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首页> 外文期刊>Journal of the American Society of Nephrology: JASN >Targeting of Macrophage Activity by Adenovirus-Mediated Intragraft Overexpression of TNFRp55-Ig, IL-12p40, and vIL-10 Ameliorates Adenovirus-Mediated Chronic Graft Injury, whereas Stimulation of Macrophages by Overexpression of IFN-gamma Accelerates
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Targeting of Macrophage Activity by Adenovirus-Mediated Intragraft Overexpression of TNFRp55-Ig, IL-12p40, and vIL-10 Ameliorates Adenovirus-Mediated Chronic Graft Injury, whereas Stimulation of Macrophages by Overexpression of IFN-gamma Accelerates

机译：腺病毒介导的TNFRp55-Ig，IL-12p40和vIL-10的移植物内过表达的巨噬细胞活性靶向改善了腺病毒介导的慢性移植物损伤，而IFN-γ的过表达促进了巨噬细胞的刺激。

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ABSTRACT. Adenovirus (Ad)-mediated gene transfer of immunoregulatory molecules prevents acute allograft rejection. It is here analyzed for the first time whether this approach may prevent the development of chronic renal allograft injury in rats. Renal allografts (F344-->Lewis rat) were ex vivo transduced in group I with control Ad-construct, group II with three different therapeutic Ad-constructs expressing the immunoregulatory molecules vIL-10, TNFRp55-Ig, and IL-12p40, and group III with AdIFN-gamma. Group IV served as untreated controls. Control grafts (IV) showed increasing proteinuria during the 24-wk follow-up. Chronic graft injury was accelerated by Ad-control (I) and even more by AdIFN-gamma (III). All rats carrying the AdIFN-gamma-transduced grafts died within 12 to 13 wk by advanced chronic renal failure associated with strong immune cell infiltration and immune gene expression. By contrast, the Ad-therapy group II showed less inflammation and improved graft histology and function if compared with the groups I and III. Moreover, significantly less infiltrating ED-1(+) macrophages and an improved histologic score even if compared with untreated controls (IV) was observed. However, after disappearance of therapeutic gene expression, group II showed increasing proteinuria probably as result of late T cell activation to the Ad-encoded proteins. Ex vivo transduction of allografts with Ad-control or even more AdIFN-gamma expression promotes intragraft inflammation and chronic graft injury. Targeting macrophage activation by a cocktail of therapeutic genes improved the results. These data support the pathogenetic role of cytokines in chronic graft injury; however, they also show the limitations of the Ad-mediated gene transfer. E-mail: thomas.ritter@charite.de
机译：抽象。腺病毒（Ad）介导的免疫调节分子的基因转移可防止急性同种异体移植排斥。本文首次分析了这种方法是否可以预防大鼠慢性肾移植的发展。肾同种异体移植物（F344-> Lewis大鼠）在具有对照Ad-con的I组，具有表达免疫调节分子vIL-10，TNFRp55-Ig和IL-12p40的三种不同治疗性Ad-con的II组中离体转导，第III组具有AdIFN-γ。 IV组用作未治疗的对照。对照移植物（IV）在24周随访期间显示蛋白尿增加。慢性移植物损伤通过Ad-control（I）加速，甚至进一步通过AdIFN-γ（III）加速。所有携带AdIFN-γ转导的移植物的大鼠均在12至13周内因与强大的免疫细胞浸润和免疫基因表达相关的晚期慢性肾衰竭而死亡。相比之下，与I和III组相比，Ad治疗组II的炎症更少，移植物的组织学和功能得到改善。此外，即使与未治疗的对照组（IV）相比，ED-1（+）巨噬细胞浸润明显减少，组织学评分也得到改善。然而，在治疗性基因表达消失后，II组显示出蛋白尿增加，这可能是由于晚期T细胞激活了Ad编码蛋白的结果。具有Ad-control或什至更多AdIFN-γ表达的同种异体移植物的离体转导促进了移植物中的炎症和慢性移植物损伤。通过治疗基因的混合物靶向巨噬细胞活化改善了结果。这些数据支持细胞因子在慢性移植物损伤中的致病作用。但是，它们也显示了Ad介导的基因转移的局限性。电子邮件：thomas.ritter@charite.de

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