Abstract
Acute graft-versus-host-disease (aGvHD) is the major cause of non-relapse mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Recently, diagnostic biomarkers for aGvHD have been shown to play important roles in evaluating disease status and mortality risk after allo-HSCT. To identify plasma biomarkers for aGvHD with high sensitivity and specificity, a quantitative proteomic approach using 8-plex isobaric tags for relative and absolute quantitation (8-plex iTRAQ) was employed to screen differentially expressed proteins in peripheral blood before and after the onset of aGvHD. Four target proteins, ceruloplasmin (CP), myeloperoxidase (MPO), complement factor H (CFH), and alpha-1-acid glycoprotein (AGP), were chosen for preliminary validation with enzyme linked immunosorbent assay (ELISA) in 20 paired samples at both the time of diagnosis of aGvHD and the time of complete response. The most promising candidate, ceruloplasmin, was further validated at fixed time points after allo-HSCT and during aGvHD. The plasma ceruloplasmin levels were significantly increased during the period of aGvHD onset and were markedly decreased as aGvHD resolved. The plasma ceruloplasmin levels at different time points post-transplant in the aGvHD (+) group were significantly higher than those in the aGvHD (−) group (p<0.001). The elevation of ceruloplasmin level in patients with active aGvHD was independent of infection status. Patients whose ceruloplasmin levels were elevated above 670 μg/ml at 7, 14 and 21 days after allo-HSCT had a remarkably increased probability of subsequently developing aGvHD. In conclusion, our results suggest that plasma ceruloplasmin is a potential plasma biomarker of aGvHD, and it also has prognostic value for risk-adapted prophylaxis during the consecutive time points monitored in the first month after allo-HSCT.
Highlights
Acute graft-versus-host-disease, one of the major causes of non-relapse mortality after allogeneic hematopoietic stem cell transplantation, involves damage to target organs by alloreactive T cells and manifests as alterations of the skin, gastrointestinal tract and liver function [1]
Our previous study established the utility of 8-plex iTRAQ quantitative proteomic technology for Acute graft-versus-host-disease (aGvHD) biomarker screening and identified lipopolysaccharide-binding protein (LBP) as a candidate aGvHD biomarker
An elevated level of ceruloplasmin has been closely correlated with some auto-immune diseases, such as rheumatoid arthritis and systemic lupus erythematous [18,19]
Summary
Acute graft-versus-host-disease (aGvHD), one of the major causes of non-relapse mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT), involves damage to target organs by alloreactive T cells and manifests as alterations of the skin, gastrointestinal tract and liver function [1]. Et al reported that in a phase 2 clinical trial, a 6-protein biomarker panel consisting of IL-2 receptor-a, tumor necrosis factor receptor-1, hepatocyte growth factor, IL-8, elafin and regenerating islet-derived 3-a could predict post-therapy nonresponse and mortality [6]. Similar to the use of well-established tumor biomarkers for the management of certain cancers, measurements of aGvHD biomarker concentrations in multi-marker panels could be incorporated into routine clinical follow-up. Lipopolysaccharide-binding protein (LBP), was discovered through the use of 8-plex iTRAQ and was validated for the diagnosis and prediction of aGvHD development [8]. We report the discovery and validation of a new candidate plasma biomarker for aGvHD, ceruloplasmin (CP), a 151-kDa protein that controls iron metabolism hemostasis and is well known for its diagnostic value in Wilson’s disease [9]. The role of ceruloplasmin as an aGvHD biomarker after allo-HSCT had not been previously investigated
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