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:

Graft-versus-host Disease

Novel mechanism of rapamycin in GVHD: increase in interstitial regulatory T cells

Bone Marrow Transplantation volume 45, pages 379–384 (2010)Cite this article

Abstract

Rapamycin (RAPA) is an immunosuppressive drug that prevents and treats graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplant (HCT). One possible mechanism for its efficacy is induction of tolerance, through increased number or enhanced survival of regulatory T cells. In our experiments, B10.D2 BM and splenocytes were injected into lethally irradiated BALB/cJ recipients. The mice received i.p. injections of either RAPA or vehicle control on days 1–28. There was a significant survival advantage in RAPA-treated mice. Evaluation of the skin biopsies showed a dense cellular infiltrate in RAPA-treated mice. Further characterization of these cells revealed a higher percentage of regulatory T cells characterized by FoxP3-positive cells in high-dose RAPA-treated mice as compared with controls on day 30. This effect appears to be dose dependent. When peripheral blood analysis for FoxP3-positive cells was performed, there was no significant difference observed in the RAPA-treated mice as compared with control mice. These data show a novel mechanism of rapamycin in GVHD, accumulation of regulatory T cells in the GVHD target tissue: the skin.

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

Similar content being viewed by others

References

  1. Blazar BR, Taylor PA, Panoskaltsis-Mortari A, Vallera DA . Rapamycin Inhibits the Generation of Graft-Versus-Host Disease- and Graft-Versus-Leukemia-Causing T Cells by Interfering with the Production of Th1 or Th1 Cytotoxic Cytokines. J Immunol 1998; 160: 5355–5365.

    CAS  PubMed  Google Scholar 

  2. Couriel DR, Saliba R, Escalon MP, Hsu Y, Ghosh S, Ippoliti C et al. Sirolimus in combination with tacrolimus and corticosteroids for the treatment of resistant chronic graft-versus-host disease. Br J Haematol 2005; 130: 409–417.

    Article  CAS  PubMed  Google Scholar 

  3. Antin JH, Cutler C . Sirolimus for GVHD prophylaxis in allogeneic stem cell transplantation. Bone Marrow Transplantation 2004; 34: 471–476.

    Article  PubMed  Google Scholar 

  4. Chen BJ, Morris R, Chao NJ . Graft-Versus-Host Disease Prevention by Rapamycin: Cellular Mechanisms. Biol Blood Marrow Transplant 2000; 6: 529–536.

    Article  CAS  PubMed  Google Scholar 

  5. Noris M, Casiraghi F, Todeschini M, Cravedi P, Cugini D, Monteferrante G et al. Regulatory T cells and T cell depletion: role of immunosuppressive drugs. J Am Soc Nephrol 2007; 18: 1007–1018.

    Article  CAS  PubMed  Google Scholar 

  6. Antin JH, Kim HT, Cutler C, Ho VT, Lee SJ, Miklos DB et al. Sirolimus, tacrolimus, and low-dose methotrexate for graft-versus-host disease prophylaxis in mismatched related donor or unrelated donor transplantation. Blood 2003; 102: 1601–1605.

    Article  CAS  PubMed  Google Scholar 

  7. Cutler C, Li S, Ho VT, Koreth J, Alyea E, Soiffer RJ et al. Extended follow-up of methotrexate-free immunosuppression using sirolimus and tacrolimus in related and unrelated donor peripheral blood stem cell transplantation. Blood 2007; 109: 3108–3114.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Valmori D, Tosello V, Souleimanian NE, Godefroy E, Scotto L, Wang Y et al. Rapamycin-mediated enrichment of T cells with regulatory activity in stimulated CD4+ T cell cultures is not due to the selective expansion of naturally occurring regulatory T cells but to the induction of regulatory functions in conventional CD4+ T cells. J Immunol 2006; 177: 944–949.

    Article  CAS  PubMed  Google Scholar 

  9. Powell JD, Lerner CG, Schwartz RH . Inhibition of cell cycle progression by rapamycin induces T cell clonal anergy even in the presence of costimulation. J Immunol 1999; 162: 2775–2784.

    CAS  PubMed  Google Scholar 

  10. Turnquist HR, Raimondi G, Zahorchak AF, Fischer RT, Wang Z, Thomson AW . Rapamycin-conditioned dendritic cells are poor stimulators of allogeneic CD4+ T cells, but enrich for antigen-specific foxp3+ T regulatory cells and promote organ transplant tolerance. J Immunol 2007; 178: 7018–7031.

    Article  CAS  PubMed  Google Scholar 

  11. Battaglia M, Stabilini A, Roncarolo M-G . Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells. Blood 2005; 105: 4743–4748.

    Article  CAS  PubMed  Google Scholar 

  12. Battaglia M, Stabilini A, Migliavacca B, Horejs-Hoeck J, Kaupper T, Roncarolo M-G . Rapamycin promotes expansion of functional CD4+CD25+FOXP3+ regulatory T cells of Both Healthy Subjects and Type 1 Diabetic Patients. J Immunol 2006; 177: 8338–8347.

    Article  CAS  PubMed  Google Scholar 

  13. Zeiser R, Leveson-Gower DB, Zambricki EA, Kambham N, Beilhack A, Loh J et al. Differential impact of mammalian target of rapamycin inhibition on CD4+CD25+Foxp3+ regulatory T cells compared with conventional CD4+ T cells. Blood 2008; 111: 453–462.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Strauss L, Whiteside TL, Knights A, Bergmann C, Knuth A, Zippelius A . Selective survival of naturally occurring human CD4+CD25+Foxp3+ regulatory T cells cultured with rapamycin. J Immunol 2007; 178: 320–329.

    Article  CAS  PubMed  Google Scholar 

  15. Ermann J, Hoffmann P, Edinger M, Dutt S, Blankenberg FG, Higgins JP et al. Only the CD62 L+ subpopulation of CD4+CD25+ regulatory T cells protects from lethal acute GVHD. Blood 2005; 105: 2220–2226.

    Article  CAS  PubMed  Google Scholar 

  16. Wysocki CA, Jiang Q, Panoskaltsis-Mortari A, Taylor PA, McKinnon KP, Su L et al. Critical role for CCR5 in the function of donor CD4+CD25+ regulatory T cells during acute graft-versus-host disease. Blood 2005; 107: 3300–3307.

    Article  Google Scholar 

  17. Hoffmann P, Ermann J, Edinger M, Fathman CG, Strober S . Donor-type CD4+CD25+ Regulatory T Cells Suppress Lethal Acute Graft-Versus-Host Disease after Allogeneic Bone Marrow Transplantation. J Exp Med 2002; 196: 389–399.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Rieger K, Loddenkemper C, Maul J, Fietz T, Wolff D, Terpe H et al. Mucosal FOXP3+ regulatory T cells are numerically deficient in acute and chronic GvHD. Blood 2006; 107: 1717–1723.

    Article  CAS  PubMed  Google Scholar 

  19. Nguyen VH, Zeiser R, Negrin RS . Role of naturally arising regulatory T cells in hematopoietic cell transplantation. Biol Blood Marrow Transplant 2006; 12: 995–1009.

    Article  CAS  PubMed  Google Scholar 

  20. Schneider M, Munder M, Karakhanova S, Ho AD, Goerner M . The initial phase of graft-versus-host disease is associated with a decrease of CD4+CD25+ regulatory T cells in the peripheral blood of patients after allogeneic stem cell transplantation. Clin Lab Hematol 2006; 28: 382–390.

    Article  CAS  Google Scholar 

  21. Nakamura T, Shima T, Saeki A, Hidaka T, Nakashima A, Takikawa O et al. Expression of indoleamine 2, 3-dioxygenase and the recruitment of Foxp3-expressing regulatory T cells in the development and progression of uterine cervical cancer. Cancer Sci 2007; 98: 874–881.

    Article  CAS  PubMed  Google Scholar 

  22. Bamias G, Okazawa A, Rivera-Nieves J, Arseneau KO, De La Rue SA, Pizarro TT et al. Commensal bacteria exacerbate intestinal inflammation but are not essential for the development of murine ileitis. J Immunol 2007; 178: 1809–1818.

    Article  CAS  PubMed  Google Scholar 

  23. Keever-Taylor CA, Browning M, Johnson B, Truitt R, Bredeson C, Behn B et al. Rapamycin enriches for CD4(+) CD25(+) CD27(+) Foxp3(+) regulatory T cells in ex vivo-expanded CD25-enriched products from healthy donors and patients with multiple sclerosis. Cytotherapy 2007; 9: 144–157.

    Article  CAS  PubMed  Google Scholar 

  24. 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 

  25. Hackstein H, Taner T, Zahorchak AF, Morelli AE, Logar AJ, Gessner A et al. Rapamycin inhibits IL-4—induced dendritic cell maturation in vitro and dendritic cell mobilization and function in vivo. Blood 2003; 101: 4457–4463.

    Article  CAS  PubMed  Google Scholar 

  26. Hackstein H, Taner T, Logar AJ, Thomson AW . Rapamycin inhibits macropinocytosis and mannose receptor-mediated endocytosis by bone marrow-derived dendritic cells. Blood 2002; 100: 1084–1087.

    Article  CAS  PubMed  Google Scholar 

  27. Woltman AM, van der Kooij SW, Coffer PJ, Offringa R, Daha MR, van Kooten C . Rapamycin specifically interferes with GM-CSF signaling in human dendritic cells, leading to apoptosis via increased p27KIP1 expression. Blood 2003; 101: 1439–1445.

    Article  CAS  PubMed  Google Scholar 

  28. Nguyen VH, Zeiser R, daSilva DL, Chang DS, Beilhack A, Contag CH et al. In vivo dynamics of regulatory T-cell trafficking and survival predict effective strategies to control graft-versus-host disease following allogeneic transplantation. Blood 2007; 109: 2649–2656.

    Article  CAS  PubMed  Google Scholar 

  29. Kang SG, Lim HW, Andrisani OM, Broxmeyer HE, Kim CH . Vitamin a metabolites induce gut-homing FoxP3+ regulatory T cells. J Immunol 2007; 179: 3724–3733.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Many thanks to Zouwei Su, PhD, for his help in the preparation of the histopathology.

Author information

Authors and Affiliations

  1. Division of Cellular Therapy, BMT Duke University Medical Center, Durham, NC, USA

    J M Palmer, B J Chen, D DeOliveira, N-D Le & N J Chao

Authors
  1. J M Palmer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. B J Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D DeOliveira
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. N-D Le
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. N J Chao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J M Palmer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Palmer, J., Chen, B., DeOliveira, D. et al. Novel mechanism of rapamycin in GVHD: increase in interstitial regulatory T cells. Bone Marrow Transplant 45, 379–384 (2010). https://doi.org/10.1038/bmt.2009.140

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2009.140

Keywords

This article is cited by

Search

Advanced search

Quick links