Limits...
Inhibition of the immunoproteasome ameliorates experimental autoimmune encephalomyelitis.

Basler M, Mundt S, Muchamuel T, Moll C, Jiang J, Groettrup M, Kirk CJ - EMBO Mol Med (2014)

Bottom Line: The immunoproteasome is a distinct class of proteasomes found predominantly in monocytes and lymphocytes.Additionally, ONX 0914 treatment prevented disease exacerbation in a relapsing-remitting model.These results implicate the immunoproteasome in the development of EAE and suggest that immunoproteasome inhibitors are promising drugs for the treatment of MS.

View Article: PubMed Central - PubMed

Affiliation: Biotechnology Institute Thurgau (BITg) at the University of Konstanz, Kreuzlingen, Switzerland.

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.

Show MeSH

Related in: MedlinePlus

C57BL/6 wild type, LMP2−/−, MECL-1−/−, and LMP7−/− mice were immunized with MOG35–55 peptide. Mice were monitored daily for clinical symptoms of EAE. Clinical score ( y-axis) is plotted versus time post immunization ( x-axis). Data points represent mean ± s.e.m. of six mice. The experiments were performed three times, yielding similar results.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3927957&req=5

fig01: C57BL/6 wild type, LMP2−/−, MECL-1−/−, and LMP7−/− mice were immunized with MOG35–55 peptide. Mice were monitored daily for clinical symptoms of EAE. Clinical score ( y-axis) is plotted versus time post immunization ( x-axis). Data points represent mean ± s.e.m. of six mice. The experiments were performed three times, yielding similar results.

Mentions: In order to analyze whether mice deficient in immunoproteasome subunits are susceptible to experimental autoimmune encephalomyelitis, LMP2−/−, LMP7−/−, MECL-1−/−, and C57BL/6 control mice were immunized with MOG35–55 peptide. The clinical score of the mice was recorded for 26 days, but no significant difference in disease score could be observed (Fig 1). A similar finding was obtained by Frausto et al (2007) in LMP2-deficient mice, whereas Seifert et al (2010) reported an exacerbation of EAE symptoms in LMP7−/− mice. However, the latter finding could not be confirmed by others (Nathan et al, 2013).


Inhibition of the immunoproteasome ameliorates experimental autoimmune encephalomyelitis.

Basler M, Mundt S, Muchamuel T, Moll C, Jiang J, Groettrup M, Kirk CJ - EMBO Mol Med (2014)

C57BL/6 wild type, LMP2−/−, MECL-1−/−, and LMP7−/− mice were immunized with MOG35–55 peptide. Mice were monitored daily for clinical symptoms of EAE. Clinical score ( y-axis) is plotted versus time post immunization ( x-axis). Data points represent mean ± s.e.m. of six mice. The experiments were performed three times, yielding similar results.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3927957&req=5

fig01: C57BL/6 wild type, LMP2−/−, MECL-1−/−, and LMP7−/− mice were immunized with MOG35–55 peptide. Mice were monitored daily for clinical symptoms of EAE. Clinical score ( y-axis) is plotted versus time post immunization ( x-axis). Data points represent mean ± s.e.m. of six mice. The experiments were performed three times, yielding similar results.
Mentions: In order to analyze whether mice deficient in immunoproteasome subunits are susceptible to experimental autoimmune encephalomyelitis, LMP2−/−, LMP7−/−, MECL-1−/−, and C57BL/6 control mice were immunized with MOG35–55 peptide. The clinical score of the mice was recorded for 26 days, but no significant difference in disease score could be observed (Fig 1). A similar finding was obtained by Frausto et al (2007) in LMP2-deficient mice, whereas Seifert et al (2010) reported an exacerbation of EAE symptoms in LMP7−/− mice. However, the latter finding could not be confirmed by others (Nathan et al, 2013).

Bottom Line: The immunoproteasome is a distinct class of proteasomes found predominantly in monocytes and lymphocytes.Additionally, ONX 0914 treatment prevented disease exacerbation in a relapsing-remitting model.These results implicate the immunoproteasome in the development of EAE and suggest that immunoproteasome inhibitors are promising drugs for the treatment of MS.

View Article: PubMed Central - PubMed

Affiliation: Biotechnology Institute Thurgau (BITg) at the University of Konstanz, Kreuzlingen, Switzerland.

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.

Show MeSH
Related in: MedlinePlus