title: Inhibition of the immunoproteasome ameliorates experimental autoimmune encephalomyelitis.
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 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.
authors.affiliation: Biotechnology Institute Thurgau (BITg) at the University of Konstanz, Kreuzlingen, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Basler
authors.forename: Sarah
authors.initials: S
authors.lastname: Mundt
authors.forename: Tony
authors.initials: T
authors.lastname: Muchamuel
authors.forename: Carlo
authors.initials: C
authors.lastname: Moll
authors.forename: Jing
authors.initials: J
authors.lastname: Jiang
authors.forename: Marcus
authors.initials: M
authors.lastname: Groettrup
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Kirk
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology; D002454:Cell Differentiation / Q000276:immunology; D004195:Disease Models, Animal; D018450:Disease Progression; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology* / Q000517:prevention & control; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis; D006801:Humans; D007249:Inflammation / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D063308:Myelin-Oligodendrocyte Glycoprotein; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use; D010446:Peptide Fragments; D046988:Proteasome Endopeptidase Complex / Q000172:deficiency / Q000276:immunology* / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism
chemical_list: D063308:Myelin-Oligodendrocyte Glycoprotein; D009842:Oligopeptides; C542291:PR-957; D010446:Peptide Fragments; D061988:Proteasome Inhibitors; C445081:myelin oligodendrocyte glycoprotein (35-55); D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex