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, 15 (2), e0228508
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A Mathematical Model for Dynamics of Soluble Form of DNAM-1 as a Biomarker for Graft-Versus-Host Disease

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A Mathematical Model for Dynamics of Soluble Form of DNAM-1 as a Biomarker for Graft-Versus-Host Disease

Yuki Goshima et al. PLoS One.

Abstract

DNAM-1 (CD226) is an activating immunoreceptor expressed on T cells and NK cells and involved in the pathogenesis of acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We previously reported that a soluble form of DNAM-1 (sDNAM-1) is generated by shedding from activated T cells. Moreover, higher serum levels of sDNAM-1 in patients before allo-HSCT is a predictive biomarker for the development of aGVHD based on the retrospective univariate and multivariate analyses in allo-HSCT patients. However, it remains unclear how the serum levels of sDNAM-1 are regulated after allo-HSCT and whether they are associated with the development of aGVHD. Here, we constructed a mathematical model to assess the dynamics of sDNAM-1 after allo-HSCT by assuming that there are three types of sDNAM-1 (the first and the second were from alloreactive and non-alloreactive donor lymphocytes, respectively, and the third from recipient lymphocytes). Our mathematical model fitted well to the data set of sDNAM-1 in patients (n = 67) who had undergone allo-HSCT and suggest that the high proportion of the first type of sDNAM-1 to the total of the first and second types is associated with high risk of the development of severe aGVHD. Thus, sDNAM-1 after allo-HSCT can be a biomarker for the development of aGVHD.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Patient disposition.
From 156 patients analyzed for sDNAM-1 in the sera, we finally included 67 in our study. Details of the inclusion criteria are given in the Materials and Methods.
Fig 2
Fig 2. Distributions of Rday_n values for day n = 20, 30, 40, and 50.
Rday_n does not follow a normal distribution. The vertical axis is the number of patients, and the horizontal axis is the value of Rday_n.
Fig 3
Fig 3. Box plots comparing Rday_n values between GVHD (+) and GVHD (–).
GVHD (+) and GVHD (-) indicate patients with and without aGVHD. A thick line in each box indicates the median value of Rday_n (n = 20,30,40 and 50).
Fig 4
Fig 4. Box plots of Rday_n (n = 20, 30, 40, and 50) values per grade of aGVHD).
Rday_n (%) values (n = 20, 30, 40, and 50) in patients with aGVHD without (grade 0) and with (grade I-IV) aGVHD. There is no box plot for GradeⅣ, as it contained only one patient.
Fig 5
Fig 5. Observed data and simulation of the dynamics of the soluble form of DNAM-1 (sDNAM-1) from different sources.
Representative patients Data of sDNAM-1 dynamics after transplantation are shown. The purple dots indicate the observed data. The blue line models the total amount of sDNAM-1; it represents the full model (= x1(t)+x2(t)+x3(t)). The green line models the first type of sDNAM-1, namely the transiently type (= x1(t)). The yellow-green line models the second type of sDNAM-1, namely the persistent type (= x2(t)). The red line models the third type of sDNAM-1, namely the residual type produced by recipient (= x3(t)). Thus, the blue line (total concentration of sDNAM-1) consists of the green, yellow-green, and red lines combined. Patients ID1 and ID2 did not develop aGVHD, whereas patients ID3 and ID4 did develop it.

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Grant support

This work was supported in part by grants provided by the Ministry of Education, Culture, Sports, Science and Technology, Japan and the Program for Promotion of Fundamental Studies in Health Science of the National Institute of Biomedical Innovation, Japan.
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