Skip to main content
SpringerLink
Log in

Acute but not chronic graft-versus-host disease is associated with a reduction of circulating CD4+CD25highCD127low/− regulatory T cells

  • Original Article
  • Published:
Annals of Hematology Aims and scope Submit manuscript

Abstract

Defects in central and peripheral tolerance are thought to contribute to life-threatening graft-versus-host disease (GvHD), a severe complication following allogeneic stem cell transplantation (SCT). Recent investigations have demonstrated regulatory T cells (Tregs) to suppress allogeneic immune reactions. Therefore, SCT patients with no or critically low numbers of Tregs may have an increased risk of GvHD. To address this hypothesis, we analyzed the recovery of CD4+CD25highCD127low/− Tregs in the peripheral blood of patients who have never developed GvHD (n = 6), patients who developed acute/chronic GvHD (n = 18), and patients who developed chronic GvHD without an earlier acute manifestation (n = 5) every 30 days for the first 6 months after peripheral blood SCT (PBSCT). The number of Tregs continuously improved in acute/chronic GvHD patients, but always remained lower than Tregs quantified in patients who never developed a GvHD. In contrast, chronic GvHD patients who did not develop acute GvHD earlier displayed significantly increased Treg cell numbers at the timepoint of chronic inflammation. These results indicate that numerically deficient Tregs following PBSCT are associated with the development of acute but not chronic GvHD.

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

Fig. 1

Similar content being viewed by others

References

  1. Przepiorka D, Anderlini P, Saliba R, Cleary K, Mehra R, Khouri I, Huh YO, Giralt S, Braunschweig I, van Besien K, Champlin R (2001) Chronic graft-versus-host disease after allogeneic blood stem cell transplantation. Blood 98:1695–1700

    Article  CAS  PubMed  Google Scholar 

  2. Przepiorka D, Smith TL, Folloder J, Khouri I, Ueno NT, Mehra R, Korbling M, Huh YO, Giralt S, Gajewski J, Donato M, Cleary K, Claxton D, Braunschweig I, van Besien K, Andersson BS, Anderlini P, Champlin R (1999) Risk factors for acute graft-versus-host disease after allogeneic blood stem cell transplantation. Blood 94:1465–1470

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  5. Hoffmann P, Ermann J, Edinger M, Fathman CG, Strober S (2002) Donor-type CD4(+)CD25(+) regulatory T cells suppress lethal acute graft-versus-host disease after allogeneic bone marrow transplantation. J Exp Med 196:389–399

    Article  CAS  PubMed  Google Scholar 

  6. Taylor PA, Lees CJ, Blazar BR (2002) The infusion of ex vivo activated and expanded CD4(+)CD25(+) immune regulatory cells inhibits graft-versus-host disease lethality. Blood 99:3493–3499

    Article  CAS  PubMed  Google Scholar 

  7. di Ianni M, Falzetti F, Carotti A, Matelli F (2009) Adoptive immunotherapy with tregs prevents GvHD and favours immune reconstitution after HLA haploidentical transplants for hematological malignancies. ASH Annual Meeting Abstracts. Blood 114 (4)

  8. Rezvani K, Mielke S, Ahmadzadeh M, Kilical Y, Savani BN, Zeilah J, Keyvanfar K, Montero A, Hensel N, Kurlander R, Barrett AJ (2006) High donor FOXP3-positive regulatory T-cell (T-reg) content is associated with a low risk of GVHD following HLA-matched allogeneic SCT. Blood 108:1291–1297

    Article  CAS  PubMed  Google Scholar 

  9. Clark FJ, Gregg R, Piper K, Dunnion D, Freeman L, Griffiths M, Begum G, Mahendra P, Craddock C, Moss P, Chakraverty R (2004) Chronic graft-versus-host disease is associated with increased numbers of peripheral blood CD4(+)CD25(high) regulatory T cells. Blood 103:2410–2416

    Article  CAS  PubMed  Google Scholar 

  10. Li Q, Zhai Z, Xu X, Shen Y, Zhang A, Sun Z, Liu H, Geng L, Wang Y (2010) Decrease of CD4(+)CD25(+) regulatory T cells and TGF-beta at early immune reconstitution is associated to the onset and severity of graft-versus-host disease following allogeneic haematogenesis stem cell transplantation. Leuk Res 34:1158–1168

    Article  CAS  PubMed  Google Scholar 

  11. Zorn E, Kim HT, Lee SJ, Floyd BH, Litsa D, Arumugarajah S, Bellucci R, Alyea EP, Antin JH, Soiffer RJ, Ritz J (2005) Reduced frequency of FOXP3(+) CD4(+)CD25(+) regulatory T cells in patients with chronic graft-versus-host disease. Blood 106:2903–2911

    Article  CAS  PubMed  Google Scholar 

  12. Weissinger EM, Schiffer E, Hertenstein B, Ferrara JL, Holler E, Stadler M, Kolb HJ, Zander A, Zurbig P, Kellmann M, Ganser A (2007) Proteomic patterns predict acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Blood 109:5511–5519

    Article  CAS  PubMed  Google Scholar 

  13. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, Thomas ED (1995) Consensus conference on acute Gvhd grading. Bone Marrow Transplant 15:825–828

    CAS  PubMed  Google Scholar 

  14. Wang J, Ioan-Facsinay A, van der Voort EIH, Huizinga TWJ, Toes REM (2007) Transient expression of FOXP3 in human activated nonregulatory CD4(+) T cells. Eur J Immunol 37:129–138

    Article  CAS  PubMed  Google Scholar 

  15. Liu WH, Putnam AL, Xu-Yu Z, Szot GL, Lee MR, Zhu S, Gottlieb PA, Kapranov P, Gingeras TR, Fazekas de St Groth B, Clayberger C, Soper DM, Ziegler SF, Bluestone JA (2006) CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4(+) T reg cells. J Exp Med 203:1701–1711

    Article  CAS  PubMed  Google Scholar 

  16. Mielke S, Rezvani K, Savani BN, Nunes R, Yong ASM, Schindler J, Kurlander R, Ghetie V, Read EJ, Solomon SR, Vitetta ES, Barrett AJ (2007) Reconstitution of FOXP3(+) regulatory T cells (T-regs) after CD25-depleted allotransplantion in elderly patients and association with acute graft-versus-host disease. Blood 110:1689–1697

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgement

This work was supported by a grant of the DFG (SFB738). We thank the clinical co-workers from the BMT unit for patient caring and their support in probe sampling. We are very thankful to Michael Morgan carefully reading the manuscript.

Competing interests

The author(s) declare having no competing interests.

Author information

Authors and Affiliations

  1. Department of Haematology, Haemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany

    Sya N. Ukena, Jens Grosse, Eva Mischak-Weissinger, Stefanie Buchholz, Michael Stadler, Arnold Ganser & Anke Franzke

Authors
  1. Sya N. Ukena
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jens Grosse
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eva Mischak-Weissinger
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Stefanie Buchholz
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Michael Stadler
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Arnold Ganser
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Anke Franzke
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anke Franzke.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ukena, S.N., Grosse, J., Mischak-Weissinger, E. et al. Acute but not chronic graft-versus-host disease is associated with a reduction of circulating CD4+CD25highCD127low/− regulatory T cells. Ann Hematol 90, 213–218 (2011). https://doi.org/10.1007/s00277-010-1068-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00277-010-1068-0

Keywords

Search

Navigation