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.

  • Letter to the Editor
  • Published:

Sirolimus enhances the effect of apoptotic cell infusion on hematopoietic engraftment and tolerance induction

Leukemia volume 22, pages 1430–1434 (2008)Cite this article

Allogeneic hematopoietic cell transplantation (AHCT) is an efficient and widely used treatment for various hematological diseases. However, the potential benefit of AHCT may be offset by graft-vs-host disease (GvHD) as well as other transplant-related toxicities. The development of the so-called nonmyeloablative or reduced intensity-conditioning regimens (RICR) has widened the indications of AHCT to a broader spectrum of elderly patients usually not candidate for standard myeloablative AHCT and diseases other than acute leukemia.1 However, and despite some initial enthusiasm,1 GvHD remains a matter of concern after RICR AHCT. Moreover, highly immunosuppressive regimens associated with the use of RICR may significantly increase the rate of infectious complications and delay immune reconstitution.2, 3 Alternative approaches to favor engraftment and limit long-term posttransplant immunosuppression are still needed.

Intravenous (i.v.) apoptotic cell infusion can modulate alloreactivity by interacting with particular dendritic cell subsets.4 We have previously established that i.v. apoptotic cell infusion facilitates engraftment—when administrated with allogeneic bone marrow (BM) transplants—without triggering autoimmunity or GvHD.5 This effect relies on a transforming growth factor (TGF)-β-dependent mechanism.5 Furthermore, i.v. apoptotic cell infusion is associated with a CD4+CD25+ regulatory T cell (Treg) increase early after BM transplantation (BMT; days 6 and 8).5 These Tregs expressed high levels of Foxp3 transcripts and exerted a potent ex vivo suppressive activity through a cell-to-cell contact mechanism.5 Nonetheless, such results5 were achieved without administration of immunosuppressive drugs. In human settings, immunosuppressive treatments are mandatory, at least during the early phase of AHCT, until tolerance is fully established. Since immunosuppressive drugs are capable of interfering with long-term tolerance induction,6 we investigated whether the widely used immunosuppressive drugs (cyclosporin A, CsA; mycophenolate mofetil, MMF or sirolimus, SRL) can modulate the effect of apoptotic cells coadministered with a hematopoietic graft in a murine BMT model.

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

Relevant articles

Open Access articles citing this article.

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

References

  1. Mohty M, Nagler A, Killmann NM . Reduced-intensity conditioning allogeneic stem cell transplantation: hype, reality or time for a rethink? Leukemia 2006; 20: 1653–1654.

    Article  CAS  PubMed  Google Scholar 

  2. Maris M, Boeckh M, Storer B, Dawson M, White K, Keng M et al. Immunologic recovery after hematopoietic cell transplantation with nonmyeloablative conditioning. Exp Hematol 2003; 31: 941–952.

    Article  CAS  PubMed  Google Scholar 

  3. Maris MB, Niederwieser D, Sandmaier BM, Storer B, Stuart M, Maloney D et al. HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative conditioning for patients with hematologic malignancies. Blood 2003; 102: 2021–2030.

    Article  CAS  PubMed  Google Scholar 

  4. Morelli AE . The immune regulatory effect of apoptotic cells and exosomes on dendritic cells: its impact on transplantation. Am J Transplant 2006; 6: 254–261.

    Article  CAS  PubMed  Google Scholar 

  5. Kleinclauss F, Perruche S, Masson E, de Carvalho Bittencourt M, Biichle S, Remy-Martin JP et al. Intravenous apoptotic spleen cell infusion induces a TGF-beta-dependent regulatory T-cell expansion. Cell Death Differ 2006; 13: 41–52.

    Article  CAS  PubMed  Google Scholar 

  6. Blaha P, Bigenzahn S, Koporc Z, Schmid M, Langer F, Selzer E et al. The influence of immunosuppressive drugs on tolerance induction through bone marrow transplantation with costimulation blockade. Blood 2003; 101: 2886–2893.

    Article  CAS  PubMed  Google Scholar 

  7. Zeiser R, Nguyen VH, Beilhack A, Buess M, Schulz S, Baker J et al. Inhibition of CD4+CD25+ regulatory T-cell function by calcineurin-dependent interleukin-2 production. Blood 2006; 108: 390–399.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N et al. Conversion of peripheral CD4+CD25− naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med 2003; 198: 1875–1886.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Dvorak CC, Callard E, Agarwal R . Use of intravenous mycophenolate mofetil for graft-versus-host disease prophylaxis in an allogeneic hematopoietic stem cell transplant recipient with an allergic reaction to cyclosporin and tacrolimus. Bone Marrow Transplant 2006; 38: 253–254.

    Article  CAS  PubMed  Google Scholar 

  10. Cutler C, Henry NL, Magee C, Li S, Kim HT, Alyea E et al. Sirolimus and thrombotic microangiopathy after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2005; 11: 551–557.

    Article  CAS  PubMed  Google Scholar 

  11. Plumas J, Manches O, Chaperot L . Mechanisms of action of extracorporeal photochemotherapy in the control of GVHD: involvement of dendritic cells. Leukemia 2003; 17: 2061–2062.

    Article  CAS  PubMed  Google Scholar 

  12. Maeda A, Schwarz A, Kernebeck K, Gross N, Aragane Y, Peritt D et al. Intravenous infusion of syngeneic apoptotic cells by photopheresis induces antigen-specific regulatory T cells. J Immunol 2005; 174: 5968–5976.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank C Ferniot and D Paris for their expertise in animal care and management, and B Gaugler for critical reading of the manuscript. This study is supported by grants from the Association de Langue Française pour l'Etude du Diabète et des Maladies Métaboliques (ALFEDIAM to FK), the Association pour la Recherche sur le Cancer (no. 3851 to PS), the Association Recherche et Transfusion (to PS), the Comité Départemental de la Ligue contre le Cancer du Jura et du Doubs—Comité de Besançon and the Etablissement Français du Sang (no. 2004-10 to PS). FB receives financial support from INSERM and the Conseil Régional de Franche-Comté. SP receives financial support from INCa (no. PL098 to PS).

Author information

Author notes

  1. F Bonnefoy and E Masson: Both the authors contributed equally to this work.

  2. P Saas and F Kleinclauss: Equal contribution as senior authors.

Authors and Affiliations

  1. INSERM, UMR645, Besançon, France

    F Bonnefoy, E Masson, S Perruche, A Marandin, C Borg, A Radlovic, P Tiberghien, P Saas & F Kleinclauss

  2. University of Franche-Comté, IFR133, Besançon, France

    F Bonnefoy, E Masson, S Perruche, A Marandin, C Borg, A Radlovic, P Tiberghien, P Saas & F Kleinclauss

  3. EFS, Bourgogne Franche-Comté, Besançon, France

    F Bonnefoy, E Masson, S Perruche, A Marandin, C Borg, A Radlovic, P Tiberghien & P Saas

  4. CHU Besançon, Service d'Oncologie, Hôpital Jean Minjoz, Besançon, France

    C Borg

  5. CHU Besançon, Service de Radiothérapie, Hôpital Jean Minjoz, Besançon, France

    B Shipman

  6. CHU Besançon, Service d'Urologie, Hôpital St Jacques, Besançon, France

    F Kleinclauss

Authors
  1. F Bonnefoy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E Masson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S Perruche
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Marandin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C Borg
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A Radlovic
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. B Shipman
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. P Tiberghien
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. P Saas
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. F Kleinclauss
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P Saas.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bonnefoy, F., Masson, E., Perruche, S. et al. Sirolimus enhances the effect of apoptotic cell infusion on hematopoietic engraftment and tolerance induction. Leukemia 22, 1430–1434 (2008). https://doi.org/10.1038/sj.leu.2405061

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2405061

This article is cited by

Search

Advanced search

Quick links