Soluble DNAM-1, as a Predictive Biomarker for Acute Graft-Versus-Host Disease

Abstract

Acute graft-versus-host disease (aGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Because diagnosis of aGVHD is exclusively based on clinical symptoms and pathological findings, reliable and noninvasive laboratory tests for accurate diagnosis are required. An activating immunoreceptor, DNAM-1 (CD226), is expressed on T cells and natural killer cells and is involved in the development of aGVHD. Here, we identified a soluble form of DNAM-1 (sDNAM-1) in human sera. In retrospective univariate and multivariate analyses of allo-HSCT patients (n = 71) at a single center, cumulative incidences of all grade (grade I–IV) and sgrade II–IV aGVHD in patients with high maximal serum levels of sDNAM-1 (≥30 pM) in the 7 days before allo-HSCT were significantly higher than those in patients with low maximal serum levels of sDNAM-1 (<30 pM) in the same period. However, sDNAM-1 was not associated with other known allo-HSCT complications. Our data suggest that sDNAM-1 is potentially a unique candidate as a predictive biomarker for the development of aGVHD.

A mathematical model for dynamics of soluble form of DNAM-1 as a biomarker for graft-versus-host disease

“…Serum samples were obtained from 156 patients at the Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Japan, between March 2009 and November 2011. Data from some of the patients had already been analyzed [7]; we basically followed their methods in terms of such features as informed consent and sample handling but here we included other patients according to our new criteria which is shown in Fig 1. Written informed consent was obtained from each patient in accordance with the Declaration of Helsinki. This study was approved by the ethics committee of the University of Tsukuba (approval No., 505) and Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital (approval No., 571).…”

“…We and others demonstrated a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 that DNAM-1 plays an important role in the development of aGVHD in mouse models [5,6]. Moreover, we have recently identified a soluble form of DNAM-1 (sDNAM-1), which is shed from the membrane type of DNAM-1 expressed on the cell surface of activated T lymphocytes, in human sera [7]. We performed retrospective univariate and multivariate analyses of serum levels of sDNAM-1 in patients before and after allo-HSCT at a single center (n = 71) [7].…”

“…Moreover, we have recently identified a soluble form of DNAM-1 (sDNAM-1), which is shed from the membrane type of DNAM-1 expressed on the cell surface of activated T lymphocytes, in human sera [7]. We performed retrospective univariate and multivariate analyses of serum levels of sDNAM-1 in patients before and after allo-HSCT at a single center (n = 71) [7]. We demonstrated that cumulative incidences of all grade (grade I-IV) and grade II-IV aGVHD in patients with high maximal serum levels of sDNAM-1 (�30 pM) in the 7 days before allo-HSCT were significantly higher than those in patients with low maximal serum levels of sDNAM-1 (<30 pM) in the same period, and concluded that the serum levels of sDNAM-1 can be a predictive biomarker for the development of aGVHD [7].…”

“…We performed retrospective univariate and multivariate analyses of serum levels of sDNAM-1 in patients before and after allo-HSCT at a single center (n = 71) [7]. We demonstrated that cumulative incidences of all grade (grade I-IV) and grade II-IV aGVHD in patients with high maximal serum levels of sDNAM-1 (�30 pM) in the 7 days before allo-HSCT were significantly higher than those in patients with low maximal serum levels of sDNAM-1 (<30 pM) in the same period, and concluded that the serum levels of sDNAM-1 can be a predictive biomarker for the development of aGVHD [7]. However, it remains unclear how the dynamics of serum levels of sDNAM-1 after allo-HSCT is regulated and whether it is associated with the development of aGVHD.…”

“…In this study, we constructed a mathematical model to assess the dynamics of serum levels of sDNAM-1, and revisited the data set of sDNAM-1, which had been analyzed previously [7], particularly after, rather than before, allo-HSCT to be applied by the mathematical model. We show that sDNAM-1 after allo-HSCT can be a biomarker for the development of aGVHD.…”