Development of autoimmune diabetes in glutamic acid decarboxylase 65 (GAD65) knockout NOD mice
Development of autoimmune diabetes in glutamic acid decarboxylase 65 (GAD65) knockout NOD mice
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DOI：
10.1007/s00125-003-1296-0
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发表时间：
2004-02-01
期刊：
影响因子：
8.2
通讯作者：
Miyazaki, JI
中科院分区：
文献类型：
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作者：
Yamamoto, T;Yamato, E;Miyazaki, JI
目标/假设。1型糖尿病是一种T细胞介导的自身免疫性疾病，是产生胰岛素的胰岛β细胞选择性破坏的结果。针对β细胞成分的自身抗体在临床上被用作该病的敏感标记物；然而，它们的生理作用尚不清楚。为了探讨谷氨酸脱羧酶65(GAD65)在非肥胖型糖尿病(NOD)小鼠1型糖尿病发病中的作用，我们分析和表征了GAD65基因靶向干扰的NOD小鼠。此前已经建立了GAD65缺陷小鼠。将基因敲除突变回交到结节遗传背景上8代后，通过杂交产生了3种基因型的雌性后代：GAD65+/+(n=23)、GAD65+/-(n=62)和GAD65-/-(n=31)。在使用Kaplan-Meier方法的纵向研究中，三组自身免疫性糖尿病的累积发病率没有显著差异。胰岛形态显示胰岛浸润的进展在三组之间没有显著差异。自身免疫性糖尿病的累积发病率不受GAD65缺陷的影响。这些数据表明，GAD65不是NOD小鼠β细胞自身免疫的主要调控靶点。
Aims/hypothesis. Type 1 diabetes mellitus, a T-cell-mediated autoimmune disease, results from the selective destruction of insulin-producing pancreatic beta cells. Autoantibodies against beta-cell components are used clinically as sensitive markers of this disease; however, their physiological role has not been clear. To investigate the role of glutamic acid decarboxylase 65 (GAD65) in the development of the Type 1 diabetes of non-obese diabetic (NOD) mice, we analysed and characterised NOD mice with targeted disruption of the GAD65 gene.Methods. GAD65-deficient mice were previously established. After backcrossing the knockout mutation onto the NOD genetic background for up to eight generations, female littermates of the three resulting genotypes were produced by intercrossing: GAD65 +/+ (n=23), GAD65 +/- (n=62), and GAD65 -/- (n=31).Results. The cumulative incidence of autoimmune diabetes showed no significant difference among the three groups in longitudinal studies using the Kaplan-Meier method. Islet morphology showed that the progression of islet infiltration did not differ significantly between the three groups.Conclusion/interpretation. The cumulative incidence of autoimmune diabetes was not influenced by the GAD65 deficiency. These data suggest that GAD65 is not a major regulatory target of beta-cell autoimmunity in NOD mice.