Transbronchial administration of adenoviral-mediated interleukin-10 gene to the donor improves function in a pig lung transplant model
Transbronchial administration of adenoviral-mediated interleukin-10 gene to the donor improves function in a pig lung transplant model
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DOI：
10.1038/sj.gt.3302357
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发表时间：
2004-12-01
期刊：
影响因子：
5.1
通讯作者：
Keshavjee, S
中科院分区：
文献类型：
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作者：
Martins, S;de Perrot, M;Keshavjee, S
移植前对供体肺进行白介素 10 (IL-10) 基因转染是减少缺血再灌注引起的肺损伤的一种有吸引力的策略。然而，目前普遍缺乏大型动物肺移植模型中基因治疗的实验数据。我们开发了一种简单的临床适用技术，用于将人 IL-10 腺病毒介导的基因递送至大型动物的肺部，在转染 12 - 24 小时后提供同质基因表达。利用这种基因递送技术，我们研究了肺移植中腺病毒基因递送至肺部的动态。尽管腺病毒载体存在持续的炎症反应，但我们在肺修复之前在肺组织中实现了人IL-10的显着表达，以避免腺病毒载体对供体肺的有害影响。在该猪肺移植模型中，向供体肺施用腺病毒介导的人IL-10可减少肺移植后的缺血再灌注损伤并改善移植物功能。将腺病毒介导的人 IL-10 转染至供体肺，可阻止肺组织和血浆中炎症细胞因子（例如 IL-6）的释放。我们已经证明IL-10基因疗法在预防或治疗肺移植中与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耐受诱导。
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.