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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.

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ONX 0914 ameliorates PLP139–151-induced EAE.SJL/J mice were immunized with PLP139–151 and were monitored daily for clinical symptoms of EAE. From day 11 on (indicated by an arrow), mice were treated with 10 mg/kg ONX 0914 three times a week (indicated 3×), 10 mg/kg ONX 0914 once a week (indicated weekly), or vehicle. Data, presented as the mean clinical score s.e.m. ( n = 10 per group), are from one experiment of three performed with similar results. *** P < 0.001 by two-way ANOVA followed by Bonferroni post-hoc comparison at the end of study.Representative histological spinal cord sections of indicated mice. From day 11 on, mice were treated with10 mg/kg ONX 0914 three times a week. Mice were analyzed on day 14 post immunization.SJL/J mice were immunized with PLP139–151 and were monitored daily for clinical symptoms of EAE. From day 19 on (indicated by an arrow), mice were treated with 10 mg/kg ONX 0914 three times a week (indicated 3×), 10 mg/kg ONX 0914 once a week (indicated weekly), or vehicle. Data, presented as the mean clinical score s.e.m. ( n = 10 per group), are from one experiment of three performed with similar results. *** P < 0.001 by two-way ANOVA followed by Bonferroni post-hoc comparison at the end of study.In vitro restimulated PLP139–151–reactive T cells were adoptively transferred into SJL/J mice. Mice were treated three times a week with 10 mg/kg ONX 0914 or vehicle beginning on day 9 and were monitored daily for clinical symptoms. Data are presented as mean clinical score s.e.m. ( n = 9–10 per group). * P < 0.05; ** P < 0.01; *** P < 0.001.
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fig07: ONX 0914 ameliorates PLP139–151-induced EAE.SJL/J mice were immunized with PLP139–151 and were monitored daily for clinical symptoms of EAE. From day 11 on (indicated by an arrow), mice were treated with 10 mg/kg ONX 0914 three times a week (indicated 3×), 10 mg/kg ONX 0914 once a week (indicated weekly), or vehicle. Data, presented as the mean clinical score s.e.m. ( n = 10 per group), are from one experiment of three performed with similar results. *** P < 0.001 by two-way ANOVA followed by Bonferroni post-hoc comparison at the end of study.Representative histological spinal cord sections of indicated mice. From day 11 on, mice were treated with10 mg/kg ONX 0914 three times a week. Mice were analyzed on day 14 post immunization.SJL/J mice were immunized with PLP139–151 and were monitored daily for clinical symptoms of EAE. From day 19 on (indicated by an arrow), mice were treated with 10 mg/kg ONX 0914 three times a week (indicated 3×), 10 mg/kg ONX 0914 once a week (indicated weekly), or vehicle. Data, presented as the mean clinical score s.e.m. ( n = 10 per group), are from one experiment of three performed with similar results. *** P < 0.001 by two-way ANOVA followed by Bonferroni post-hoc comparison at the end of study.In vitro restimulated PLP139–151–reactive T cells were adoptively transferred into SJL/J mice. Mice were treated three times a week with 10 mg/kg ONX 0914 or vehicle beginning on day 9 and were monitored daily for clinical symptoms. Data are presented as mean clinical score s.e.m. ( n = 9–10 per group). * P < 0.05; ** P < 0.01; *** P < 0.001.

Mentions: Immunization of SJL/J mice with PLP139–151 induces a relapsing-remitting EAE that resembles the relapsing-remitting form of MS in humans (McRae et al, 1992). In this model, mice fully or almost fully recover from the first wave of paralysis after immunization and after a disease-free period of 1–2 weeks, 50–100% of the mice develop a second wave of paralysis. When clinical symptoms were visible, animals were treated once or three times a week with ONX 0914 or vehicle. Treatment with ONX 0914 almost completely blocked the first wave of paralysis in these mice (Fig 7A). Interestingly, a relapse was noted in inhibitor treated mice but was significantly lower compared to vehicle treated animals. In accordance with the clinical symptoms, reduced cellular infiltration into the spinal cord could be observed by microscopic assessment of cross-sections of the spinal cord of ONX 0914 treated mice (Fig 7B). To investigate whether a relapse could be prevented in the PLP-induced mouse model of EAE, PLP139–151-immunized SJL/J mice were randomized on day 19 after the first wave of paralysis and were then treated with either ONX 0914 or vehicle (Fig 7C). In contrast to the vehicle treated mice, no relapse was observed in the ONX 0914 treated group. Hence, both disease progression and relapse can be prevented by LMP7 inhibition in this mouse model of MS.


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)

ONX 0914 ameliorates PLP139–151-induced EAE.SJL/J mice were immunized with PLP139–151 and were monitored daily for clinical symptoms of EAE. From day 11 on (indicated by an arrow), mice were treated with 10 mg/kg ONX 0914 three times a week (indicated 3×), 10 mg/kg ONX 0914 once a week (indicated weekly), or vehicle. Data, presented as the mean clinical score s.e.m. ( n = 10 per group), are from one experiment of three performed with similar results. *** P < 0.001 by two-way ANOVA followed by Bonferroni post-hoc comparison at the end of study.Representative histological spinal cord sections of indicated mice. From day 11 on, mice were treated with10 mg/kg ONX 0914 three times a week. Mice were analyzed on day 14 post immunization.SJL/J mice were immunized with PLP139–151 and were monitored daily for clinical symptoms of EAE. From day 19 on (indicated by an arrow), mice were treated with 10 mg/kg ONX 0914 three times a week (indicated 3×), 10 mg/kg ONX 0914 once a week (indicated weekly), or vehicle. Data, presented as the mean clinical score s.e.m. ( n = 10 per group), are from one experiment of three performed with similar results. *** P < 0.001 by two-way ANOVA followed by Bonferroni post-hoc comparison at the end of study.In vitro restimulated PLP139–151–reactive T cells were adoptively transferred into SJL/J mice. Mice were treated three times a week with 10 mg/kg ONX 0914 or vehicle beginning on day 9 and were monitored daily for clinical symptoms. Data are presented as mean clinical score s.e.m. ( n = 9–10 per group). * P < 0.05; ** P < 0.01; *** P < 0.001.
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fig07: ONX 0914 ameliorates PLP139–151-induced EAE.SJL/J mice were immunized with PLP139–151 and were monitored daily for clinical symptoms of EAE. From day 11 on (indicated by an arrow), mice were treated with 10 mg/kg ONX 0914 three times a week (indicated 3×), 10 mg/kg ONX 0914 once a week (indicated weekly), or vehicle. Data, presented as the mean clinical score s.e.m. ( n = 10 per group), are from one experiment of three performed with similar results. *** P < 0.001 by two-way ANOVA followed by Bonferroni post-hoc comparison at the end of study.Representative histological spinal cord sections of indicated mice. From day 11 on, mice were treated with10 mg/kg ONX 0914 three times a week. Mice were analyzed on day 14 post immunization.SJL/J mice were immunized with PLP139–151 and were monitored daily for clinical symptoms of EAE. From day 19 on (indicated by an arrow), mice were treated with 10 mg/kg ONX 0914 three times a week (indicated 3×), 10 mg/kg ONX 0914 once a week (indicated weekly), or vehicle. Data, presented as the mean clinical score s.e.m. ( n = 10 per group), are from one experiment of three performed with similar results. *** P < 0.001 by two-way ANOVA followed by Bonferroni post-hoc comparison at the end of study.In vitro restimulated PLP139–151–reactive T cells were adoptively transferred into SJL/J mice. Mice were treated three times a week with 10 mg/kg ONX 0914 or vehicle beginning on day 9 and were monitored daily for clinical symptoms. Data are presented as mean clinical score s.e.m. ( n = 9–10 per group). * P < 0.05; ** P < 0.01; *** P < 0.001.
Mentions: Immunization of SJL/J mice with PLP139–151 induces a relapsing-remitting EAE that resembles the relapsing-remitting form of MS in humans (McRae et al, 1992). In this model, mice fully or almost fully recover from the first wave of paralysis after immunization and after a disease-free period of 1–2 weeks, 50–100% of the mice develop a second wave of paralysis. When clinical symptoms were visible, animals were treated once or three times a week with ONX 0914 or vehicle. Treatment with ONX 0914 almost completely blocked the first wave of paralysis in these mice (Fig 7A). Interestingly, a relapse was noted in inhibitor treated mice but was significantly lower compared to vehicle treated animals. In accordance with the clinical symptoms, reduced cellular infiltration into the spinal cord could be observed by microscopic assessment of cross-sections of the spinal cord of ONX 0914 treated mice (Fig 7B). To investigate whether a relapse could be prevented in the PLP-induced mouse model of EAE, PLP139–151-immunized SJL/J mice were randomized on day 19 after the first wave of paralysis and were then treated with either ONX 0914 or vehicle (Fig 7C). In contrast to the vehicle treated mice, no relapse was observed in the ONX 0914 treated group. Hence, both disease progression and relapse can be prevented by LMP7 inhibition in this mouse model of MS.

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