovarian cancer. Gynecol Oncol 1998; 71: 94–98.

    Article  CAS  PubMed  Google Scholar 

  16. Neuber K, Tom DA, Blodorn-Schlicht N et al. Treosulfan is an effective alkylating cytostatic for malignant melanoma in vitro and in vivo. Melanoma Res 1999; 9: 125–132.

    Article  CAS  PubMed  Google Scholar 

  17. Kopf-Maier P, Sass G . Antitumor activity of treosulfan against human breast carcinomas. Cancer Chemother Pharmacol 1992; 31: 103–110.

    Article  CAS  PubMed  Google Scholar 

  18. Fichtner I, Becker M, Baumgart J . Antileukaemic activity of treosulfan in xenografted human acute lymphoblastic leukemias (ALL) Eur J Cancer 2003; 39: 801–807.

    Article  CAS  PubMed  Google Scholar 

  19. Meden H, Wittkop Y, Kuhn W . Maintenance chemotherapy with oral treosulfan following first-line treatment in patients with advanced ovarian cancer: feasibility and toxicity. Anti-cancer Res 1997; 17: 2221–2223.

    CAS  Google Scholar 

  20. Leo O, Foo M, Sachs DH et al. Identification of a monoclonal antibody specific for a murine T3 polypeptide. Proc Natl Acad Sci USA 1987; 84: 1374–1378.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ploemacher RE, van der Sluijs JP, Voerman JS et al. An in vitro limiting-dilution assay of long-term repopulating hematopoietic stem cells in the mouse. Blood 1989; 74: 2755–2763.

    CAS  PubMed  Google Scholar 

  22. Ferran C, Sheehan K, Dy M et al. Cytokine-related syndrome following injection of anti-CD3 monoclonal antibody: further evidence for transient in vivo T cell activation. Eur J Immunol 1990; 20: 509–515.

    Article  CAS  PubMed  Google Scholar 

  23. de Vries-van der Zwan, van der Pol MA, Besseling AC et al. Haematopoietic stem cells can induce specific skin graft acceptance across full MHC barriers. Bone Marrow Transplant 1998; 22: 91–98.

    Article  Google Scholar 

  24. Okada S, Nakauchi H, Nagayoshi K et al. Enrichment and characterization of murine hematopoietic stem cells that express c-kit molecule. Blood 1991; 78: 1706–1712.

    CAS  PubMed  Google Scholar 

  25. Kaufman CL, Colson YL, Wren SM et al. Phenotypic characterization of a novel bone marrow-derived cell that facilitates engraftment of allogeneic bone marrow stem cells. Blood 1994; 84: 2436–2446.

    CAS  PubMed  Google Scholar 

  26. Gandy KL, Domen J, Aguila H et al. CD8+TCR+ and CD8+TCR− cells in whole bone marrow facilitate the engraftment of hematopoietic stem cells across allogeneic barriers. Immunity 1999; 11: 579–590.

    Article  CAS  PubMed  Google Scholar 

  27. Uchida N, Weissman IL . Searching for hematopoietic stem cells: evidence that Thy-1.1lo Lin− Sca-1+ cells are the only stem cells in C57BL/Ka-Thy-1.1 bone marrow. J Exp Med 1992; 175: 175–184.

    Article  CAS  PubMed  Google Scholar 

  28. Gandy KL, Weissman IL . Tolerance of allogeneic heart grafts in mice simultaneously reconstituted with purified allogeneic hematopoietic stem cells. Transplantation 1998; 65: 295–304.

    Article  CAS  PubMed  Google Scholar 

  29. Hashimoto F, Sugiura K, Inoue K et al. Major histocompatibility complex restriction between hematopoietic stem cells and stromal cells in vivo. Blood 1997; 89: 49–54.

    CAS  PubMed  Google Scholar 

  30. Zeiger E, Pagano DA . Mutagenicity of the human carcinogen treosulphan in Salmonella. Environ Mol Mutagen 1989; 13: 343–346.

    Article  CAS  PubMed  Google Scholar 

  31. Westerhof GR, Blokland I, Down JD et al. In vivo and in vitro sensitivity of murine bone marrow hematopoietic progenitors for treosulfan. Blood 1998; 92: 197b.

    Google Scholar 

  32. Westerhof GR, Ploemacher RE, Boudewijn A et al. Comparison of different busulfan analogues for depletion of hematopoietic stem cells and promotion of donor-type chimerism in murine bone marrow transplant recipients. Cancer Res 2000; 60: 5470–5478.

    CAS  PubMed  Google Scholar 

  33. Ploemacher RE, Westerhof GR, Blokland I et al. Treosulfan as an alternative conditioning agent in bone marrow transplantation. Bone Marrow Transplant 2000; 25: abstract no P421.

  34. Adams AB, Durham MM, Kean L et al. Costimulation blockade, busulfan, and bone marrow promote titratable macrochimerism, induce transplantation tolerance, and correct genetic hemoglobinopathies with minimal myelosuppression. J Immunol 2001; 167: 1103–1111.

    Article  CAS  PubMed  Google Scholar 

  35. Leong LY, Qin S, Cobbold SP et al. Classical transplantation tolerance in the adult: the interaction between myeloablation and immunosuppression. Eur J Immunol 1992; 22: 2825–2830.

    Article  CAS  PubMed  Google Scholar 

  36. Tomita Y, Yoshikawa M, Zhang QW et al. Induction of permanent mixed chimerism and skin allograft tolerance across fully MHC-mismatched barriers by the additional myelosuppressive treatments in mice primed with allogeneic spleen cells followed by cyclophosphamide. J Immunol 2000; 165: 34–41.

    Article  CAS  PubMed  Google Scholar 

  37. de Vries-van der Zwan, van der Pol MA, de Waal LP et al. An alternative conditioning regimen for induction of specific skin graft tolerance across full major histocompatibility complex barriers. Transplant Immunol 1998; 6: 147–151.

    Article  Google Scholar 

  38. Beelen DW . Evaluation of safety efficacy and pharmacokinetics of dose-escalated treosulfan (TREO)/cyclophosohamide (CY) conditioning prior to allogeneic transplantation of high-risk leukemia patients. Blood 2002; 100: 415a, absract no. 1608.

    Article  Google Scholar 

  39. Casper J, knauf W, Doelken G et al. Treosulfan and fludarabine as conditioning for allogeneic blood stem cell transplantation-final analysis of a phase I/II study. Onkologie 2002; 54: 93, absract 320.

    Google Scholar 

Download references

Acknowledgements

We thank Sacco Luypen and Mathijs van Eck for assistance in the animal experiments and animal care, and Joachim Baumgart (Medac) for a critical reading of the manuscript. This study was financially supported by the Dutch Kidney Foundation (Grant No. C97.1669).

Author information

Authors and Affiliations

  1. Laboratory for Vaccine Research, National Institute of Public Health and the Environment (RIVM), Bilthoven, The Netherlands

    M van Pel, D W J G van Breugel & C J P Boog

  2. Central Animal Laboratory, National Institute of Public Health and the Environment (RIVM), Bilthoven, The Netherlands

    W Vos

  3. Department of Hematology, Erasmus University, Rotterdam, The Netherlands

    R E Ploemacher

Authors
  1. M van Pel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D W J G van Breugel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. W Vos
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R E Ploemacher
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C J P Boog
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

van Pel, M., van Breugel, D., Vos, W. et al. Towards a myeloablative regimen with clinical potential: I. Treosulfan conditioning and bone marrow transplantation allow induction of donor-specific tolerance for skin grafts across full MHC barriers. Bone Marrow Transplant 32, 15–22 (2003). https://doi.org/10.1038/sj.bmt.1704094

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.bmt.1704094

Keywords

This article is cited by

Search

Advanced search

Quick links