Martins S, de Perrot M, Imai Y, Yamane M, Quadri S M, Segall L, Dutly A, Sakiyama S, Chaparro A, Davidson B L, Waddell T K, Liu M, Keshavjee S
Thoracic Surgery Research Laboratory, Toronto General Hospital Research Institute, University Health Network, University of Toronto, Toronto, ON, Canada.
Gene Ther. 2004 Dec;11(24):1786-96. doi: 10.1038/sj.gt.3302357.
Interleukin-10 (IL-10) gene transfection of donor lungs prior to transplantation is an attractive strategy to reduce ischemia-reperfusion induced lung injury. However, experimental data with gene therapy in large animal models of lung transplantation are generally lacking. We have developed a simple clinically applicable technique for adenoviral-mediated gene delivery of human IL-10 to the lung of large animals that provides homogenous gene expression after 12-24 h of transfection. Using this technique of gene delivery, we have studied the dynamics of adenoviral gene delivery to the lung in the setting of lung transplantation. Although there is a persistent inflammatory response to the adenoviral vector, we achieved significant expression of human IL-10 in lung tissue before lung retrieval to obviate the deleterious impact of the adenoviral vector on the donor lung. The administration of adenoviral-mediated human IL-10 to the donor lung reduced ischemia-reperfusion injury and improved graft function after lung transplantation in this pig lung transplantation model. Transfection of adenoviral-mediated human IL-10 to the donor lung prevented the release of inflammatory cytokines such as IL-6 in lung tissue and plasma. We have demonstrated that IL-10 gene therapy has significant potential to prevent or treat the inflammatory response associated with ischemia-reperfusion injury in lung transplantation. In the future, IL-10 gene therapy could also be used for immunomodulation or tolerance induction.
移植前对供体肺进行白细胞介素-10（IL-10）基因转染是减轻缺血再灌注诱导的肺损伤的一种有吸引力的策略。然而，在大型动物肺移植模型中进行基因治疗的实验数据普遍缺乏。我们开发了一种简单的、可应用于临床的技术，用于将人IL-10通过腺病毒介导的基因传递至大型动物的肺，该技术在转染12 - 24小时后可提供均匀的基因表达。利用这种基因传递技术，我们研究了在肺移植背景下腺病毒基因传递至肺的动力学。尽管对腺病毒载体存在持续的炎症反应，但我们在肺获取前在肺组织中实现了人IL-10的显著表达，以消除腺病毒载体对供体肺的有害影响。在这个猪肺移植模型中，向供体肺给予腺病毒介导的人IL-10可减轻缺血再灌注损伤并改善肺移植后的移植物功能。将腺病毒介导的人IL-10转染至供体肺可防止肺组织和血浆中炎性细胞因子如IL-6的释放。我们已经证明，IL-10基因治疗在预防或治疗与肺移植缺血再灌注损伤相关的炎症反应方面具有巨大潜力。未来，IL-10基因治疗还可用于免疫调节或诱导免疫耐受。
