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.
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.
Authors: Moufida Ben Nasr; Andrea Vergani; James Avruch; Liye Liu; Eirini Kefaloyianni; Francesca D'Addio; Sara Tezza; Domenico Corradi; Roberto Bassi; Alessandro Valderrama-Vasquez; Vera Usuelli; James Kim; Jamil Azzi; Basset El Essawy; James Markmann; Reza Abdi; Paolo Fiorina Journal: Acta Diabetol Date: 2015-03-27 Impact factor: 4.280
Authors: Marcella Franquesa; Martin J Hoogduijn; Marlies E Reinders; Elke Eggenhofer; Anja U Engela; Fane K Mensah; Joan Torras; Antonello Pileggi; Cees van Kooten; Bernard Mahon; Oliver Detry; Felix C Popp; Volker Benseler; Federica Casiraghi; Christian Johnson; Janis Ancans; Barbara Fillenberg; Olga delaRosa; Josep M Aran; Marieke Roemeling-van Rhijn; Marieke Roemeling-vanRhijn; Jef Pinxteren; Norberto Perico; Eliana Gotti; Bruno Christ; James Reading; Martino Introna; Robert Deans; Murat Shagidulin; Ramon Farré; Alessandro Rambaldi; Albert Sanchez-Fueyo; Natasha Obermajer; Andrey Pulin; Frank J M F Dor; Isabel Portero-Sanchez; Carla C Baan; Ton J Rabelink; Giuseppe Remuzzi; Michiel G H Betjes; Marc H Dahlke; Josep M Grinyó Journal: Transplantation Date: 2013-08-15 Impact factor: 4.939