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Lentivirus IL‐10 Gene Therapy Down‐Regulates IL‐17 and Attenuates Mouse Orthotopic Lung Allograft Rejection
Author(s) -
Hirayama S.,
Sato M.,
LoiselMeyer S.,
Matsuda Y.,
Oishi H.,
Guan Z.,
Saito T.,
Yeung J.,
Cypel M.,
Hwang D. M.,
Medin J. A.,
Liu M.,
Keshavjee S.
Publication year - 2013
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/ajt.12230
Subject(s) - lentivirus , genetic enhancement , luciferase , medicine , lung transplantation , immunology , transplantation , isograft , lung , immune system , cancer research , gene , biology , transfection , virus , viral disease , biochemistry
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.