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Post-Transplant Events

Rapamycin, not cyclosporine, permits thymic generation and peripheral preservation of CD4+CD25+FoxP3+ T cells

Bone Marrow Transplantation volume 39, pages 537–545 (2007)Cite this article

Abstract

Graft-versus-host-disease (GVHD) is the most common cause of poor outcome after allogeneic stem cell transplantation (SCT). Of late, exploitation of FOXP3+ regulatory T-cell (TREG) function is emerging as a promising strategy in suppression of GVHD, while preserving graft-versus-leukemia (GVL). Cyclosporine and rapamycin reduce the expansion of effector T cells by blocking interleukin (IL)-2, but signaling by IL-2 is pivotal for TREG homeostasis. The resolution of GVHD is critically dependent on thymus-dependent reconstitution of the immunoregulatory system. Thus, there has been concern about the impact of blocking IL-2 signaling by immunosuppressive agents on TREG homeostasis. Here we demonstrate in a mouse model that in contrast to rapamycin, cyclosporine compromises not only the thymic generation of CD4+CD25+FoxP3+ T cells but also their homeostatic behavior in peripheral immune compartments. Treatment with cyclosporine resulted in a sharp reduction of peripheral CD25+FoxP3+ T cells in all immune compartments studied. Prolonged rapamycin treatment allowed for thymic generation of CD4+FoxP3+ T cells, whereas treatment with cyclosporine led to a reduced generation of these cells. In conclusion, cyclosporine and rapamycin differentially affect homeostasis of CD4+FoxP3+ TREG in vivo. As peripheral tolerance induction is a prerequisite for successful treatment outcome after allogeneic SCT, these findings are of potential clinical relevance.

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References

  1. 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  Google Scholar 

  2. Johnston LJ, Brown J, Shizuru JA, Stockerl-Goldstein KE, Stuart MJ, Blume KG et al. Rapamycin (sirolimus) for treatment of chronic graft-versus-host disease. Biol Blood Marrow Transplant 2005; 11: 47–55.

    Article  CAS  Google Scholar 

  3. 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  Google Scholar 

  4. Edinger M, Hoffmann P, Ermann J, Drago K, Fathman CG, Strober S et al. CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation. Nat Med 2003; 9: 1144–1150.

    Article  CAS  Google Scholar 

  5. Joffre O, van Meerwijk JP . CD4(+)CD25(+) regulatory T lymphocytes in bone marrow transplantation. Semin Immunol 2006; 18: 128–135.

    Article  CAS  Google Scholar 

  6. Cohen JL, Trenado A, Vasey D, Klatzmann D, Salomon BL . CD4(+)CD25(+) immunoregulatory T Cells: new therapeutics for graft-versus-host disease. J Exp Med 2002; 196: 401–406.

    Article  CAS  Google Scholar 

  7. Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY . A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol 2005; 6: 1142–1151.

    Article  CAS  Google Scholar 

  8. D'Cruz LM, Klein L . Development and function of agonist-induced CD25+Foxp3+ regulatory T cells in the absence of interleukin 2 signaling. Nat Immunol 2005; 6: 1152–1159.

    Article  CAS  Google Scholar 

  9. Setoguchi R, Hori S, Takahashi T, Sakaguchi S . Homeostatic maintenance of natural Foxp3(+) CD25(+) CD4(+) regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization. J Exp Med 2005; 201: 723–735.

    Article  CAS  Google Scholar 

  10. Fontenot JD, Gavin MA, Rudensky AY . Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 2003; 4: 330–336.

    Article  CAS  Google Scholar 

  11. Watanabe N, Wang YH, Lee HK, Ito T, Wang YH, Cao W et al. Hassall's corpuscles instruct dendritic cells to induce CD4+CD25+ regulatory T cells in human thymus. Nature 2005; 436: 1181–1185.

    Article  CAS  Google Scholar 

  12. Sakaguchi S, Sakaguchi N . Regulatory T cells in immunologic self-tolerance and autoimmune disease. Int Rev Immunol 2005; 24: 211–226.

    Article  CAS  Google Scholar 

  13. Matsuda S, Koyasu S . Mechanisms of action of cyclosporine. Immunopharmacology 2000; 47: 119–125.

    Article  CAS  Google Scholar 

  14. Bierer BE, Mattila PS, Standaert RF, Herzenberg LA, Burakoff SJ, Crabtree G et al. Two distinct signal transmission pathways in T lymphocytes are inhibited by complexes formed between an immunophilin and either FK506 or rapamycin. Proc Natl Acad Sci USA 1990; 87: 9231–9235.

    Article  CAS  Google Scholar 

  15. Abraham RT, Wiederrecht GJ . Immunopharmacology of rapamycin. Annu Rev Immunol 1996; 14: 483–510.

    Article  CAS  Google Scholar 

  16. Chung J, Kuo CJ, Crabtree GR, Blenis J . Rapamycin-FKBP specifically blocks growth-dependent activation of and signaling by the 70 kd S6 protein kinases. Cell 1992; 69: 1227–1236.

    Article  CAS  Google Scholar 

  17. Corry RJ, Winn HJ, Russell PS . Primarily vascularized allografts of hearts in mice. The role of H-2D, H-2K, and non-H-2 antigens in rejection. Transplantation 1973; 16: 343–350.

    Article  CAS  Google Scholar 

  18. Willerford DM, Chen J, Ferry JA, Davidson L, Ma A, Alt FW . Interleukin-2 receptor alpha chain regulates the size and content of the peripheral lymphoid compartment. Immunity 1995; 3: 521–530.

    Article  CAS  Google Scholar 

  19. Siegel JP, Sharon M, Smith PL, Leonard WJ . The IL-2 receptor beta chain (p70): role in mediating signals for LAK, NK, and proliferative activities. Science 1987; 238: 75–78.

    Article  CAS  Google Scholar 

  20. Homma M, Damoiseaux JG, Breda Vriesman PJ . Differential effects of cyclosporin-A and rapamycin on in vivo thymocyte maturation. Transplant Proc 1997; 29: 1743–1744.

    Article  CAS  Google Scholar 

  21. Hsieh CS, Zheng Y, Liang Y, Fontenot JD, Rudensky AY . An intersection between the self-reactive regulatory and nonregulatory T cell receptor repertoires. Nat Immunol 2006; 7: 401–410.

    Article  CAS  Google Scholar 

  22. Germain RN . T cell development and the CD4-CD8 lineage decision. Nat Rev Immunol 2002; 2: 309–322.

    Article  CAS  Google Scholar 

  23. Sakaguchi S . Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 2004; 22: 531–562.

    Article  CAS  Google Scholar 

  24. Fisson S, Darrasse-Jeze G, Litvinova E, Septier F, Klatzmann D, Liblau R et al. Continuous activation of autoreactive CD4+ CD25+ regulatory T cells in the steady state. J Exp Med 2003; 198: 737–746.

    Article  CAS  Google Scholar 

  25. Damoiseaux JG, Beijleveld LJ, Breda Vriesman PJ . Multiple effects of cyclosporin A on the thymus in relation to T cell development and autoimmunity. Clin Immunol Immunopathol 1997; 82: 197–202.

    Article  CAS  Google Scholar 

  26. Fontenot JD, Rudensky AY . A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3. Nat Immunol 2005; 6: 331–337.

    Article  CAS  Google Scholar 

  27. Koonpaew S, Shen S, Flowers L, Zhang W . LAT-mediated signaling in CD4+CD25+ regulatory T cell development. J Exp Med 2006; 203: 119–129.

    Article  CAS  Google Scholar 

  28. Fontenot JD, Dooley JL, Farr AG, Rudensky AY . Developmental regulation of Foxp3 expression during ontogeny. J Exp Med 2005; 202: 901–906.

    Article  CAS  Google Scholar 

  29. Mantel PY, Ouaked N, Ruckert B, Karagiannidis C, Welz R, Blaser K et al. Molecular mechanisms underlying FOXP3 induction in human T cells. J Immunol 2006; 176: 3593–3602.

    Article  CAS  Google Scholar 

  30. Damoiseaux JG, Defresne MP, Reutelingsperger CP, Breda Vriesman PJ . Cyclosporin-A differentially affects apoptosis during in vivo rat thymocyte maturation. Scand J Immunol 2002; 56: 353–360.

    Article  CAS  Google Scholar 

  31. Zorn E, Kim HT, Lee SJ, Floyd BH, Litsa D, Arumugarajah S et al. Reduced frequency of FOXP3+ CD4+CD25+ regulatory T cells in patients with chronic graft-versus-host disease. Blood 2005; 106: 2903–2911.

    Article  CAS  Google Scholar 

  32. Bensinger SJ, Walsh PT, Zhang J, Carroll M, Parsons R, Rathmell JC et al. Distinct IL-2 receptor signaling pattern in CD4+CD25+ regulatory T cells. J Immunol 2004; 172: 5287–5296.

    Article  CAS  Google Scholar 

  33. Damoiseaux JG, Breda Vriesman PJ . Cyclosporin A-induced autoimmunity: the result of defective de novo T cell development. Folia Biol (Praha) 1998; 44: 1–9.

    CAS  Google Scholar 

  34. Wu DY, Goldschneider I . Cyclosporin A-induced autologous graft-versus-host disease: a prototypical model of autoimmunity and active (dominant) tolerance coordinately induced by recent thymic emigrants. J Immunol 1999; 162: 6926–6933.

    CAS  PubMed  Google Scholar 

  35. Li Y, Li XC, Zheng XX, Wells AD, Turka LA, Strom TB . Blocking both signal 1 and signal 2 of T cell activation prevents apoptosis of alloreactive T cells and induction of peripheral allograft tolerance. Nat Med 1999; 5: 1298–1302.

    Article  CAS  Google Scholar 

  36. 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  Google Scholar 

  37. Smiley ST, Csizmadia V, Gao W, Turka LA, Hancock WW . Differential effects of cyclosporine A, methylprednisolone, mycophenolate, and rapamycin on CD154 induction and requirement for NFkappaB: implications for tolerance induction. Transplantation 2000; 70: 415–419.

    Article  CAS  Google Scholar 

  38. Sakaguchi S, Sakaguchi N . Organ-specific autoimmune disease induced in mice by elimination of T cell subsets. V. Neonatal administration of cyclosporin A causes autoimmune disease. J Immunol 1989; 142: 471–480.

    CAS  PubMed  Google Scholar 

  39. Zeiser RS, 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  Google Scholar 

  40. Wu DY, Goldschneider I . Tolerance to cyclosporin A-induced autologous graft-versus-host disease is mediated by a CD4+CD25+ subset of recent thymic emigrants. J Immunol 2001; 166: 7158–7164.

    Article  CAS  Google Scholar 

  41. Zheng XX, Sanchez-Fueyo A, Domenig C, Strom TB . The balance of deletion and regulation in allograft tolerance. Immunol Rev 2003; 196: 75–84.

    Article  CAS  Google Scholar 

  42. Rezvani K, Mielke S, Ahmadzadeh M, Kilical Y, Savani BN, Zeilah J et al. High donor FOXP3-positive regulatory T cell (Treg) content is associated with a low risk of GVHD following HLA-matched allogeneic SCT. Blood 2006; 108: 1291–1297.

    Article  CAS  Google Scholar 

  43. Miura Y, Thoburn CJ, Bright EC, Phelps ML, Shin T, Matsui EC et al. Association of Foxp3 regulatory gene expression with graft-versus-host disease. Blood 2004; 104: 2187–2193.

    Article  CAS  Google Scholar 

  44. 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  Google Scholar 

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Acknowledgements

We acknowledge Dr AV Schattenberg for careful reading of the manuscript. This study was in part supported by the Dutch Kidney Foundation (Grant C02.2004).

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Author notes

  1. L B Hilbrands and I Joosten: These authors share senior authorship.

Authors and Affiliations

  1. Department of Bloodtransfusion and Transplantation Immunology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

    J J A Coenen, H J P M Koenen, E van Rijssen & I Joosten

  2. Department of Nephrology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

    J J A Coenen & L B Hilbrands

  3. Laboratory of Experimental Immunology, Catholic University of Leuven, Leuven, Belgium

    A Kasran

  4. Bioceros, Yalelaan 46, Utrecht, The Netherlands

    L Boon

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  1. J J A Coenen
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Correspondence to I Joosten.

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Coenen, J., Koenen, H., van Rijssen, E. et al. Rapamycin, not cyclosporine, permits thymic generation and peripheral preservation of CD4+CD25+FoxP3+ T cells. Bone Marrow Transplant 39, 537–545 (2007). https://doi.org/10.1038/sj.bmt.1705628

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