Abstract
BackgroundMultiple myeloma (MM) is a malignant plasma cell disorder with poor long-term survival and high recurrence rates. Despite evidence of graft-versus-myeloma (GvM) effects, the use of allogeneic hematopoietic stem cell transplantation (allo-SCT) remains controversial in MM. In the current study, we investigated the anti-myeloma effects of allo-SCT from B10.D2 mice into MHC-matched myeloma-bearing Balb/cJ mice, with concomitant development of chronic graft-versus-host disease (GvHD).Methods and resultsBalb/cJ mice were injected intravenously with luciferase-transfected MOPC315.BM cells, and received an allogeneic (B10.D2 donor) or autologous (Balb/cJ donor) transplant 30 days later. We observed a GvM effect in 94% of the allogeneic transplanted mice, as the luciferase signal completely disappeared after transplantation, whereas all the autologous transplanted mice showed myeloma progression. Lower serum paraprotein levels and lower myeloma infiltration in bone marrow and spleen in the allogeneic setting confirmed the observed GvM effect. In addition, the treated mice also displayed chronic GvHD symptoms. In vivo and in vitro data suggested the involvement of effector memory CD4 and CD8 T cells associated with the GvM response. The essential role of CD8 T cells was demonstrated in vivo where CD8 T-cell depletion of the graft resulted in reduced GvM effects. Finally, TCR Vβ spectratyping analysis identified Vβ families within CD4 and CD8 T cells, which were associated with both GvM effects and GvHD, whereas other Vβ families within CD4 T cells were associated exclusively with either GvM or GvHD responses.ConclusionsWe successfully established an immunocompetent murine model of graft-versus-myeloma. This is the first murine GvM model using immunocompetent mice that develop MM which closely resembles human MM disease and that are treated after disease establishment with an allo-SCT. Importantly, using TCR Vβ spectratyping, we also demonstrated the presence of GvM unique responses potentially associated with the curative capacity of this immunotherapeutic approach.
Highlights
Multiple myeloma (MM) is a malignant plasma cell disorder that accounts for approximately 10% of all hematological cancers [1]
The results showed an expansion of CD8 T cells, in contrast to CD4 T cells, but the expansion observed in co-cultures with MOPC315.BM cells was not different from cocultures with Balb/cJ splenocytes, suggesting a close relationship between epitopes recognized in chronic graft-versus-host disease (GvHD) and GvM processes
We describe a graft-versus-myeloma effect in the context of MHC-matched allogeneic transplantation in myeloma-bearing mice
Summary
Multiple myeloma (MM) is a malignant plasma cell disorder that accounts for approximately 10% of all hematological cancers [1]. Long-term survival is rare after autologous stem cell transplantation and/or treatment with recently introduced anti-myeloma agents, and disease recurs in virtually all patients. Several immune alterations have been described in MM patients These alterations are caused in part by the replacement of normal bone marrow with malignant plasma cells, suppressing normal hematopoiesis. Despite evidence of graft-versusmyeloma (GvM) effects, the use of allogeneic hematopoietic stem cell transplantation (allo-SCT) remains controversial in MM. We investigated the anti-myeloma effects of allo-SCT from B10.D2 mice into MHCmatched myeloma-bearing Balb/cJ mice, with concomitant development of chronic graft-versus-host disease (GvHD). We observed a GvM effect in 94% of the allogeneic transplanted mice, as the luciferase signal completely disappeared after transplantation, whereas all the autologous transplanted mice showed myeloma progression. TCR Vb spectratyping analysis identified Vb families within CD4 and CD8 T cells, which were associated with both GvM effects and PLOS ONE | DOI:10.1371/journal.pone.0113764 November 21, 2014
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