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IL-23 dependent and independent stages of experimental arthritis: no clinical effect of therapeutic IL-23p19 inhibition in collagen-induced arthritis.

Cornelissen F, Asmawidjaja PS, Mus AM, Corneth O, Kikly K, Lubberts E - PLoS ONE (2013)

Bottom Line: Neutralizing IL-23 after onset of CIA in rats has been shown to reduce paw volume, but the effect on synovial inflammation and the immunological autoimmune response is not clear.Importantly, neutralizing IL-23 after the first signs of CIA did not ameliorate the disease.These data suggest that specific neutralization of IL-23p19 after onset of autoimmune arthritis may not be beneficial as a therapeutic therapy for patients with rheumatoid arthritis (RA).

View Article: PubMed Central - PubMed

Affiliation: Department of Rheumatology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands.

ABSTRACT
IL-23p19 deficient mice have revealed a critical role of IL-23 in the development of experimental autoimmune diseases, such as collagen-induced arthritis (CIA). Neutralizing IL-23 after onset of CIA in rats has been shown to reduce paw volume, but the effect on synovial inflammation and the immunological autoimmune response is not clear. In this study, we examined the role of IL-23 at different stages of CIA and during T cell memory mediated flare-up arthritis with focus on changes in B cell activity and Th1/Th17 modulation. Anti-IL-23p19 antibody (anti-IL23p19) treatment, starting 15 days after the type II collagen (CII)-immunization but before clinical signs of disease onset, significantly suppressed the severity of CIA. This was accompanied with significantly lower CII-specific IgG1 levels and lower IgG2a levels in the anti-IL-23p19 treated mice compared to the control group. Importantly, neutralizing IL-23 after the first signs of CIA did not ameliorate the disease. This was in contrast to arthritic mice that underwent an arthritis flare-up since a significantly lower disease score was observed in the IL-23p19 treated mice compared to the control group, accompanied by lower synovial IL-17A and IL-22 expression in the knee joints of these mice. These data show IL-23-dependent and IL-23-independent stages during autoimmune CIA. Furthermore, the memory T cell mediated flare-up arthritis is IL-23-mediated. These data suggest that specific neutralization of IL-23p19 after onset of autoimmune arthritis may not be beneficial as a therapeutic therapy for patients with rheumatoid arthritis (RA). However, T cell mediated arthritis relapses in patients with RA might be controlled by anti-IL-23p19 treatment.

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Neutralizing IL-23 after onset of CIA does not ameliorate disease activity.CIA was induced in DBA/1 mice and directly after the first signs of CIA anti-IL-23p19 or control antibody was injected when an arthritis score between 0.5–1.5 was observed. (A and C) Arthritis severity was scored macroscopically. Numbers on the x-axis indicate the day after the first injection with either antibody and the arrows indicate each time point an injection was given. Data are from (A) n = 8 and (B) n = 10 mice per group. (B and D) At the end of each experiment, serum was collected and anti-CII antibody production of the IgG1, IgG2a and IgG2b subclasses was measured.
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pone-0057553-g004: Neutralizing IL-23 after onset of CIA does not ameliorate disease activity.CIA was induced in DBA/1 mice and directly after the first signs of CIA anti-IL-23p19 or control antibody was injected when an arthritis score between 0.5–1.5 was observed. (A and C) Arthritis severity was scored macroscopically. Numbers on the x-axis indicate the day after the first injection with either antibody and the arrows indicate each time point an injection was given. Data are from (A) n = 8 and (B) n = 10 mice per group. (B and D) At the end of each experiment, serum was collected and anti-CII antibody production of the IgG1, IgG2a and IgG2b subclasses was measured.

Mentions: Next, we asked whether anti-IL-23p19 has a therapeutic effect in CIA. To evaluate this, mice were treated with anti-IL-23p19 or control antibody weekly for 3 weeks after the first signs of CIA. Anti-IL-23p19 did not significantly suppress the arthritis score, compared with isotype control-treated mice (Figure 4A), and no differences in anti-CII specific IgG antibody levels were noted between the two groups (Figure 4B). To determine if longer treatment with anti-IL-23p19 would lead to a significant improvement in the arthritis score, anti-IL-23p19 or control antibody was administrated for a period of 6 weeks after disease onset. However, no ameliorative effect was observed (Figure 4C) after blockade of IL-23 compared to control and this also did not affect the production of anti-CII antibodies (Figure 4D). Together, these data indicate that specific neutralization of IL-23 after CIA onset has no beneficial effect on the CII-antibody titer or clinical score of CIA.


IL-23 dependent and independent stages of experimental arthritis: no clinical effect of therapeutic IL-23p19 inhibition in collagen-induced arthritis.

Cornelissen F, Asmawidjaja PS, Mus AM, Corneth O, Kikly K, Lubberts E - PLoS ONE (2013)

Neutralizing IL-23 after onset of CIA does not ameliorate disease activity.CIA was induced in DBA/1 mice and directly after the first signs of CIA anti-IL-23p19 or control antibody was injected when an arthritis score between 0.5–1.5 was observed. (A and C) Arthritis severity was scored macroscopically. Numbers on the x-axis indicate the day after the first injection with either antibody and the arrows indicate each time point an injection was given. Data are from (A) n = 8 and (B) n = 10 mice per group. (B and D) At the end of each experiment, serum was collected and anti-CII antibody production of the IgG1, IgG2a and IgG2b subclasses was measured.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585376&req=5

pone-0057553-g004: Neutralizing IL-23 after onset of CIA does not ameliorate disease activity.CIA was induced in DBA/1 mice and directly after the first signs of CIA anti-IL-23p19 or control antibody was injected when an arthritis score between 0.5–1.5 was observed. (A and C) Arthritis severity was scored macroscopically. Numbers on the x-axis indicate the day after the first injection with either antibody and the arrows indicate each time point an injection was given. Data are from (A) n = 8 and (B) n = 10 mice per group. (B and D) At the end of each experiment, serum was collected and anti-CII antibody production of the IgG1, IgG2a and IgG2b subclasses was measured.
Mentions: Next, we asked whether anti-IL-23p19 has a therapeutic effect in CIA. To evaluate this, mice were treated with anti-IL-23p19 or control antibody weekly for 3 weeks after the first signs of CIA. Anti-IL-23p19 did not significantly suppress the arthritis score, compared with isotype control-treated mice (Figure 4A), and no differences in anti-CII specific IgG antibody levels were noted between the two groups (Figure 4B). To determine if longer treatment with anti-IL-23p19 would lead to a significant improvement in the arthritis score, anti-IL-23p19 or control antibody was administrated for a period of 6 weeks after disease onset. However, no ameliorative effect was observed (Figure 4C) after blockade of IL-23 compared to control and this also did not affect the production of anti-CII antibodies (Figure 4D). Together, these data indicate that specific neutralization of IL-23 after CIA onset has no beneficial effect on the CII-antibody titer or clinical score of CIA.

Bottom Line: Neutralizing IL-23 after onset of CIA in rats has been shown to reduce paw volume, but the effect on synovial inflammation and the immunological autoimmune response is not clear.Importantly, neutralizing IL-23 after the first signs of CIA did not ameliorate the disease.These data suggest that specific neutralization of IL-23p19 after onset of autoimmune arthritis may not be beneficial as a therapeutic therapy for patients with rheumatoid arthritis (RA).

View Article: PubMed Central - PubMed

Affiliation: Department of Rheumatology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands.

ABSTRACT
IL-23p19 deficient mice have revealed a critical role of IL-23 in the development of experimental autoimmune diseases, such as collagen-induced arthritis (CIA). Neutralizing IL-23 after onset of CIA in rats has been shown to reduce paw volume, but the effect on synovial inflammation and the immunological autoimmune response is not clear. In this study, we examined the role of IL-23 at different stages of CIA and during T cell memory mediated flare-up arthritis with focus on changes in B cell activity and Th1/Th17 modulation. Anti-IL-23p19 antibody (anti-IL23p19) treatment, starting 15 days after the type II collagen (CII)-immunization but before clinical signs of disease onset, significantly suppressed the severity of CIA. This was accompanied with significantly lower CII-specific IgG1 levels and lower IgG2a levels in the anti-IL-23p19 treated mice compared to the control group. Importantly, neutralizing IL-23 after the first signs of CIA did not ameliorate the disease. This was in contrast to arthritic mice that underwent an arthritis flare-up since a significantly lower disease score was observed in the IL-23p19 treated mice compared to the control group, accompanied by lower synovial IL-17A and IL-22 expression in the knee joints of these mice. These data show IL-23-dependent and IL-23-independent stages during autoimmune CIA. Furthermore, the memory T cell mediated flare-up arthritis is IL-23-mediated. These data suggest that specific neutralization of IL-23p19 after onset of autoimmune arthritis may not be beneficial as a therapeutic therapy for patients with rheumatoid arthritis (RA). However, T cell mediated arthritis relapses in patients with RA might be controlled by anti-IL-23p19 treatment.

Show MeSH
Related in: MedlinePlus