Inhibition of Rho GTPases with protein prenyltransferase inhibitors prevents leukocyte recruitment to the central nervous system and attenuates clinical signs of disease in an animal model of multiple sclerosis.
Inhibition of Rho GTPases with protein prenyltransferase inhibitors prevents leukocyte recruitment to the central nervous system and attenuates clinical signs of disease in an animal model of multiple sclerosis.
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DOI：
10.4049/jimmunol.168.8.4087
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发表时间：
2002-04-15
期刊：
影响因子：
--
通讯作者：
Adamson P
中科院分区：
文献类型：
--
作者：
Walters CE;Pryce G;Hankey DJR;Sebti SM;Hamilton AD;Baker D;Greenwood J;Adamson P
粘附淋巴细胞诱导的ICAM-1介导的脑内皮细胞信号传导途径是促进淋巴细胞迁移通过脑的紧密内皮屏障的核心要素。Rho蛋白必须经过翻译后异戊烯化才具有功能活性，已被证明是这种信号级联的重要组成部分。在这项研究中，我们评估了抑制脑内皮细胞中蛋白质异戊二烯化对其支持T淋巴细胞迁移能力的影响。在体外用蛋白质异戊二烯化抑制剂（PTI）处理的内皮细胞导致跨内皮T淋巴细胞迁移显著减少。为了确定这种方法的治疗潜力，在Biozzi ABH小鼠中诱导多发性硬化症的动物模型，实验性自身免疫性脑脊髓炎。与未治疗的动物相比，在疾病发作前用PTI治疗的动物表现出中枢神经系统（CNS）中的白细胞浸润和疾病的临床表现的显著和显著减少。这些研究首次证明了靶向CNS内皮细胞信号传导应答，特别是内皮Rho蛋白作为减弱白细胞向CNS募集的手段的潜力。
The ICAM-1 mediated brain endothelial cell signalling pathway induced by adherent lymphocytes is a central element in facilitating lymphocyte migration through the tight endothelial barrier of the brain. Rho proteins, which must undergo post-translational prenylation to be functionally active, have been shown to be an essential component of this signalling cascade. In this study we have evaluated the effect of inhibiting protein prenylation in brain endothelial cells on their ability to support T lymphocyte migration. Endothelial cells treated in vitro with protein prenylation inhibitors (PTI) resulted in a significant reduction in transendothelial T lymphocyte migration. To determine the therapeutic potential of this approach an animal model of multiple sclerosis, experimental autoimmune encephalomyelitis, was induced in Biozzi ABH mice. Animals treated prior to disease onset with PTI exhibited a dramatic and significant reduction in both leucocyte infiltration into the central nervous system (CNS) and clinical presentation of disease compared to untreated animals. These studies demonstrate, for the first time, the potential for pharmacologically targeting CNS endothelial cell signalling responses, and particularly endothelial Rho proteins, as a means of attenuating leucocyte recruitment to the CNS.
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影响因子：
4.3
作者：
ALLEN, SJ;BAKER, D;TURK, JL
通讯作者：
TURK, JL
影响因子：
4.8
作者：
Lebowitz, PF;Casey, PJ;Thissen, JA
通讯作者：
Thissen, JA
影响因子：
5.4
作者：
HUITINGA, I;DAMOISEAUX, JGMC;DIJKSTRA, CD
通讯作者：
DIJKSTRA, CD
影响因子：
4.8
作者：
LERNER, EC;QIAN, YM;SEBTI, SM
通讯作者：
SEBTI, SM
影响因子：
4.8
作者：
McGuire, TF;Qian, YM;Sebti, SM
通讯作者：
Sebti, SM