Blockade of late stages of autoimmune diabetes by inhibition of the receptor for advanced glycation end products
Blockade of late stages of autoimmune diabetes by inhibition of the receptor for advanced glycation end products
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DOI：
10.4049/jimmunol.173.2.1399
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发表时间：
2004-07-15
影响因子：
4.4
通讯作者：
Herold, KC
中科院分区：
文献类型：
--
作者：
Chen, YL;Yan, SSD;Herold, KC
晚期糖基化终末产物 (RAGE) 受体的连接发生在炎症过程中。 RAGE 的参与导致地址素表达增强，因此，先前的研究表明 RAGE/配体相互作用在免疫反应（包括细胞/细胞接触）中的作用并不奇怪，但 RAGE 在自发性自身免疫中的作用尚未明确定义。为了研究 RAGE/配体相互作用在自身免疫性糖尿病中的作用，我们测试了可溶性 RAGE（一种 RAGE 配体清除剂）在糖尿病发展后期的能力，其中包括用致糖尿病 T 细胞转移的 NOD 小鼠疾病以及同基因胰岛移植的 NOD/scid 受体中的复发疾病。在糖尿病小鼠的 CD4(+)、CD8(+) 和 B 细胞上检测到 RAGE 表达，并将其转移至 NOD/scid 受体。在患糖尿病的 NOD/scid 小鼠的胰岛中发现了 RAGE 及其配体 S100B。用可溶性 RAGE 治疗受体 NOD/scid 小鼠可防止糖尿病转移并延迟同基因胰岛移植中的复发性疾病。 RAGE 阻断与受保护小鼠胰岛中 IL-10 和 TGF-β 表达增加相关。 RAGE阻断减少了富集T细胞的疾病转移，但当糖尿病通过激活的CD4(+) T细胞克隆BDC2.5转移时则没有效果。我们得出的结论是，在糖尿病发展的后期，RAGE/配体相互作用参与了 T 细胞向成熟致病表型的分化。
Ligation of the receptor for advanced glycation end products (RAGE) occurs during inflammation. Engagement of RAGE results in enhanced expression of addressins and it is therefore, not surprising that previous studies have shown a role of RAGE/ligand interactions in immune responses including cell/cell contact but the role of RAGE in spontaneous autoimmunity has not been clearly defined. To study the role of RAGE/ligand interactions in autoimmune diabetes, we tested the ability of soluble RAGE, a scavenger of RAGE ligands, in late stages of diabetes development in the NOD mouse-disease transferred with diabetogenic T cells and recurrent disease in NOD/scid recipients of syngeneic islet transplants. RAGE expression was detected on CD4(+), CD8(+), and B cells from diabetic mice and transferred to NOD/scid recipients. RAGE and its ligand, S100B, were found in the islets of NOD/scid mice that developed diabetes. Treatment of recipient NOD/scid mice with soluble RAGE prevented transfer of diabetes and delayed recurrent disease in syngeneic islet transplants. RAGE blockade was associated with increased expression of IL-10 and TGF-beta in the islets from protected mice. RAGE blockade reduced the transfer of disease with enriched T cells, but had no effect when diabetes was transferred with the activated CD4(+) T cell clone, BDC2.5. We conclude that RAGE/ligand interactions are involved in the differentiation of T cells to a mature pathogenic phenotype during the late stages of the development of diabetes.