Inhibition of the immunoproteasome ameliorates experimental autoimmune encephalomyelitis

EMBO Molecular Medicine

Michael Basler²  Sarah Mundt³  Tony Muchamuel⁴  Carlo Moll¹  Jing Jiang⁴  Marcus Groettrup² 

[1] Institute of Pathology, Cantonal Hospital Muensterlingen, Muensterlingen, Switzerland;Biotechnology Institute Thurgau (BITg) at the University of Konstanz, Kreuzlingen, Switzerland;Division of Immunology, Department of Biology, University of Konstanz, Konstanz, Germany;Onyx Pharmaceuticals, South San Francisco, CA, USA

关键词: experimental autoimmune encephalomyelitis;    immunoproteasome;    multiple sclerosis;    proteasome;   

DOI  :  10.1002/emmm.201303543

来源: Wiley

【 摘 要 】

Abstract

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 MOG_35–55 and PLP_139–151-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.

Synopsis

The immunoproteasome is found implicated in the development of experimental autoimmune encephalomyelitis and LMP7 inhibitors shown promising for the treatment of multiple sclerosis and other autoimmune diseases that rely on Th1/Th17 response.

• Immunoproteasome inhibition reduces clinical symptoms in two different animal model for multiple sclerosis
• Immunoproteasome inhibition impedes Th1 and Th17 cell differentiation in experimental autoimmune encephalomyelitis
• Immunoproteaome inhibition reduces cellular infiltration into the CNS in experimental autoimmune encephalomyelitis
• Immunoproteasome inhibitors are promising targets for the treatment of multiple sclerosis

【 授权许可】

CC BY   
© 2014 The Authors.

Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.