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Effect of Timing and Complement Receptor Antagonism on Intragraft Recruitment and Protolerogenic Effects of Mesenchymal Stromal Cells in Murine Kidney Transplantation

Casiraghi, Federica, PhD1; Todeschini, Marta, BiolSci D1; Azzollini, Nadia, BiolSci D1; Cravedi, Paolo, MD, PhD2; Cassis, Paola, PhD1; Solini, Samantha, PhD1; Fiori, Sonia, PhD1; Rota, Cinzia, PhD1; Karachi, Aida, PhD3; Carrara, Camillo, MD1; Noris, Marina, PhD1; Perico, Norberto, MD1; Remuzzi, Giuseppe, MD1,4,5

doi: 10.1097/TP.0000000000002611
Original Basic Science—General
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Background. Mesenchymal stromal cells (MSCs) have protolerogenic effects in renal transplantation, but they induce long-term regulatory T cells (Treg)-dependent graft acceptance only when infused before transplantation. When given posttransplant, MSCs home to the graft where they promote engraftment syndrome and do not induce Treg. Unfortunately, pretransplant MSC administration is unfeasible in deceased-donor kidney transplantation.

Methods. To make MSCs a therapeutic option also for deceased organ recipients, we tested whether MSC infusion at the time of transplant (day 0) or posttransplant (day 2) together with inhibition of complement receptors prevents engraftment syndrome and allows their homing to secondary lymphoid organs for promoting tolerance. We analyzed intragraft and splenic MSC localization, graft survival, and alloimmune response in mice recipients of kidney allografts and syngeneic MSCs given on day 0 or on posttransplant day 2. C3a receptor (C3aR) or C5a receptor (C5aR) antagonists were administered to mice in combination with the cells or were used together to treat MSCs before infusion.

Results. Syngeneic MSCs given at day 0 homed to the spleen increased Treg numbers and induced long-term graft acceptance. Posttransplant MSC infusion, combined with a short course of C3aR or C5aR antagonist or administration of MSCs pretreated with C3aR and C5aR antagonists, prevented intragraft recruitment of MSCs and graft inflammation, inhibited antidonor T-cell reactivity, but failed to induce Treg, resulting in mild prolongation of graft survival.

Conclusions. These data support testing the safety/efficacy profile of administering MSCs on the day of transplant in deceased-donor transplant recipients and indicate that complement is crucial for MSC recruitment into the kidney allograft.

1 IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Bergamo, Italy.

2 Icahn School of Medicine at Mount Sinai, New York, NY.

3 Lillian S. Wells Department of Neurosurgery, University of Florida, Gainesville, FL.

4 Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy.

5 L. Sacco Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy.

Received 6 June 2018. Revision received 17 December 2018.

Accepted 30 December 2018.

The authors declare no conflicts of interest.

This study has been partially supported by grants from Fondazione ART per la Ricerca sui Trapianti (Milan, Italy).

F.C., P.C., and G.R. participated in research design, analyzed the data, and wrote the article; M.T., S.F., and A.K. performed the biochemical and ex vivo immune assays, C.R. prepared mesenchymal stromal cell; P.C., S.S. S.F., and C.C. performed immunohistochemical experiments; N.A. performed kidney transplant experiments; and M.N., N.P., and G.R. gave intellectual input for study design and revised the article.

Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantjournal.com).

Correspondence: Federica Casiraghi, PhD, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Via GB Camozzi 3, 24020 Ranica, Bergamo, Italy. (federica.casiraghi@marionegri.it)

Paolo Cravedi, MD, PhD, Department of Medicine, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029. (paolo.cravedi@mssm.edu).

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