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Lentivirus IL-10 gene therapy down-regulates IL-17 and attenuates mouse orthotopic lung allograft rejection
S Hirayama1, M Sato, S Loisel-Meyer
1Latner Thoracic Surgery Research Laboratories, University Health Network, University of Toronto, Toronto, Ontario, Canada.
The purpose of the study was to examine the effect of lentivirus-mediated IL-10 gene therapy to target lung allograft rejection in a mouse orthotopic left lung transplantation model. IL-10 may regulate posttransplant immunity mediated by IL-17. Lentivirus-mediated trans-airway luciferase gene transfer to the donor lung resulted in persistent luciferase activity up to 6 months posttransplant in the isograft (B6 to B6); luciferase activity decreased in minor-mismatched allograft lungs (B10 to B6) in association with moderate rejection. Fully MHC-mismatched allograft transplantation (BALB/c to B6) resulted in severe rejection and complete loss of luciferase activity. In minor-mismatched allografts, IL-10-encoding lentivirus gene therapy reduced the acute rejection score compared with the lentivirus-luciferase control at posttransplant day 28 (3.0 ± 0.6 vs. 2.0 ± 0.6 (mean ± SD); p = 0.025; n = 6/group). IL-10 gene therapy also significantly reduced gene expression of IL-17, IL-23, and retinoic acid-related orphan receptor (ROR)-γt without affecting levels of IL-12 and interferon-γ (IFN-γ). Cells expressing IL-17 were dramatically reduced in the allograft lung. In conclusion, lentivirus-mediated IL-10 gene therapy significantly reduced expression of IL-17 and other associated genes in the transplanted allograft lung and attenuated posttransplant immune responses after orthotopic lung transplantation.
The purpose of the study was to examine the effect of lentivirus-mediated IL-10 gene therapy to target lung allograft rejection in a mouse orthotopic left lung transplantation model. IL-10 may regulate posttransplant immunity mediated by IL-17. Lentivirus-mediated trans-airway luciferase gene transfer to the donor lung resulted in persistent luciferase activity up to 6 months posttransplant in the isograft (B6 to B6); luciferase activity decreased in minor-mismatched allograft lungs (B10 to B6) in association with moderate rejection. Fully MHC-mismatched allograft transplantation (BALB/c to B6) resulted in severe rejection and complete loss of luciferase activity. In minor-mismatched allografts, IL-10-encoding lentivirus gene therapy reduced the acute rejection score compared with the lentivirus-luciferase control at posttransplant day 28 (3.0 ± 0.6 vs. 2.0 ± 0.6 (mean ± SD); p = 0.025; n = 6/group). IL-10 gene therapy also significantly reduced gene expression of IL-17, IL-23, and retinoic acid-related orphan receptor (ROR)-γt without affecting levels of IL-12 and interferon-γ (IFN-γ). Cells expressing IL-17 were dramatically reduced in the allograft lung. In conclusion, lentivirus-mediated IL-10 gene therapy significantly reduced expression of IL-17 and other associated genes in the transplanted allograft lung and attenuated posttransplant immune responses after orthotopic lung transplantation.
