Multipotentialmesenchymal Stromal Cells (MMSC) Ameliorate Graft versus Host Disease (GVHD) in a Mouse Model, But Major Suppression of GVHD Permits Leukemic Relapse

摘要

A significant complication in allogeneic stem cell transplantation is graft versus host disease (GVHD). The use of multipotential mesenchymal stem cells (MMSC) for the amelioration of GVHD has shown promise as a therapeutic intervention. Given that MMSC can suppress allogeneic immune responses, there is a concern that using these cells may promote leukemic relapse. We describe a murine model of GVHD in the presence of leukemic cells (L1210). Acute GVHD was induced in DBA mice by transplanting bone marrow and spleen cells from C57Bl/6J mice with or without prior injection of L1210 cells. The recipient mice were monitored for signs of GVHD. The mice were then treated with primary MMSC or a C57Bl bone marrow derived cloned mesenchymal cell line (OMA-AD). The results without L1210 cells, demonstrated that mice treated with primary MMSC that had developed moderate GVHD had increased long-term survival when compared to controls. The group treated with OMA-AD cells showed minimal GVHD so cloned OMA-AD MMSC cells provided a significant protective effect against GVHD, and the survival rate was superior to that of animals treated with primary MMSC on the same day. In the presence of L1210, the control mice all died by day 11, and the mice receiving OMA-AD and L1210 cells died by day 9. Both had minimal GVHD. Only the mice receiving primary MMSC that developed moderate to severe GVHD survived long term. It appears that although MMSC and OMA-AD cells can ameliorate GVHD; the greater immunosuppressive effect of OMA-AD cells permitted the re-growth of the leukemic cells. In contrast, the moderate GVHD that remained after primary MMSC treatment eliminated the leukemia in the majority of mice. These studies demonstrated that in the mouse model, as in man, administration of primary or cloned MMSC ameliorated GVHD. However, complete suppression of GVHD permitted leukemic relapse.