Persistent transgene expression following intravenous administration of a liposomal complex: role of interleukin-10-mediated immune suppression.
Persistent transgene expression following intravenous administration of a liposomal complex: role of interleukin-10-mediated immune suppression.
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DOI：
10.1016/j.ymthe.2004.01.007
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发表时间：
2004-03
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影响因子：
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通讯作者：
Isao Ito;Tomoyuki Saeki;I. Mohuiddin;Yuji Saito;C. Branch;A. Vaporciyan;J. Roth;R. Ramesh
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文献类型：
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作者：
Isao Ito;Tomoyuki Saeki;I. Mohuiddin;Yuji Saito;C. Branch;A. Vaporciyan;J. Roth;R. Ramesh
在非肿瘤免疫活性小鼠中进行的研究表明，静脉注射脂质体-DNA 复合物会引发炎症反应，导致无法维持足够的转基因表达。然而，在本研究中，我们研究了阳离子脂质体DOTAP：胆固醇（DOTAP：Chol）-DNA复合物对实验性肺肿瘤（TB）小鼠和非肿瘤（NTB）同系小鼠和裸鼠中细胞因子产生和转基因表达的影响。静脉注射 DOTAP:Chol-荧光素酶 (luc) DNA 复合物导致 TB 小鼠的肿瘤坏死因子-α 水平比 NTB 小鼠低 50%，白介素-10 水平比 NTB 小鼠高 50-60%。此外，在结核病小鼠中观察到 luc 表达显着增加（P = 0.001），并持续 7 天。相比之下，NTB 小鼠中 luc 表达从第 1 天到第 2 天显着下降。此外，多次注射 DOTAP:Chol-luccomplex 的 TB 小鼠的 luc 表达量比接受单次注射的小鼠高两到三倍。相比之下，NTB 小鼠多次注射后 luc 表达显着受到抑制（P = 0.01）。进一步分析揭示了结核小鼠肿瘤细胞表达 IL-10 蛋白。与注射对照抗体的小鼠相比，在TB小鼠中注射抗IL-10抗体导致luc表达显着降低（P=0.01）。基于这些发现，我们得出结论，转基因表达在结核病小鼠中持续存在，并且部分由 IL-10 介导。此外，多次注射脂质体-DNA复合物可以增加结核病小鼠的转基因表达。这些发现在癌症治疗中具有临床应用。
Studies conducted in non-tumor-bearing, immunocompetent mice have shown that intravenous administration of liposome–DNA complex elicits an inflammatory response that results in a failure to sustain adequate transgene expression. In the present study, however, we investigated the effects of a cationic liposomal DOTAP:cholesterol (DOTAP:Chol)–DNA complex on cytokine production and transgene expression in both experimental lung tumor-bearing (TB) mice and non-tumor-bearing (NTB) syngeneic mice and nude mice. Intravenous injection of DOTAP:Chol–luciferase (luc) DNA complex resulted in tumor necrosis factor-α levels that were 50% lower and interleukin-10 levels that were 50–60% higher in TB mice than in NTB mice. Furthermore, a significant increase in luc expression (P= 0.001) that persisted for 7 days was observed in TB mice. In contrast, luc expression decreased significantly from day 1 to day 2 in NTB mice. Also, luc expression was two- to threefold higher in TB mice that were given multiple injections of DOTAP:Chol-luccomplex than in mice who received a single injection. In contrast, luc expression was significantly suppressed following multiple injections in NTB mice (P= 0.01). Further analysis revealed IL-10 protein expression by the tumor cells in TB mice. Injection of anti-IL-10 antibody in TB mice resulted in a significant decrease in luc expression (P= 0.01) compared with that in mice injected with a control antibody. Based on these findings, we conclude that transgene expression persists in TB mice and is partly mediated by IL-10. Additionally, multiple injections of liposome–DNA complex can increase transgene expression in TB mice. These findings have clinical applications in the treatment of cancer.