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

Background. Mesenchymal stromal cells (MSCs) have pro-tolerogenic effects in renal transplantation, but they induce long-term 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 Tregs. 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. C3aR or 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 anti-donor T-cell reactivity, but failed to induce Tregs, resulting in mild prolongation of graft survival. Conclusion. 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. DISCLOSURE: The Authors declare no conflicts of interest. FUNDING: This study has been partially supported by grants from Fondazione ART per la Ricerca sui Trapianti (Milan, Italy). PC is supported by NIH grant R01 AI132949 and by the GOFARR Fundand. Correspondence to: Federica Casiraghi, PhD, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri Via GB Camozzi 3, 24020 Ranica (Bergamo), Italy. Email: federica.casiraghi@marionegri.it Phone: +39 035 4535361, Fax: +39 035 4535377 Paolo Cravedi, MD, PhD, Department of Medicine, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, USA. Email: paolo.cravedi@mssm.edu, Phone: +1 212 241 3349, Fax: +1 212 987 0389 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

https://ift.tt/2tKUgiM