Advertisement

Annals of Hematology

, Volume 96, Issue 7, pp 1127–1133 | Cite as

Prediction of graft-versus-host disease: a biomarker panel based on lymphocytes and cytokines

  • Holger BuddeEmail author
  • Susanne Papert
  • Jens-Holger Maas
  • Holger M. Reichardt
  • Gerald Wulf
  • Justin Hasenkamp
  • Joachim Riggert
  • Tobias J. Legler
Original Article

Abstract

Graft-versus-host disease (GvHD) still belongs to the major challenges after allogeneic hematopoietic stem cell transplantation (HSCT). Immune-suppressive therapy against GvHD is a double-edged sword due to risk of infections and relapse. The ability to adapt prophylactic treatment according to the probability of severe GvHD would be an essential advantage for the patients. We analyzed different biomarkers for their potential to predict the development of GvHD in 28 patients who underwent allogeneic HSCT. Blood was taken once directly after hematopoietic engraftment. In this study, patients were monitored for 12 months after HSCT for the occurrence of acute GvHD or acute/chronic GvHD overlap syndrome. Soluble IL-2 receptor and CD4/CD8 T cell ratio were independently associated with the occurrence of GvHD in the observation period. However, the largest area under the receiver operating characteristic curve with 0.90 was observed when a 5-parameter biomarker score based on CD4+ T cells, CD8+ T cells, CD19 CD21+ precursor B cells, CD4/CD8 T cell ratio, and soluble IL-2 receptor was used to predict GvHD. In addition, CD8+ T cell levels above 2.3% of all mononuclear cells after engraftment may predict relapse-free survival at least for 12 months. In summary, we found a new biomarker panel for prediction of GvHD which is featured by established laboratory assays and high statistical significance. In order to introduce the biomarker panel into routine clinical protocols, we suggest performing a larger multi-center study.

Keywords

Hematopoietic stem cell transplantation Graft-versus-host disease Biomarker Relapse-free survival 

Notes

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

This article does not contain any studies with animals performed by any of the authors.

Informed consent

Informed consent was obtained from all individual participants included in the study.

References

  1. 1.
    Blazar BR, Murphy WJ, Abedi M (2012) Advances in graft-versus-host disease biology and therapy. Nat Rev Immunol 12:443–458CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Greinix HT, Worel N, Knobler R (2010) Role of extracorporeal photopheresis (ECP) in treatment of steroid-refractory acute graft-versus-host disease. Biol Blood Marrow Transplant 16:1747–1748CrossRefPubMedGoogle Scholar
  3. 3.
    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 34:1158–1168CrossRefPubMedGoogle Scholar
  4. 4.
    Ukena SN, Grosse J, Mischak-Weissinger E, Buchholz S, Stadler M, Ganser A, Franzke A (2011) Acute but not chronic graft-versus-host disease is associated with a reduction of circulating CD4(+)CD25 (high)CD127 (low/−) regulatory T cells. Ann Hematol 90:213–218CrossRefPubMedGoogle Scholar
  5. 5.
    Rosenzwajg M, Dhédin N, Maury S, Bensimon G, Landau DA, Norol F, Trébéden-Negre H, Uzunov M, Vernant JP, Klatzmann D, Cohen JL (2011) Regulatory T cell content in the bone marrow graft does not predict the occurrence of acute GVHD. Biol Blood Marrow Transplant 17:265–269CrossRefPubMedGoogle Scholar
  6. 6.
    Kim DH, Sohn SK, Lee NY, Baek JH, Kim JG, Won DI, Suh JS, Lee KB, Shin IH (2005) Transplantation with higher dose of natural killer cells associated with better outcomes in terms of non-relapse mortality and infectious events after allogeneic peripheral blood stem cell transplantation from HLA-matched sibling donors. Eur J Haematol 75:299–308CrossRefPubMedGoogle Scholar
  7. 7.
    Yamashita K, Choi U, Woltz PC, Foster SF, Sneller MC, Hakim FT, Fowler DH, Bishop MR, Pavletic SZ, Tamari M, Castro K, Barrett AJ, Childs RW, Illei GG, Leitman SF, Malech HL, Horwitz ME (2004) Severe chronic graft-versus-host disease is characterized by a preponderance of CD4(+) effector memory cells relative to central memory cells. Blood 103:3986–3988CrossRefPubMedGoogle Scholar
  8. 8.
    Abrahamsen IW, Sømme S, Heldal D, Egeland T, Kvale D, Tjønnfjord GE (2005) Immune reconstitution after allogeneic stem cell transplantation: the impact of stem cell source and graft-versus-host disease. Haematologica 90:86–93PubMedGoogle Scholar
  9. 9.
    D'Asaro M, Dieli F, Caccamo N, Musso M, Porretto F, Salerno A (2006) Increase of CCR7- CD45RA+ CD8 T cells (T(EMRA)) in chronic graft-versus-host disease. Leukemia 20:545–547CrossRefPubMedGoogle Scholar
  10. 10.
    Greinix HT, Pohlreich D, Kouba M, Körmöczi U, Lohmann I, Feldmann K, Zielinski C, Pickl WF (2008) Elevated numbers of immature/transitional CD21- B lymphocytes and deficiency of memory CD27+ B cells identify patients with active chronic graft-versus-host disease. Biol Blood Marrow Transplant 14:208–219CrossRefPubMedGoogle Scholar
  11. 11.
    Paczesny S, Krijanovski OI, Braun TM, Choi SW, Clouthier SG, Kuick R, Misek DE, Cooke KR, Kitko CL, Weyand A, Bickley D, Jones D, Whitfield J, Reddy P, Levine JE, Hanash SM, Ferrara JL (2009) A biomarker panel for acute graft-versus-host disease. Blood 113:273–278CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Kokalj A, Greinix HT, Ciovica M, Kittler H, Kalhs P, Knobler RM, Volc-Platzer B (2002) Effects of extracorporeal photoimmunotherapy on soluble IL-2Ralpha, TNF-RI, and CD8 in patients with steroid-resistant acute graft-versus-host disease. Clin Immunol 104:248–255CrossRefPubMedGoogle Scholar
  13. 13.
    August KJ, Chiang KY, Bostick RM, Flanders WD, Waller EK, Langston A, Worthington-White D, Rowland P, Moore KF, Khoury HJ, Horan JT (2011) Biomarkers of immune activation to screen for severe, acute GVHD. Bone Marrow Transplant 46:601–604CrossRefPubMedGoogle Scholar
  14. 14.
    Renteria AS, Levine JE, Ferrara JL (2016) Development of a biomarker scoring system for use in graft-versus-host disease. Biomark Med 10:793–795CrossRefPubMedGoogle Scholar
  15. 15.
    Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, Thomas ED (1995) 1994 consensus conference on acute GVHD grading. Bone Marrow Transplant 15:825–828PubMedGoogle Scholar
  16. 16.
    Vigorito AC, Campregher PV, Storer BE, Carpenter PA, Moravec CK, Kiem HP, Fero ML, Warren EH, Lee SJ, Appelbaum FR, Martin PJ, Flowers ME (2009) Evaluation of NIH consensus criteria for classification of late acute and chronic GVHD. Blood 114:702–708CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, Martin P, Chien J, Przepiorka D, Couriel D, Cowen EW, Dinndorf P, Farrell A, Hartzman R, Henslee-Downey J, Jacobsohn D, McDonald G, Mittleman B, Rizzo JD, Robinson M, Schubert M, Schultz K, Shulman H, Turner M, Vogelsang G, Flowers ME (2005) National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant 11:945–956CrossRefPubMedGoogle Scholar
  18. 18.
    Berger M, Signorino E, Muraro M, Quarello P, Biasin E, Nesi F, Vassallo E, Fagioli F (2013) Monitoring of TNFR1, IL-2Rα, HGF, CCL8, IL-8 and IL-12p70 following HSCT and their role as GVHD biomarkers in paediatric patients. Bone Marrow Transplant 48:1230–1236CrossRefPubMedGoogle Scholar
  19. 19.
    Kaida K, Ikegame K, Ikemoto J, Murata R, Irie R, Yoshihara S, Ishii S, Okada M, Inoue T, Tamaki H, Soma T, Fujimori Y, Kai S, Ogawa H (2014) Soluble interleukin-2 receptor level on day 7 as a predictor of graft-versus-host disease after HLA-haploidentical stem cell transplantation using reduced-intensity conditioning. Int J Hematol 99:463–470CrossRefPubMedGoogle Scholar
  20. 20.
    Huttunen P, Taskinen M, Siitonen S, Saarinen-Pihkala UM (2015) Impact of very early CD4(+) /CD8(+) T cell counts on the occurrence of acute graft-versus-host disease and NK cell counts on outcome after pediatric allogeneic hematopoietic stem cell transplantation. Pediatr Blood Cancer 62:522–528CrossRefPubMedGoogle Scholar
  21. 21.
    Mercier-Letondal P, Montcuquet N, Sauce D, Certoux JM, Jeanningros S, Ferrand C, Bonyhadi M, Tiberghien P, Robinet E (2008) Alloreactivity of ex vivo-expanded T cells is correlated with expansion and CD4/CD8 ratio 10:275–88Google Scholar
  22. 22.
    Kuzmina Z, Greinix HT, Knobler R, Worel N, Kouba M, Weigl R, Körmöczi U, Rottal A, Pohlreich D, Zielinski C, Pickl WF (2009) Proportions of immature CD19+CD21- B lymphocytes predict the response to extracorporeal photopheresis in patients with chronic graft-versus-host disease. Blood 114:744–746CrossRefPubMedGoogle Scholar
  23. 23.
    Reshef R, Huffman AP, Gao A, Luskin MR, Frey NV, Gill SI, Hexner EO, Kambayashi T, Loren AW, Luger SM, Mangan JK, Nasta SD, Richman LP, Sell M, Stadtmauer EA, Vonderheide RH, Mick R, Porter DL (2015) High graft CD8 cell dose predicts improved survival and enables better donor selection in allogeneic stem-cell transplantation with reduced-intensity conditioning. J Clin Oncol 33:2392–2398CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Liu J, Chang YJ, Yan CH, Xu LP, Jiang ZF, Zhang XH, Liu KY, Huang XJ (2016) Poor CMV-specific CD8+ T central memory subset recovery at early stage post-HSCT associates with refractory and recurrent CMV reactivation. J Inf Secur 73:261–270Google Scholar
  25. 25.
    Or-Geva N, Reisner Y (2016) The evolution of T-cell depletion in haploidentical stem-cell transplantation. Br J Haematol 172:667–684CrossRefPubMedGoogle Scholar
  26. 26.
    Dutt S, Baker J, Kohrt HE, Kambham N, Sanyal M, Negrin RS, Strober S (2011) CD8+CD44(hi) but not CD4+CD44(hi) memory T cells mediate potent graft antilymphoma activity without GVHD. Blood 117:3230–3239CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Levine JE, Logan BR, Wu J, Alousi AM, Bolaños-Meade J, Ferrara JL, Ho VT, Weisdorf DJ, Paczesny S (2012) Acute graft-versus-host disease biomarkers measured during therapy can predict treatment outcomes: a blood and marrow Transplant clinical trials network study. Blood 119:3854–3860CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Holger Budde
    • 1
    Email author
  • Susanne Papert
    • 1
  • Jens-Holger Maas
    • 1
  • Holger M. Reichardt
    • 2
  • Gerald Wulf
    • 3
  • Justin Hasenkamp
    • 3
  • Joachim Riggert
    • 1
  • Tobias J. Legler
    • 1
  1. 1.Department of Transfusion MedicineUniversity Medical Center GöttingenGöttingenGermany
  2. 2.Institute for Cellular and Molecular ImmunologyUniversity Medical Center GöttingenGöttingenGermany
  3. 3.Department of Hematology and OncologyUniversity Medical Center GöttingenGöttingenGermany

Personalised recommendations