Features of synergism between mesenchymal stem cells and immunosuppressive drugs in a murine heart transplantation model

Background: Mesenchymal stem cells (MSCs) can be used for immunomodulation therapy after solid organ transplantation. Here, we focus on the immunoregulatory potential of combination therapies of MSCs and classic pharmacotherapy to mediate acceptance of solid organ grafts. Methods: To determine which drugs influence the immunosuppressive effect of MSCs, we assessed the interaction of MSCs and common clinical immunosuppresants (MMF, sirolimus [Srl], and ciclosporin A [CiA]) in a parent-into-F1 cell transfer model. In this model, the transfer of parental strain T cells into semi-allogeneic F1 recipients induces a graft-versus-host reaction (GvHR). Re-isolated CFSE-labelled T lymphocytes were analyzed by flow cytometry. These findings were compared to a fully allogeneic heart transplantation model. Results: We found that MSC treatment alone had no significant effect on allograft survival of heterotopic heart grafts. However, MSCs combined with short-term mycophenolate mofetil (MMF) significantly prolonged graft survival. Quantitative analysis of three different MSC - drug combinations in the F1 model revealed, that only the MSC-MMF combination led to a super-additive immunosuppressive effect. We also investigated the effect of MMF and CiA on IFNγ production of stimulated lymphocytes and found that MMF left the expression of IFNγ unaffected, whereas CiA completely abolished the production of IFNγ. Conclusion: Our data show that the type of concurrent immunosuppression strongly influences the immunosuppressive effect of MSC, most likely through differential secretion of IFNγ. A regimen combining MSCs and MMF was most immunosuppressive.