Treatment of relapsing paralysis in experimental encephalomyelitis by targeting Th1 cells through atorvastatin.
Treatment of relapsing paralysis in experimental encephalomyelitis by targeting Th1 cells through atorvastatin.
复制标题
通过通过阿托伐他汀靶向Th1细胞，治疗实验性脑脊髓炎中的复发性麻痹。
DOI：
10.1084/jem.20021425
复制
发表时间：
2003-03-17
影响因子：
15.3
通讯作者：
Zipp, F
中科院分区：
文献类型：
--
作者：
Aktas, O;Waiczies, S;Smorodchenko, A;Dörr, J;Seeger, B;Prozorovski, T;Sallach, S;Endres, M;Brocke, S;Nitsch, R;Zipp, F
他汀类药物是3-羟基-3-甲基戊二酰辅酶A(HMG-CoA)还原酶的抑制剂，具有多种与炎症相关的功能，如下调MHCⅡ类分子、干扰T细胞黏附和诱导细胞凋亡等。在这里，我们证明了皮下和口服阿托伐他汀都能抑制SJL/J小鼠主动诱导的慢性实验性自身免疫性脑脊髓炎的发展，并显着减少炎症向中枢神经系统(CNS)的渗透。当疾病发作后开始治疗时，阿托伐他汀降低了复发的发生率，并防止了进一步的残疾发展。通过对脑源性多肽PLP139-151的增殖来衡量自身反应性T细胞反应的减少，以及细胞因子谱都表明有效地阻断了T辅助细胞1型免疫反应。在体外实验中，阿托伐他汀不仅抑制抗原特异性反应，而且还抑制T细胞的增殖，这种T细胞是通过TCR直接参与介导的，而不依赖于MHC II类和LFA-1。抑制增殖不是由于诱导细胞凋亡，而是与对细胞周期进程的负调控有关。然而，早期T细胞的激活没有受到影响，反映在未改变的钙离子流量上。因此，我们的结果为他汀类药物在治疗中枢神经系统自身免疫性攻击中的有益作用提供了证据。
Statins, known as inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, exhibit numerous functions related to inflammation, such as MHC class II down-regulation, interference with T cell adhesion, and induction of apoptosis. Here we demonstrate that both subcutaneous and oral administration of atorvastatin inhibit the development of actively induced chronic experimental autoimmune encephalomyelitis in SJL/J mice and significantly reduce the inflammatory infiltration into the central nervous system (CNS). When treatment was started after disease onset, atorvastatin reduced the incidence of relapses and protected from the development of further disability. Both the reduced autoreactive T cell response measured by proliferation toward the encephalitogenic peptide PLP139–151 and the cytokine profile indicate a potent blockade of T helper cell type 1 immune response. In in vitro assays atorvastatin not only inhibited antigen-specific responses, but also decreased T cell proliferation mediated by direct TCR engagement independently of MHC class II and LFA-1. Inhibition of proliferation was not due to apoptosis induction, but linked to a negative regulation on cell cycle progression. However, early T cell activation was unaffected, as reflected by unaltered calcium fluxes. Thus, our results provide evidence for a beneficial role of statins in the treatment of autoimmune attack on the CNS.
登录
查看更多内容
DOI：
10.1006/meth.1996.0053
发表时间：
1996-01-01
期刊：
Methods (Orlando)
影响因子：
--
作者：
Brocke, Stefan;Quigley, Laura;Steinman, Lawrence
通讯作者：
Steinman, Lawrence
影响因子：
3.7
作者：
Naderi, S;Blomhoff, R;Blomhoff, HK
通讯作者：
Blomhoff, HK
影响因子：
56.9
作者：
Hengst, L;Reed, SI
通讯作者：
Reed, SI
影响因子：
120.7
作者：
Albert, MA;Danielson, E;Ridker, PM
通讯作者：
Ridker, PM
影响因子：
2.2
作者：
GRIFFIOEN, AW;RIJKERS, GT;ZEGERS, BJM
通讯作者：
ZEGERS, BJM