Atorvastatin fails to prevent the development of autoimmune diabetes despite inhibition of pathogenic β-cell-specific CD8 T-cells
Atorvastatin fails to prevent the development of autoimmune diabetes despite inhibition of pathogenic β-cell-specific CD8 T-cells
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DOI：
10.2337/diabetes.55.04.06.db05-1261
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发表时间：
2006-04-01
期刊：
影响因子：
7.7
通讯作者：
Peakman, M
中科院分区：
文献类型：
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作者：
Lozanoska-Ochser, B;Barone, F;Peakman, M
他汀类药物是广泛使用的胆固醇生物合成抑制剂，也具有免疫调节特性。他汀类药物最近已被证明具有有益的预防和治疗作用，在积极诱导，自身免疫性疾病多发性硬化症和类风湿性关节炎的短期动物模型，导致临床试验。因此，我们研究了他汀类药物的保护作用是否可以在非肥胖糖尿病（NOD）小鼠，自发的，慢性自身免疫性糖尿病模型中重现。小鼠用0、1、10或50 mg（.）从6或12周龄开始，每天口服阿托伐他汀（-1）kg，对糖尿病发展、胰岛浸润或胰岛主要组织相容性复合物11类表达的速率或患病率无影响。然而，有明确的证据表明他汀类药物在体内具有疾病相关的免疫学效应，因为短期（12天）治疗显著减少了识别主要致病表位的促炎（产生γ-干扰素）CD 8细胞的数量。这种作用在较长时间治疗的小鼠中不存在，表明阿托伐他汀随着时间的推移而失去抑制自身抗原特异性T细胞的效率。这一观察结果可以解释他汀类药物在急性诱导模型中报告的成功与在慢性自发性自身免疫性疾病模型中缺乏成功之间的差异，并对人类采用这种治疗具有影响。
Statins, the widely used inhibitors of cholesterol biosynthesis, also have immunomodulatory properties. Statins have recently been shown to have beneficial prophylactic and therapeutic effects in actively induced, short-term animal models of the autoimmune diseases multiple sclerosis and rheumatoid arthritis, leading to clinical trials. We therefore investigated whether statins' protective effects could be reproduced in the nonobese diabetic (NOD) mouse, a spontaneous, chronic model of autoimmune diabetes. Mice were treated with 0, 1, 10, or 50 mg (.) kg(-1) day(-1) oral atorvastatin from 6 or 12 weeks of age, without effect on the rate or prevalence of diabetes development, islet infiltration, or islet major histocompatibility complex class 11 expression. However, there was clear evidence of a disease-relevant immunological effect of statins in vivo, since short-term (12-day) treatment significantly reduced the number of proinflammatory (gamma-interferon-producing) CD8 cells recognizing a dominant pathogenic epitope. This effect was absent in mice treated for longer periods, suggesting that atorvastatin loses efficiency in inhibiting antoantigen-specific T-cells over time. This observation may explain the discrepancy between the reported success of statins in acutely induced models and the lack of it in a chronic, spontaneous model of autoimmune disease and has implications for the adoption of such therapy in humans.