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Войти в исследования The Journal of thoracic and cardiovascular surgery · 2018
A novel combined ex vivo and in vivo lentiviral interleukin-10 gene delivery strategy at the time of transplantation decreases chronic lung allograft rejection in mice.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Oishi Hisashi, Juvet Stephen C, Martinu Tereza, Sato Masaaki, Medin Jeffrey A, Liu Mingyao, Keshavjee Shaf
Аннотация
OBJECTIVE: Our objective was to develop a rapid-onset and durable gene-delivery strategy that is applicable at the time of transplant to determine its effects on both acute rejection and chronic lung allograft fibrosis using a mouse orthotopic lung transplant model.
METHODS: C57BL/6 mice received an orthotopic left lung transplant from syngeneic donors or C57BL/10 donors. By using syngeneic lung transplantation, we established a novel gene transfer protocol with lentivirus luciferase intrabronchial administration to the donor lung ex vivo before transplantation. This strategy was applied in allogeneic lung transplantation with lentivirus engineering expression of human interleukin-10 or lentivirus luciferase (control).
RESULTS: Bioluminescent imaging revealed that the highest early transgene expression was achieved when lentivirus luciferase was administered both directly into the donor lung graft ex vivo before implantation and subsequently to the recipient in vivo daily on post-transplant days 1 to 4, compared with post-transplant in vivo administration only (days 0 to 4). Our previous work with adenoviral interleukin-10 gene therapy indicates that early interleukin-10 expression in the allograft is desirable. Therefore, we selected the combined protocol for human interleukin-10 encoding lentiviral vector therapy. In the allogeneic transplant setting, ex vivo and in vivo human interleukin-10 encoding lentiviral vector therapy reduced acute rejection grade (2.0 vs 3.0, P < .05) at day 28. The percentage of fibrotic obliterated airways was reduced in the human interleukin-10 encoding lentiviral vector-treated group (10.9% ± 7.7% vs 40.9% ± 9.3%, P < .05).
CONCLUSIONS: Delivery of lentiviral interleukin-10 gene therapy, using a novel combined ex vivo and in vivo delivery strategy, significantly improves acute and chronic rejection in the mouse lung transplant model.
METHODS: C57BL/6 mice received an orthotopic left lung transplant from syngeneic donors or C57BL/10 donors. By using syngeneic lung transplantation, we established a novel gene transfer protocol with lentivirus luciferase intrabronchial administration to the donor lung ex vivo before transplantation. This strategy was applied in allogeneic lung transplantation with lentivirus engineering expression of human interleukin-10 or lentivirus luciferase (control).
RESULTS: Bioluminescent imaging revealed that the highest early transgene expression was achieved when lentivirus luciferase was administered both directly into the donor lung graft ex vivo before implantation and subsequently to the recipient in vivo daily on post-transplant days 1 to 4, compared with post-transplant in vivo administration only (days 0 to 4). Our previous work with adenoviral interleukin-10 gene therapy indicates that early interleukin-10 expression in the allograft is desirable. Therefore, we selected the combined protocol for human interleukin-10 encoding lentiviral vector therapy. In the allogeneic transplant setting, ex vivo and in vivo human interleukin-10 encoding lentiviral vector therapy reduced acute rejection grade (2.0 vs 3.0, P < .05) at day 28. The percentage of fibrotic obliterated airways was reduced in the human interleukin-10 encoding lentiviral vector-treated group (10.9% ± 7.7% vs 40.9% ± 9.3%, P < .05).
CONCLUSIONS: Delivery of lentiviral interleukin-10 gene therapy, using a novel combined ex vivo and in vivo delivery strategy, significantly improves acute and chronic rejection in the mouse lung transplant model.