Abstract
No predictive factors are currently available to establish patient-specific GVHD risk. A panel of six serum cytokines (TNF receptor 1, IL-2 receptor alfa (IL-2Rα), hepatocyte growth factor (HGF), monocyte chemo-attractant protein-2, IL-8, IL-12p70) were monitored at established time points (days −1, +1, +7, +14, +21, +28 and +60) in 170 paediatric hematopoietic SCT (HSCT) recipients. We found that higher concentrations of IL-2Rα on days +14 and +21 together with HGF on days +14 and +21 were significantly associated at a higher probability of both grade II–IV GVHD (on day +14 it was: 60% vs 28%, P=0.007) and grade III–IV (on day +14 it was: 40% vs 15%, P=0.001). The higher IL-8 serum concentration on day +28 was associated with a lower probability of chronic GVHD being 4% vs 29% (P=0.01) for patients with higher vs lower IL-8 serum concentration. These findings were confirmed when the analysis was restricted to the the matched unrelated donor group. In conclusion, even if the serum cytokine levels were related to several variables associated with HSCT, we identified two cytokines as predictors of GVHD II–IV and III–IV, translating into a higher TRM risk (17% vs 3%, P=0.004).
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Billigham RE . The biology of graft-versus-host reaction. Harvey Lect 1966; 62: 21.
Wolf D, von Lilienfeld-Toal M, Wolf AM, Schleuning M, von Berhwelt-Baildon M, Held SA et al. Novel treatment concepts for graft-versus-host disease. Blood 2012; 119: 16–25.
Choi SW, Kitko CL, Braun T, Paczesny S, Yanik G, Mineishi S et al. Change in plasma tumor necrosis factor receptor 1 levels in the first week after myeloablative allogeneic transplantation correlates with the severity and incidence of GVHD and survival. Blood 2008; 112: 1539–1542.
Kami M, Matsomura T, Tanaka Y, Mikami Y, Ueyama J, Morinaga S et al. Serum levels of soluble interleukin-2 receptor after bone marrow transplantation: a true marker of acute graft-versus-host disease. Leuk Lymphoma 2000; 38: 533–540.
Lunn RA, Sumar N, Bansal AS, Treleaven J . Cytokine profiles in stem cell transplantation: possible use as a predictor of graft-versus-host disease. Hematology 2005; 10: 107–114.
Yamamoto M, Ota A, Hori T, Imai S, Sohma H, Suzuki N et al. Early expression of plasma CCL8 closely correlates with survival rate of acute graft-vs.-host disease in mice. Exp Hematol 2011; 39: 1101–1112.
Reddy V, Winer AG, Eksioglu E, Meier-Kriesche HU, Schold JD, Wingard JR . Interleukin 12 is associated with reduced relapsed without increased incidennce of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2005; 11: 1041–21.
Paczesny S, Krijanovski OI, Braun TM, Choi SW, Clouthier SG, Kuick R et al. A biomarker panel for acute graft-versus-host disease. Blood 2009; 8: 273–278.
Paczesny S, Braun TM, Levine JE, Hogan J, Crawford J, Coffing B et al. Elafin is a biomarker of graft versus host disease of the skin. Sci Transl Med 2010; 2: 13ra.
Levine JE, Logan BR, Wu J, Alousi AM, Bolanos-Meade J, Ferrara JL et al. Acute graft-versus-host disease biomarkers measured during therapy can predict treatment outcome: a Blood and Marrow Transplant Clinical Trials Network study. Blood 2012; 119: 3854–3860.
Martin PJ, Schoch G, Fisher L, Byers V, Anasetti C, Appelbaum FR et al. A retrospective analysis of therapy for acute graft-versus-host disease: initial treatment. Blood 1990; 76: 1464–1472.
Sullivan KM, Agura E, Anasetti C, Appelbaum F, Badger C, Beraman S et al. Chronic graft-versus-host disease and other late complications of bone marrow transplantation. Semin Hemat 1991; 28: 250–259.
Gray RJ . A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann. Stat. 1988; 16: 1141–1154.
Kaplan EL, Meier P . Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–481.
Mathias C, Mick R, Grupp S, Duffy K, Harris F, Laport G et al. Soluble Interleukin-2 Receptor concentration as a biochemical indicator for acute graft-versus-host disease after allogeneic bone marrow transplantation. JHematother Stem Cell Res 2000; 9: 393–400.
Shaiegan M, Iravani M, Babaee GR, Ghavamzedeh A . Effect of IL-18 and sIL2R on a GVHD occurrence after hematopoietic stem cell transplantation in some Iranian patients. Transpl Immunol 2006; 15: 223–227.
Mohty M, Blaise D, Faucher C, Vey N, Bouabdallah R, Stoppa AM et al. Inflammatory cytokines and acute graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation. Blood 2005; 106: 4407–4411.
Okamoto T, Takatsuka H, Fujimori Y, Wada H, Iwasaki T, Kakishita E . Increased hepatocyte growth factor in serum in acute graft-versus-host disease. Bone Marrow Transplant 2001; 28: 197–200.
Ferrara JL, Harris AC, Greenson JK, Braun TM, Holler E, Teshima T et al. Regenerating islet-derived 3 alpha is a biomarker of gastrointestinal graft-versus-host disease. Blood 2011; 118: 6702–6708.
Luft T, Conzelmann M, Benner A, Rieger M, Hess M, Strohhaecker U et al. Serum cytokeratin-18 fragments as quantitative markers of epithelial apoptosis in liver and intestinal graft-versus-host disease. Blood 2007; 118: 1685–1692.
Dean RM, Fry T, Mackall C, Steinberg SM, Hakim F, Fowler D et al. Association of serum interleukin-7 levels with the development of acute graft-versus-host disease. J Clin Oncol 2008; 26: 5735–5741.
Nakamura T, Nishizawa T, Hagiya M, Seki T, Shimonishi M, Sugimura A et al. Molecular cloning and expression of human hepatocyte growth factor. Nature 1989; 342: 440–443.
Kmiecik TE, Rosen KE, Van de Woude GF . Hepatocyte growth factor is a synergistic factor for the growth of hematopoietic progenitor cells. Blood 1992; 80: 2454–2457.
Bottaro DP, Rubin JS, Faletto DL, Chan AM, Kmiecik TE, Vande Woude GF et al. Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. Science 1991; 251: 802–804.
Acknowledgements
We are grateful to Mr Andrew Martin Garvey for editorial assistance.
Author contributions: MB wrote the paper and analysed the data, ES and MM carried out research, PQ, EB, FN, and EV analysed the data, FF designed research.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies this paper on Bone Marrow Transplantation website
Supplementary information
Rights and permissions
About this article
Cite this article
Berger, M., Signorino, E., Muraro, M. et al. 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, 1230–1236 (2013). https://doi.org/10.1038/bmt.2013.41
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/bmt.2013.41
Keywords
This article is cited by
-
High prevalence of CD3, NK, and NKT cells in the graft predicts adverse outcome after matched-related and unrelated transplantations with post transplantation cyclophosphamide
Bone Marrow Transplantation (2020)
-
Prediction of graft-versus-host disease: a biomarker panel based on lymphocytes and cytokines
Annals of Hematology (2017)
-
Soluble interleukin-2 receptor index predicts the development of acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation from unrelated donors
International Journal of Hematology (2016)