Third-party bone marrow-derived mesenchymal stromal cell infusion before liver transplantation: A randomized controlled trial

Federica Casiraghi, Norberto Perico, Manuel A Podestà, Marta Todeschini, Marco Zambelli, Michele Colledan, Stefania Camagni, Stefano Fagiuoli, Antonio D Pinna, Matteo Cescon, Valentina Bertuzzo, Lorenzo Maroni, Martino Introna, Chiara Capelli, Josee T Golay, Marina Buzzi, Marilena Mister, Pamela Y R Ordonez, Matteo Breno, Caterina Mele, Alessandro Villa, Giuseppe Remuzzi, MSC-LIVER Study Group, Marco F Zambelli, Giulia Magini, Anna Baldan, Maria G Lucà, Loredana Rota, Matteo Ravaioli, Mariacristina Morelli, Olga Pedrini, Sabrina Manara, Barbara Morara, Nadia Rubis, Olimpia Diadei, Davide Martinetti, Sergio Carminati, Giovanni A Giuliano, Paola Boccardo, Sara Peracchi, Federica Casiraghi, Norberto Perico, Manuel A Podestà, Marta Todeschini, Marco Zambelli, Michele Colledan, Stefania Camagni, Stefano Fagiuoli, Antonio D Pinna, Matteo Cescon, Valentina Bertuzzo, Lorenzo Maroni, Martino Introna, Chiara Capelli, Josee T Golay, Marina Buzzi, Marilena Mister, Pamela Y R Ordonez, Matteo Breno, Caterina Mele, Alessandro Villa, Giuseppe Remuzzi, MSC-LIVER Study Group, Marco F Zambelli, Giulia Magini, Anna Baldan, Maria G Lucà, Loredana Rota, Matteo Ravaioli, Mariacristina Morelli, Olga Pedrini, Sabrina Manara, Barbara Morara, Nadia Rubis, Olimpia Diadei, Davide Martinetti, Sergio Carminati, Giovanni A Giuliano, Paola Boccardo, Sara Peracchi

Abstract

Mesenchymal stromal cells (MSC) have emerged as a promising therapy to minimize the immunosuppressive regimen or induce tolerance in solid organ transplantation. In this randomized open-label phase Ib/IIa clinical trial, 20 liver transplant patients were randomly allocated (1:1) to receive a single pretransplant intravenous infusion of third-party bone marrow-derived MSC or standard of care alone. The primary endpoint was the safety profile of MSC administration during the 1-year follow-up. In all, 19 patients completed the study, and none of those who received MSC experienced infusion-related complications. The incidence of serious and non-serious adverse events was similar in the two groups. Circulating Treg/memory Treg and tolerant NK subset of CD56bright NK cells increased slightly over baseline, albeit not to a statistically significant extent, in MSC-treated patients but not in the control group. Graft function and survival, as well as histologic parameters and intragraft expression of tolerance-associated transcripts in 1-year protocol biopsies were similar in the two groups. In conclusion, pretransplant MSC infusion in liver transplant recipients was safe and induced mild positive changes in immunoregulatory T and NK cells in the peripheral blood. This study opens the way for a trial on possible tolerogenic efficacy of MSC in liver transplantation. ClinicalTrials.gov identifier: NCT02260375.

Keywords: clinical research/practice; liver transplantation/hepatology; stem cells; tolerance.

© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.

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