Prevention and reversal of lupus in NZB/NZW mice by costimulatory blockade with adeno-associated virus-mediated gene transfer.
Prevention and reversal of lupus in NZB/NZW mice by costimulatory blockade with adeno-associated virus-mediated gene transfer.
复制标题
通过腺相关病毒介导的基因转移共刺激阻断来预防和逆转 NZB/NZW 小鼠狼疮。
DOI：
10.1002/art.21417
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发表时间：
2005
影响因子：
--
通讯作者：
Xiao,Xiao
中科院分区：
文献类型：
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作者：
Ye,Xiaojing;Zhu,Tong;Bastacky,Sheldon;McHale,Teresa;Li,Juan;Xiao,Xiao
目的探讨腺相关病毒（AAV）介导的基因转移共刺激阻断在小鼠模型中预防和逆转狼疮的功效。方法将表达CTLA-4Ig或CD40Ig的AAV载体注射到NZB/NZW小鼠体内。通过酶联免疫吸附测定测定转基因表达和自身抗体滴度的血清水平。评估对蛋白尿、肾脏病理特征和生存率的治疗效果。通过流式细胞术分析脾T细胞表型。还检查了治疗小鼠对外来抗原的体液免疫反应。结果在新生 NZB/NZW 小鼠狼疮发病前单次注射 AAV 血清型 8 (AAV8)-CTLA-4Ig 可以有效延迟和抑制自身抗体产生、蛋白尿和肾脏损伤，并延长其寿命。此外，将AAV8-CTLA-4Ig和AAV8-CD40Ig载体共同注射到新生小鼠体内达到了协同效应，疗效最佳。预防作用归因于抑制 CD4+ T 细胞活化以及从幼稚 T 细胞向记忆 T 细胞的转变。此外，在成年小鼠体内同时注射这两种载体可以逆转现有的自身抗体水平，抑制蛋白尿的发展，并延长其寿命。发现治疗效果取决于载体剂量。此外，AAV介导的长期基因表达并没有严重抑制宿主对外源抗原的体液反应。结论我们的研究结果表明，通过AAV载体传递共刺激抑制剂转基因可以预防和逆转该小鼠模型中的狼疮，这表明AAV介导的基因转移有可能作为狼疮的替代治疗方法。
ObjectiveTo investigate the potency of costimulatory blockade with adeno‐associated virus (AAV)–mediated gene transfer in the prevention and reversal of lupus in a murine model.MethodsAAV vectors expressing CTLA‐4Ig or CD40Ig were injected into NZB/NZW mice. Serum levels of transgene expression and autoantibody titers were determined by enzyme‐linked immunosorbent assay. The therapeutic effects on proteinuria, renal pathologic features, and survival rate were evaluated. Splenic T cell phenotypes were analyzed by flow cytometry. The humoral immune response to a foreign antigen was also examined in treated mice.ResultsA single injection of AAV serotype 8 (AAV8)–CTLA‐4Ig in neonatal NZB/NZW mice before the onset of lupus effectively delayed and inhibited autoantibody production, proteinuria, and kidney damage and prolonged their lifespan. In addition, coinjection of AAV8‐CTLA‐4Ig and AAV8‐CD40Ig vectors into neonatal mice achieved a synergistic effect and the best efficacy. The preventive effects were attributed to suppression of CD4+ T cell activation and the transition from naive to memory T cells. Moreover, coinjection of these 2 vectors in adult mice reversed the existing autoantibody levels, suppressed the development of proteinuria, and prolonged their lifespan. The therapeutic effects were found to be dependent on the vector dose. In addition, AAV‐mediated long‐term gene expression did not severely suppress the host humoral response to foreign antigen.ConclusionOur findings show that delivery of costimulatory inhibitor transgenes by AAV vectors could prevent and reverse lupus in this murine model, suggesting the potential of AAV‐mediated gene transfer as an alternative treatment for lupus.