Moufida Ben Nasr1,2, Andrea Vergani1,2, James Avruch3, Liye Liu3, Eirini Kefaloyianni4, Francesca D'Addio1,2, Sara Tezza1, Domenico Corradi5, Roberto Bassi1, Alessandro Valderrama-Vasquez2, Vera Usuelli2, James Kim3, Jamil Azzi6, Basset El Essawy7, James Markmann3, Reza Abdi6, Paolo Fiorina8,9. 1. Nephrology Division, Boston Children's Hospital, Harvard Medical School, Enders Building 5th Floor Room EN511, 300 Longwood Ave, Boston, MA, USA. 2. Transplant Medicine, Ospedale San Raffaele, Milan, Italy. 3. Transplantation Unit, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA. 4. Renal Division, Brigham and Women's Hospital, Harvard Institute of Medicine, HIM510, Harvard Medical School, Boston, MA, 02115, USA. 5. Pathology and Laboratory Medicine, University of Parma, Parma, Italy. 6. Nephrology Division, Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. 7. Department of Medicine, Al-Azhar University, Cairo, Egypt. 8. Nephrology Division, Boston Children's Hospital, Harvard Medical School, Enders Building 5th Floor Room EN511, 300 Longwood Ave, Boston, MA, USA. paolo.fiorina@childrens.harvard.edu. 9. Transplant Medicine, Ospedale San Raffaele, Milan, Italy. paolo.fiorina@childrens.harvard.edu.
Abstract
AIMS: Mesenchymal stem cells (MSCs) are multipotent cells with immunomodulatory properties. We tested the ability of MSCs to delay islet allograft rejection. METHODS: Mesenchymal stem cells were generated in vitro from C57BL/6 and BALB/c mice bone marrow, and their immunomodulatory properties were tested in vitro. We then tested the effect of a local or systemic administration of heterologous and autologous MSCs on graft survival in a fully allogeneic model of islet transplantation (BALB/c islets into C57BL/6 mice). RESULTS: In vitro, autologous, but not heterologous, MSCs abrogated immune cell proliferation in response to alloantigens and skewed the immune response toward a Th2 profile. A single dose of autologous MSCs co-transplanted under the kidney capsule with allogeneic islets delayed islet rejection, reduced graft infiltration, and induced long-term graft function in 30 % of recipients. Based on ex vivo analysis of recipient splenocytes, the use of autologous MSCs did not appear to have any systemic effect on the immune response toward graft alloantigens. The systemic injection of autologous MSCs or the local injection of heterologous MSCs failed to delay islet graft rejection. CONCLUSION: Autologous, but not heterologous, MSCs showed multiple immunoregulatory properties in vitro and delayed allograft rejection in vivo when co-transplanted with islets; however, they failed to prevent rejection when injected systemically. Autologous MSCs thus appear to produce a local immunoprivileged site, which promotes graft survival.
AIMS: Mesenchymal stem cells (MSCs) are multipotent cells with immunomodulatory properties. We tested the ability of MSCs to delay islet allograft rejection. METHODS: Mesenchymal stem cells were generated in vitro from C57BL/6 and BALB/c mice bone marrow, and their immunomodulatory properties were tested in vitro. We then tested the effect of a local or systemic administration of heterologous and autologous MSCs on graft survival in a fully allogeneic model of islet transplantation (BALB/c islets into C57BL/6 mice). RESULTS: In vitro, autologous, but not heterologous, MSCs abrogated immune cell proliferation in response to alloantigens and skewed the immune response toward a Th2 profile. A single dose of autologous MSCs co-transplanted under the kidney capsule with allogeneic islets delayed islet rejection, reduced graft infiltration, and induced long-term graft function in 30 % of recipients. Based on ex vivo analysis of recipient splenocytes, the use of autologous MSCs did not appear to have any systemic effect on the immune response toward graft alloantigens. The systemic injection of autologous MSCs or the local injection of heterologous MSCs failed to delay islet graft rejection. CONCLUSION: Autologous, but not heterologous, MSCs showed multiple immunoregulatory properties in vitro and delayed allograft rejection in vivo when co-transplanted with islets; however, they failed to prevent rejection when injected systemically. Autologous MSCs thus appear to produce a local immunoprivileged site, which promotes graft survival.
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