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Pretransplant Infusion of Mesenchymal Stem Cells Prolongs the Survival of a Semiallogeneic Heart Transplant through the Generation of Regulatory T Cells¹

Federica Casiraghi^*,, Nadia Azzollini^*,, Paola Cassis^*,, Barbara Imberti, Marina Morigi, Daniela Cugini^*,, Regiane Aparecida Cavinato^*,, Marta Todeschini^*,, Samantha Solini^*,, Aurelio Sonzogni, Norberto Perico^*,, Giuseppe Remuzzi^*,, and Marina Noris^2,*,

^* Transplant Research Center, "Chiara Cucchi De Alessandri & Gilberto Crespi," Ranica, Department of Medicine and Transplantation, Ospedali Riuniti, and Mario Negri Institute for Pharmacological Research, Bergamo, Italy

In this study, we investigated whether mesenchymal stem cells (MSC) had immunomodulatory properties in solid organ allotransplantation, using a semiallogeneic heart transplant mouse model, and studied the mechanism(s) underlying MSC tolerogenic effects. Either single (portal vein, day –7) or double (portal vein, day –7 and tail vein, day –1) pretransplant infusions of donor-derived B6C3 MSC in B6 recipients induced a profound T cell hyporesponsiveness and prolonged B6C3 cardiac allograft survival. The protolerogenic effect was abrogated when donor-derived MSC were injected together with B6C3 hematopoietic stem cells (HSC), suggesting that HSC negatively impact MSC immunomodulatory properties. Both the induction (pretransplant) and the maintenance phase (>100 days posttransplant) of donor-derived MSC-induced tolerance were associated with CD4⁺CD25⁺Foxp3⁺ Treg expansion and impaired anti-donor Th1 activity. MSC-induced regulatory T cells (Treg) were donor-specific since adoptive transfer of splenocytes from tolerant mice prevented the rejection of fully MHC-mismatched donor-specific secondary allografts but not of third-party grafts. In addition, infusion of recipient-derived B6 MSC tolerized a semiallogeneic B6C3 cardiac allograft, but not a fully MHC-mismatched BALB/c graft, and expanded Treg. A double i.v. pretransplant infusion of recipient-derived MSC had the same tolerogenic effect as the combined intraportal/i.v. MSC infusions, which makes the tolerogenic protocol applicable in a clinical setting. In contrast, single MSC infusions given either peritransplant or 1 day after transplant were less effective. Altogether these findings indicate that MSC immunomodulatory properties require HSC removal, partial sharing of MHC Ags between the donor and the recipient and pretransplant infusion, and are associated with expansion of donor-specific Treg.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was partially supported by a grant from Foundation ART for Research on Transplantation and from Banca Aletti (Milan, Italy). D.C. received fellowships from Cavaliere. Grana in memory of Libera Dossi Grana and from Fondazione ART. P.C., R.A.C., and S.S. received a fellowship from Fondazione ART.

² Address correspondence and reprint requests to Dr. Marina Noris, Mario Negri Institute for Pharmacological Research, Via Camozzi 3, 24020 Ranica (Bergamo), Italy. E-mail address: noris{at}marionegri.it

³ Abbreviations used in this paper: MSC, mesenchymal stem cell; HSC, hematopoietic stem cell; BM, bone marrow; Foxp3, forkhead box p3; Treg, regulatory T cell; MHCII, MHC class II; MST, median survival time; AU, arbitrary unit.

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