Trittibach P, Barker S E, Broderick C A, Natkunarajah M, Duran Y, Robbie S J, Bainbridge J W B, Smith A J, Sarra G-M, Dick A D, Ali R R
Division of Molecular Therapy, Institute of Ophthalmology, University College London, London, UK.
Gene Ther. 2008 Nov;15(22):1478-88. doi: 10.1038/gt.2008.109. Epub 2008 Jun 26.
Uveitis is a sight threatening inflammatory disorder that remains a significant cause of visual loss. We investigated lentiviral gene delivery of interleukin 1 receptor antagonist (IL-1ra) or interleukin (IL)-10 to ameliorate murine endotoxin-induced uveitis (EIU). An human immunodeficiency virus-1-based vector containing the mIL-1ra or mIL-10 cDNA demonstrated high expression of biologically active cytokine. Following administration of Lenti.GFP into the anterior chamber, transgene expression was observed in corneal endothelial cells, trabecular meshwork and iris cells. To treat EIU, mice were injected with Lenti.IL-1ra, Lenti.IL-10 or a combination of these. EIU was induced 14 days after vector administration and mice were culled 12 h following disease induction. Lenti.IL-1ra or Lenti.IL-10-treated eyes showed significantly lower mean inflammatory cell counts in the anterior and posterior chambers compared with controls. The aqueous total protein content was also significantly lower in treated eyes, demonstrating better preservation of the blood-ocular barrier. Furthermore, the treated eyes showed less in vivo fluorescein leakage from inner retinal vessels compared with controls. The combination of both IL-1ra and IL-10 had no additive effect. Thus, lentiviral gene delivery of IL-1ra or IL-10 significantly reduces the severity of experimental uveitis, suggesting that lentiviral-mediated expression of immunomodulatory genes in the anterior chamber offers an opportunity to treat uveitis.
葡萄膜炎是一种威胁视力的炎症性疾病，仍然是导致视力丧失的重要原因。我们研究了慢病毒介导的白细胞介素1受体拮抗剂（IL-1ra）或白细胞介素（IL）-10基因递送，以改善小鼠内毒素诱导的葡萄膜炎（EIU）。一种基于人类免疫缺陷病毒1的载体，含有小鼠IL-1ra或小鼠IL-10 cDNA，可高表达具有生物活性的细胞因子。在前房注射慢病毒绿色荧光蛋白（Lenti.GFP）后，在角膜内皮细胞、小梁网和虹膜细胞中观察到转基因表达。为了治疗EIU，给小鼠注射Lenti.IL-1ra、Lenti.IL-10或两者的组合。在载体给药14天后诱导EIU，在疾病诱导后12小时处死小鼠。与对照组相比，Lenti.IL-1ra或Lenti.IL-10治疗的眼睛在前房和后房中的平均炎症细胞计数显著降低。治疗组眼睛的房水总蛋白含量也显著降低，表明血眼屏障得到了更好的保护。此外，与对照组相比，治疗组眼睛的视网膜内血管在体内的荧光素渗漏较少。IL-1ra和IL-10联合使用没有相加作用。因此，慢病毒介导的IL-1ra或IL-10基因递送显著降低了实验性葡萄膜炎的严重程度，这表明在前房慢病毒介导的免疫调节基因表达为治疗葡萄膜炎提供了一个机会。
