α1-antitrypsin gene therapy modulates cellular immunity and efficiently prevents type 1 diabetes in nonobese diabetic mice
α1-antitrypsin gene therapy modulates cellular immunity and efficiently prevents type 1 diabetes in nonobese diabetic mice
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DOI：
10.1089/hum.2006.17.625
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发表时间：
2006-06-01
影响因子：
4.2
通讯作者：
Song, Sihong
中科院分区：
文献类型：
--
作者：
Lu, Yuanqing;Tang, Mei;Song, Sihong
免疫调节途径的失衡在1型糖尿病的发生中发挥着重要作用。因此，免疫调节和免疫抑制策略对于预防这种自身免疫性疾病具有很大的潜力。研究表明，两种丝氨酸蛋白酶抑制剂，α（1）-抗胰蛋白酶（AAT）和弹性蛋白酶，作为有效的抗肿瘤剂。在本研究中，我们试图开发一种有效的基因治疗方法来预防1型糖尿病。用rAAV 1-CB-hAAT、rAAV 1-CB-hElafin或盐水肌内注射4周龄雌性非肥胖糖尿病（NOD）小鼠的群组。AAV 1载体介导持续高水平的转基因表达，足以克服针对hAAT的体液免疫反应。AAT基因治疗对1型糖尿病的预防效果明显优于弹力素和生理盐水。T细胞受体谱表明，AAT基因治疗改变了NOD小鼠脾细胞中T细胞库的多样性。连续转移实验表明，AAT基因治疗减弱了与β细胞破坏相关的细胞免疫。这项研究表明，AAT基因治疗减弱细胞介导的自身免疫，改变T细胞受体库，并有效地预防NOD小鼠模型中的1型糖尿病。这些结果强烈表明，rAAV 1介导的AAT基因治疗可能是预防1型糖尿病的一种新方法。
An imbalance of the immune-regulatory pathways plays an important role in the development of type 1 diabetes. Therefore, immunoregulatory and antiinflammatory strategies hold great potential for the prevention of this autoimmune disease. Studies have demonstrated that two serine proteinase inhibitors, alpha(1)-antitrypsin (AAT) and elafin, act as potent antiinflammatory agents. In the present study, we sought to develop an efficient gene therapy approach to prevent type 1 diabetes. Cohorts of 4-week-old female nonobese diabetic (NOD) mice were injected intramuscularly with rAAV1-CB-hAAT, rAAV1-CB-hElafin, or saline. AAV1 vector mediated sustained high levels of transgene expression, sufficient to overcome a humoral immune response against hAAT. AAT gene therapy, contrary to elafin and saline, was remarkably effective in preventing type 1 diabetes. T cell receptor spectratyping indicated that AAT gene therapy altered T cell repertoire diversity in splenocytes from NOD mice. Adoptive transfer experiments demonstrated that AAT gene therapy attenuated cellular immunity associated with beta cell destruction. This study demonstrates that AAT gene therapy attenuates cell-mediated autoimmunity, alters the T cell receptor repertoire, and efficiently prevents type 1 diabetes in the NOD mouse model. These results strongly suggest that rAAV1-mediated AAT gene therapy may be useful as a novel approach to prevent type 1 diabetes.