Biotechnology Institute Thurgau (BITg) at the University of Konstanz, Kreuzlingen, Switzerland.
EMBO Mol Med. 2014 Feb;6(2):226-38. doi: 10.1002/emmm.201303543. Epub 2014 Jan 16.
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.
多发性硬化症（MS）是一种中枢神经系统的慢性脱髓鞘免疫介导疾病。免疫蛋白酶体是一种主要存在于单核细胞和淋巴细胞中的独特蛋白酶体类别。最近，我们证明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。ONX 0914 减弱了主动和被动诱导实验性自身免疫性脑脊髓炎（EAE）后的疾病进展，在 MOG₃₅-₅₅ 和 PLP₁₃₉₋₁₅₁诱导的 EAE 中均如此。从大脑或脊髓中分离淋巴细胞表明，ONX 0914 治疗的小鼠中产生细胞因子的 CD4(+)细胞数量明显减少。此外，ONX 0914 治疗可预防复发缓解模型中的疾病恶化。EAE 诱导后对引流淋巴结的分析表明，ONX 0914 治疗的小鼠中 Th17 或 Th1 细胞的分化受到强烈抑制。这些结果表明免疫蛋白酶体在 EAE 的发展中起作用，并表明免疫蛋白酶体抑制剂是治疗 MS 的有前途的药物。
