Progression to islet destruction in a cyclophosphamide-induced transgenic model - A microarray overview
Progression to islet destruction in a cyclophosphamide-induced transgenic model - A microarray overview
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DOI：
10.2337/diabetes.53.9.2310
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发表时间：
2004-09-01
期刊：
影响因子：
7.7
通讯作者：
Benoist, C
中科院分区：
文献类型：
--
作者：
Matos, M;Park, R;Benoist, C
1型糖尿病的进展似乎不是对胰岛β细胞的不受控制的自身免疫攻击，而是以一种高度调节的方式。自体免疫细胞或胰岛素炎对胰岛的白细胞浸润，可在β细胞最终被破坏之前持续很长时间。为了深入了解糖尿病发生的最后阶段，我们在NOD小鼠模型的CD4(+) t细胞受体转基因变体中研究了糖尿病的进展，在这种小鼠模型中，单次注射环磷酰胺可以在几天内同步诱导糖尿病。使用微阵列对纯化胰岛的基因表达谱进行了时间过程分析。与预期相反，药物治疗后转录本的变化并不反映CD4(+) t细胞中基因表达的扰动或调节性t细胞群体特征基因表达的减少。相反，b细胞特异性基因的转录明显减少，随后趋化因子基因（cxcl1、cxcl5和ccl7）和其他骨髓单核细胞谱系的典型基因的转录增加。干扰素- γ在基因表达的变化中起着显著的主导作用，因为近一半的诱导转录本来自干扰素- γ调节的基因。
Type 1 diabetes appears to progress not as an uncontrolled autoimmune attack on the pancreatic islet beta-cells, but rather in a highly regulated manner. Leukocytic infiltration of the pancreatic islets by autoimmune cells, or insulitis, can persist for long periods of time before the terminal destruction of beta-cells. To gain insight on the final stage of diabetogenesis, we have studied progression to diabetes in a CD4(+) T-cell receptor transgenic variant of the NOD mouse model, in which diabetes can be synchronously induced within days by a single injection of cyclophosphamide. A time-course analysis of the gene expression profiles of purified islets was performed using microarrays. Contrary to expectations, changes in transcripts subsequent to drug treatment did not reflect a perturbation of gene expression in CD4(+) T-cells or a reduction in the expression of genes characteristic of regulatory T-cell populations. Instead, there was a marked decrease in transcripts of genes specific to B-cells, followed by an increase in transcripts of chemokine genes (cxcl1, cxcl5, and ccl7) and of other genes typical of the myelo-monocytic lineages. Interferon-gamma dominated the changes in gene expression to a striking degree, because close to one-half of the induced transcripts issued from interferon-gamma-regulated genes.