Enhancement of Graft-versus-leukemia Effects by Mesenchymal Stem Cells in Mixed Chimerisim after a Murine Non-myeloablative Hematopoietic Stem Cell Transplantation

Abstract

Background: Mesenchymal stem cells (MSCs) may be useful for reducing graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The GVHD and a graft-versus-leukemia (GVL) effect are inversely related. We therefore wanted to determine whether MSCs can preserve the GVL effect following experimental allo-HSCT. Methods: After non-myeloablative allogeneic hematopoietic stem cell transplantation (NM-HSCT) using C57BL/6 (H-2b)→B6D2F1 (H-2b/d), some mice received donor lymphocyte infusion (DLI) for induction of GVL effects by virtue of complete chimerism (CC), while the other groups did not receive DLI with persistence of mixed chimerism (MC). All mice were inoculated subcutaneously with P815 tumor cells and were intravenously treated with either donor MSCs or diluents. Results: Between the DLI-treated groups with CC, tumor-related deaths and tumor growths were comparable irrespective to the infusion of MSCs. On the contrary, among mice without DLI which showed MC, the administration of MSCs significantly delayed tumor-related deaths compared to those without the administration of MSCs (50-day percent survival, 54.5% vs. 18.1%, P=0.0225). In the MC animals, tumor growth seemed to be more delayed in the mice injected with MSCs than in the controls (P=0.09). Donor MSCs injection was associated with increased donor effector/memory CD62L- T cells in MC but not in CC. Conclusion: In spite of the observed immunosuppressive effects of donor MSCs, our results indicate that the GVL effects were not influenced by the injection of MSCs but that under a given condition such as MC, the injection of donor MSCs could result in enhanced GVL effects.