Protection against experimental autoimmune encephalomyelitis by a proteasome modulator
Protection against experimental autoimmune encephalomyelitis by a proteasome modulator
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DOI：
10.1016/s0165-5728(01)00352-6
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发表时间：
2001-08-30
影响因子：
3.3
通讯作者：
Lotteau, V
中科院分区：
文献类型：
--
作者：
Hosseini, H;André, P;Lotteau, V
干扰素β改变多发性硬化症病程的能力促进了一种新的治疗概念，其基于免疫应答的调节而不是其抑制。由于蛋白酶体在炎症过程和免疫细胞存活的控制中起着至关重要的作用，靶向蛋白酶体似乎是预防和治疗炎性自身免疫性疾病的新方法。我们以前已经表明，利托那韦，艾滋病治疗中使用的HIV-1蛋白酶抑制剂，可以通过抑制胰凝乳蛋白酶样活性和增强胰蛋白酶样活性来调节蛋白酶体功能。因此，我们在刘易斯大鼠和SJL小鼠中探索了其对实验性自身免疫性脑脊髓炎（EAE）（多发性硬化的实验模型）的治疗潜力。在自身免疫抗原刺激期间每日给予利托那韦以剂量和时间依赖性方式预防EAE的临床症状。这种保护作用伴随着对EAE中通常观察到的单核细胞浸润到中枢神经系统的抑制。尽管在第一次EAE诱导期间完全没有临床症状，但利托那韦治疗的动物对进一步诱导EAE产生了抗性，表明了免疫保护机制。这些结果表明，使用利托那韦或类似物的蛋白酶体调制可能是多发性硬化症患者感兴趣的。(C)2001 Elsevier Science BN，版权所有。
The capacity of interferon beta to alter the course of multiple sclerosis has promoted a new therapeutic concept, based upon the modulation of the immune response rather than its suppression. As the proteasome plays a crucial role in the control of the inflammatory process and immune cell survival, targeting the proteasome appears as a novel approach for the prevention and treatment of inflammatory autoimmune diseases. We have previously shown that ritonavir, an HIV-1 protease inhibitor used in AIDS therapy, can modulate the proteasome function by inhibiting the chymotrypsin-like activity and enhancing the trypsin-like activity. We have, therefore, explored its therapeutic potential on experimental autoimmune encephalomyelitis (EAE), an experimental model of multiple sclerosis, in Lewis rats and SJL mice. Daily administration of ritonavir during autoimmune antigen stimulation prevented clinical symptoms of EAE in a dose-and time-dependent manner. This protection was accompanied by an inhibition of the mononuclear cell infiltration into the central nervous system usually observed in EAE. Despite a complete absence of clinical symptoms during first EAE induction, ritonavir-treated animals became resistant to further induction of EAE, suggesting an immune mechanism of protection. These results suggest that proteasome modulation using ritonavir or analogues may be of interest for patients with multiple sclerosis. (C) 2001 Elsevier Science BN, All rights reserved.