Inhibition of the immunoproteasome ameliorates experimental autoimmune encephalomyelitis.
Inhibition of the immunoproteasome ameliorates experimental autoimmune encephalomyelitis.
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DOI：
10.1002/emmm.201303543
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发表时间：
2014-02
影响因子：
11.1
通讯作者：
Kirk, Christopher J.
中科院分区：
文献类型：
--
作者：
Basler, Michael;Mundt, Sarah;Muchamuel, Tony;Moll, Carlo;Jiang, Jing;Groettrup, Marcus;Kirk, Christopher J.
多发性硬化症(MS)是一种慢性脱髓鞘免疫介导的中枢神经系统疾病。免疫蛋白酶体是一类独特的蛋白酶体，主要存在于单核细胞和淋巴细胞中。最近，我们展示了免疫蛋白酶体在细胞因子产生和T细胞分化中的新功能。在这项研究中，我们研究了免疫蛋白酶体抑制剂(ONX 0914)在两种不同的MS小鼠模型中的治疗效果。在MOG35-55和PLP139-151诱导的实验性自身免疫性脑脊髓炎(EAE)主动和被动诱导后，ONX 0914延缓了疾病的进展。从大脑或脊髓分离淋巴细胞显示，在ONX 0914处理的小鼠中，产生细胞因子的CD4+细胞显著减少。此外，ONX 0914治疗在复发-缓解模式下防止了疾病恶化。对EAE诱导后引流淋巴结的分析表明，ONX 0914处理的小鼠向Th17或Th1细胞的分化严重受损。这些结果提示免疫蛋白酶体参与了EAE的发生发展，提示免疫蛋白酶体抑制剂是治疗MS的有前途的药物。
Multiple sclerosis (MS) is a chronic demyelinating immune mediated disease of the central nervous system. The immunoproteasome is a distinct class of proteasomes found predominantly in monocytes and lymphocytes. Recently, we demonstrated a novel function of immunoproteasomes in cytokine production and T cell differentiation. In this study, we investigated the therapeutic efficacy of an inhibitor of the immunoproteasome (ONX 0914) in two different mouse models of MS. ONX 0914 attenuated disease progression after active and passive induction of experimental autoimmune encephalomyelitis (EAE), both in MOG35–55 and PLP139–151-induced EAE. Isolation of lymphocytes from the brain or spinal cord revealed a strong reduction of cytokine-producing CD4+ cells in ONX 0914 treated mice. Additionally, ONX 0914 treatment prevented disease exacerbation in a relapsing-remitting model. An analysis of draining lymph nodes after induction of EAE revealed that the differentiation to Th17 or Th1 cells was strongly impaired in ONX 0914 treated mice. These results implicate the immunoproteasome in the development of EAE and suggest that immunoproteasome inhibitors are promising drugs for the treatment of MS.
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影响因子：
3.3
作者：
Frausto, Ricardo F.;Crocker, Stephen J.;Whitton, J. Lindsay
通讯作者：
Whitton, J. Lindsay
影响因子：
3.3
作者：
Hosseini, H;André, P;Lotteau, V
通讯作者：
Lotteau, V
影响因子：
100.3
作者：
Groettrup, Marcus;Kirk, Christopher J.;Basler, Michael
通讯作者：
Basler, Michael
免疫蛋白酶体塑造抗病毒CD8（+）T细胞在T细胞库水平和病毒抗原的表现下的免疫主导层次结构。
影响因子：
15.3
作者：
Chen, W;Norbury, C C;Cho, Y;Yewdell, J W;Bennink, J R
通讯作者：
Bennink, J R
影响因子：
--
作者：
Ichikawa HT;Conley T;Muchamuel T;Jiang J;Lee S;Owen T;Barnard J;Nevarez S;Goldman BI;Kirk CJ;Looney RJ;Anolik JH
通讯作者：
Anolik JH