Immune cell infiltration, cytokine expression, and β-cell apoptosis during the development of type 1 diabetes in the spontaneously diabetic LEW.1AR1/Ztm-iddm rat
Immune cell infiltration, cytokine expression, and β-cell apoptosis during the development of type 1 diabetes in the spontaneously diabetic LEW.1AR1/Ztm-iddm rat
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DOI：
10.2337/diabetes.54.7.2041
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发表时间：
2005-07-01
期刊：
影响因子：
7.7
通讯作者：
Lenzen, S
中科院分区：
文献类型：
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作者：
Jörns, A;Günther, A;Lenzen, S
IDDM(LEW.1AR1/ZTM-IDDM)大鼠是一种以快速凋亡的胰岛β细胞破坏为特征的1型糖尿病动物模型。在这里，我们分析了从糖尿病前期到糖尿病状态转变过程中胰岛浸润的时间进程，细胞因子表达模式的变化，以及β细胞的凋亡。当β细胞丢失超过60-70%时，从正常血糖到高血糖的转变发生。在胰岛浸润的早期阶段，巨噬细胞是周围浸润性胰岛的主要免疫细胞类型。β细胞丢失的进展与CD8(+)T细胞对整个胰岛的严重渗透密切相关。随着胰岛的进行性浸润，白细胞介素1β(IL-1β)和肿瘤坏死因子-α(TNF-α)在免疫细胞中表达，而在β细胞中不表达。这种促炎细胞因子的表达模式与诱导型一氧化氮合酶(INOS)和前天冬氨酸氨基转移酶3(Proaspase3)在β细胞中的表达相一致，其峰值凋亡率为6.7%。临床糖尿病表现后，胰岛浸润减少，终末期胰岛缺乏β细胞和免疫细胞，没有任何细胞因子表达的迹象。观察到免疫细胞中IL-1β和TNF-α的表达以及β细胞中iNOS和proaspase 3mRNA的诱导表达的一致性，描述了导致IDDM大鼠β细胞凋亡的一系列病理变化。这一系列事件为人类1型糖尿病动物模型中糖尿病综合征的发展提供了一种机制解释。
The IDDM (LEW.1AR1/Ztm-iddm) rat is a type 1 diabetic animal model characterized by a rapid apoptotic pancreatic beta-cell destruction. Here we have analyzed the time course of islet infiltration, changes in the cytokine expression pattern, and beta-cell apoptosis in the transition from the pre-diabetic to the diabetic state. Transition from normoglycemia to hyperglycemia occurred when beta-cell loss exceeded 60-70%. At the early stages of islet infiltration, macrophages were the predominant immune cell type in the peripherally infiltrated islets. Progression of beta-cell loss was closely linked to a severe infiltration of the whole islet by CD8(+) T-cells. With progressive islet infiltration, interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) were expressed in immune cells but not in beta-cells. This proinflammatory cytokine expression pattern coincided with the expression of inducible nitric oxide synthase (iNOS) and procaspase 3 in beta-cells and a peak apoptosis rate of 6.7%. Islet infiltration declined after manifestation of clinical diabetes, yielding end-stage islets devoid of beta-cells and immune cells without any sign of cytokine expression. The observed coincidence of IL-1 beta and TNF-alpha expression in the immune cells and the induction of iNOS and procaspase 3 mRNA expression in the beta-cells depicts a sequence of pathological changes leading to apoptotic beta-cell death in the IDDM rat. This chain of events provides a mechanistic explanation for the development of the diabetic syndrome in this animal model of human type 1 diabetes.