Apoptosis Is the Mode of β-Cell Death Responsible for the Development of IDDM in the Nonobese Diabetic (NOD) Mouse
Apoptosis Is the Mode of β-Cell Death Responsible for the Development of IDDM in the Nonobese Diabetic (NOD) Mouse
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DOI：
10.2337/diab.46.5.750
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发表时间：
1997-05
期刊：
影响因子：
7.7
通讯作者：
B. O'Brien;B. Harmon;D. Cameron;D. Allan
中科院分区：
文献类型：
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作者：
B. O'Brien;B. Harmon;D. Cameron;D. Allan
NOD/Lt小鼠是一种广泛使用的人类自身免疫性IDDM模型，用于建立IDDM发生的β细胞死亡模式。3- 18周龄雌性NOD/Lt小鼠胰岛的苏木精和伊红染色切片显示朗格汉斯胰岛内存在凋亡细胞（每100个胰岛有11-50个凋亡细胞）。胰岛素免疫组化定位于死亡细胞证实了凋亡的β细胞来源。尽管来自年龄匹配的雌性NOD/scid小鼠的一些胰岛含有凋亡细胞，但免疫组织化学检测发现，几乎所有这些细胞都是胰岛素阴性的。与NOD/Lt小鼠相比，NOD/scid小鼠胰岛中发现的少量胰岛素阳性凋亡细胞（每100个胰岛中0-1个凋亡细胞）无统计学意义。所有死亡细胞均表现出细胞凋亡死亡的形态学变化特征，并通过末端标记DNA链断裂的TUNEL染色呈阳性。NOD/Lt小鼠中β细胞凋亡的最大平均数量出现在第15周（每100个胰岛有50个凋亡细胞），根据血糖、尿糖和胰腺免疫反应性胰岛素测量，这与糖尿病的最早发病时间一致。虽然在整个研究期间（3-18周）β细胞凋亡发生率没有达到峰值，但凋亡发生率在第18周下降，此时50%的动物有明显的糖尿病。观察到的低水平β细胞凋亡表明，在该模型中观察到的广泛的临床前阶段，β细胞群逐渐缺失，这足以解释导致IDDM的β细胞丢失。胰岛β细胞凋亡先于t细胞出现（免疫组化cd3阳性）。直到第6周才发现胰岛淋巴细胞浸润（胰岛炎）。结果表明，β细胞凋亡与NOD/Lt小鼠IDDM的发展有关，其发病早于胰岛淋巴细胞浸润。
The NOD/Lt mouse, a widely used model of human autoimmune IDDM, was used to establish the mode of β-cell death responsible for the development of IDDM. Apoptotic cells were present within the islets of Langerhans in hematoxylin and eosin–stained sections of pancreases harvested from 3- to 18-week-old female NOD/Lt mice (a range of 11–50 apoptotic cells per 100 islets). Immunohistochemical localization of insulin to the dying cells confirmed the β-cell origin of the apoptosis. Although some islets from age-matched control female NOD/scid mice contained apoptotic cells, virtually all of these cells were insulin negative as determined by immunohistochemistry. The small number of apoptotic insulin-positive cells identified in islets from NOD/scid mice (a range of 0–1 apoptotic cells per 100 islets) was not statistically significant, compared with the numbers recorded in NOD/Lt mice. All dying cells showed the morphological changes characteristic of cell death by apoptosis and stained positively with the TUNEL method for end-labeling DNA strand breaks. The maximum mean amount of β-cell apoptosis occurring in NOD/Lt mice was at week 15 (50 apoptotic cells per 100 islets), which coincided with the earliest onset of diabetes as determined by blood glucose, urine glucose, and pancreatic immunoreactive insulin measurements. While there was no peak incidence of β-cell apoptosis throughout the time period studied (weeks 3–18), the incidence of apoptosis decreased at week 18, by which time 50% of the animals had overt diabetes. The low levels of β-cell apoptosis observed is indicative of a gradual deletion of the β-cell population throughout the extensive preclinical period seen in this model and would be sufficient to account for the β-cell loss resulting in IDDM. Apoptosis of β-cells preceded the appearance of T-cells (CD3-positive by immunohistochemistry) in islets. Lymphocytic infiltration of islets (insulitis) was not detected until week 6. The results show that β-cell apoptosis is responsible for the development of IDDM in the NOD/Lt mouse and that its onset precedes lymphocytic infiltration of the islets.