title: Lentivirus IL-10 gene therapy down-regulates IL-17 and attenuates mouse orthotopic lung allograft rejection.
abstract: 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.
authors.affiliation: Latner Thoracic Surgery Research Laboratories, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Hirayama
authors.forename: M
authors.initials: M
authors.lastname: Sato
authors.forename: S
authors.initials: S
authors.lastname: Loisel-Meyer
authors.forename: Y
authors.initials: Y
authors.lastname: Matsuda
authors.forename: H
authors.initials: H
authors.lastname: Oishi
authors.forename: Z
authors.initials: Z
authors.lastname: Guan
authors.forename: T
authors.initials: T
authors.lastname: Saito
authors.forename: J
authors.initials: J
authors.lastname: Yeung
authors.forename: M
authors.initials: M
authors.lastname: Cypel
authors.forename: D M
authors.initials: DM
authors.lastname: Hwang
authors.forename: J A
authors.initials: JA
authors.lastname: Medin
authors.forename: M
authors.initials: M
authors.lastname: Liu
authors.forename: S
authors.initials: S
authors.lastname: Keshavjee
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D006084:Graft Rejection / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D006085:Graft Survival / Q000235:genetics; D016753:Interleukin-10 / Q000235:genetics / Q000627:therapeutic use*; D020381:Interleukin-17 / Q000096:biosynthesis / Q000235:genetics*; D016086:Lentivirus / Q000235:genetics*; D016040:Lung Transplantation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D012313:RNA / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D014184:Transplantation, Homologous
chemical_list: D020381:Interleukin-17; D016753:Interleukin-10; D012313:RNA