Martin Andrea P, Grisotto Marcos G, Canasto-Chibuque Claudia, Kunkel Steven L, Bromberg Jonathan S, Furtado Glaucia C, Lira Sergio A
Immunology Institute, Mount Sinai School of Medicine, 1425 Madison Ave., Box 1630, New York, NY 10029-6574, USA.
Diabetes. 2008 Feb;57(2):387-94. doi: 10.2337/db07-1309. Epub 2007 Nov 14.
Type 1 diabetes is an autoimmune disease characterized by a local inflammatory reaction in and around islets followed by selective destruction of insulin-secreting beta-cells. We tested the hypothesis that chemokines affect different mechanisms responsible for the development of diabetes in NOD mice.
We examined chemokine expression in islets of NOD mice and tested their functional relevance to development of diabetes using transgenic mice expressing the mouse herpesvirus 68-encoded chemokine decoy receptor M3 (NOD-M3 mice) in insulin-secreting beta-cells.
Multiple chemokines were expressed in pancreatic islets of NOD mice before development of diabetes. Islet-specific expression of the pan-chemokine inhibitor M3 dramatically reduced leukocyte infiltration and islet destruction and completely blocked development of diabetes in NOD-M3 mice. M3 blocked diabetes by inhibiting the priming of diabetogenic cells in the pancreatic lymph nodes and their recruitment into the islets. This effect was specific to the pancreatic islets because M3 expression did not affect other ongoing autoimmune processes.
These results demonstrate that chemokines mediate afferent and efferent immunity in type 1 diabetes and suggest that broad chemokine blockade may represent a viable strategy to prevent insulitis and islet destruction.
1型糖尿病是一种自身免疫性疾病，其特征是胰岛及其周围发生局部炎症反应，随后胰岛素分泌β细胞被选择性破坏。我们检验了趋化因子影响非肥胖糖尿病（NOD）小鼠糖尿病发生的不同机制这一假说。
我们检测了NOD小鼠胰岛中趋化因子的表达，并使用在胰岛素分泌β细胞中表达小鼠疱疹病毒68编码的趋化因子诱饵受体M3的转基因小鼠（NOD-M3小鼠），测试了它们与糖尿病发生的功能相关性。
在糖尿病发生之前，多种趋化因子在NOD小鼠的胰岛中表达。全趋化因子抑制剂M3在胰岛中的特异性表达显著减少了白细胞浸润和胰岛破坏，并完全阻断了NOD-M3小鼠糖尿病的发生。M3通过抑制胰腺淋巴结中致糖尿病细胞的致敏及其向胰岛的募集来阻断糖尿病。这种作用对胰腺胰岛具有特异性，因为M3的表达不影响其他正在进行的自身免疫过程。
这些结果表明趋化因子介导1型糖尿病中的传入和传出免疫，并提示广泛的趋化因子阻断可能是预防胰岛炎和胰岛破坏的一种可行策略。
