Mesenchymal stromal cells inhibit graft-versus-host disease of mice in a dose-dependent manner

Abstract

Background aims. Graft-versus-host disease (GvHD) remains a major complication after allogeneic hematopoietic cell transplantation (HCT). Recent literature demonstrates a potential benefit of human mesenchymal stromal cells (MSC) for the treatment of refractory GvHD; however, the optimal dose remains uncertain. We set out to develop an animal model that can be used to study the effect of MSC on GvHD. Methods. A GvHD mouse model was established by transplanting C3H/he donor bone marrow (BM) cells and spleen cells into lethally irradiated BALB/c recipient mice. MSC were obtained from C3H/he mice and the C3H/10T1/2 murine MSC line. Results. The mRNA expression of Foxp3 in regional lymph nodes (LN) localized with T cells was markedly increased by the addition of C3H10T1/2 cells in a real-time polymerase chain reaction (PCR). Using a mixed lymphocyte reaction, we determined the optimal splenocyte proliferation inhibition dose (MSC:splenocyte ratios 1:2 and 1:1). Three different C3H10T1/2 cell doses (low, 0.5 × 106, intermediate, 1 × 10 6, and high, 2 × 106) with a consistent splenocyte dose (1 × 106) were evaluated for their therapeutic potential in an in vivo GvHD model. The clinical and histologic GvHD score and KaplanMeier survival rate were improved after MSC transplantation, and these results demonstrated a dose-dependent inhibition. Conclusions. We conclude that MSC inhibit GvHD in a dose-dependent manner in this mouse model and this model can be used to study the effects of MSC on GvHD.