Dendritic cell-based amelioration of graft versus host disease in humanized mice

Abstract

Abstract Graft versus host disease (GVHD) is a severe, often lethal, complication of hematopoietic stem cell transplantation, and although prophylactic regimens are given as standard pre-transplantation therapy, up to 60% of these patients develop aGVHD, and require additional immunosuppressive intervention. Previously we showed that treatment of mice with a purified probiotic molecule, exopolysaccharide (EPS) from Bacillus subtilis, significantly increased survival of GVHD mice compared to control PBS-treated mice (70% vs 10%, respectively), with EPS-treated mice surviving more than 100 days after aGVHD induction. To test if EPS can also ameliorate GVHD in humans, we used humanized NSG-HLA-A2 mice and induced GVHD by i.v. injection of HLA-A2neg human PBMCs. After deriving dendritic cells (DC) from CD34+ cord blood cells, we pretreated them with EPS or PBS, and injected them together with PMBCs into the NSG-HLA-A2 mice. We found that EPS-treated DC significantly prolonged the survival of these mice, compared to PBS-treated DC. We also found that EPS-treated DC downregulated expression of activation markers (CD80, CD86), upregulated expression of inhibitory molecules (PD-L1, PD-L2), and inhibited activation of alloreactive T cells in MLR. We conclude that EPS induces tolerogenic human DC, which ameliorate GVHD in humanized NSG-HLA-A2 mice, likely by inhibiting alloreactive T cell response. Supported by NIH R41 AI155281