Suppression of graft-versus-host disease and retention of graft-versus-tumour reaction by murine genetically engineered dendritic cells following bone marrow transplantation

Abstract

The effect of infusion of lentiviral vector-mediated, genetically engineered dendritic cells (DCs) following allogeneic bone marrow transplantation (allo-BMT) on graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) was investigated in a mouse model. Lentivirus-mediated expression of soluble tumor necrosis factor receptor 1 (sTNFR1) converted immature DCs (imDCs) from BABL/c mice into engineered DCs in vitro. An EL4 leukemia allo-BMT model of BABL/c to C57BL/6 mice was established. Engineered DCs with donor bone marrow cells and splenocytes were subsequently transplanted into myeloablatively irradiated recipients. The average survival duration in the sTNFR1-and pXZ9-imDC groups was significantly prolonged compared with that of the allo-BMT group (P<0.05). Mild histological changes in GVHD or leukemia were observed in the recipients in the sTNFR1-imDC group and clinical GVHD scores in this group were significantly decreased compared with those of the transplantation and pXZ9-imDC groups. Serum interferon-γ levels were decreased in the pXZ9-imDC and sTNFR1-imDC groups compared with those in the allo-BMT group (P<0.05), with the reduction being more significant in the sTNFR1-imDC group (P<0.05). Serum interleukin-4 expression levels were decreased in the allo-BMT group, but gradually increased in the pXZ9-imDC and sTNFR1-imDC groups (P<0.05). Co-injection of donor genetically-engineered imDCs was able to efficiently protect recipient mice from lethal GVHD while preserving GVL effects during allo-BMT.