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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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IL-23 does not enhance CII-specific IL-17A production.(A) DBA/1 mice were immunized with CFA only, with CII/CFA or left untreated. At days 10 (CFA and CFA/CII) and 25 (CFA/CII) post-immunization, splenocytes were isolated and assessed for intracellular expression of IL-17A and IFN-γ. Numbers in quadrant indicate percentage positive cells in that quadrant. Plots are representative of n = 3–6 per group. (B) IL-17A and IFN-γ secretion levels after antigen (CII) specific restimulation of purified splenic CD4+ T cells with irradiated APCs in the absence (−) or presence of exogenous IL-23. Data are the mean +SEM from n = 3 mice per group and *P<0.05; **P<0.01; ***P<0.001 as calculated by Mann-Whitney U test.
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pone-0057553-g001: IL-23 does not enhance CII-specific IL-17A production.(A) DBA/1 mice were immunized with CFA only, with CII/CFA or left untreated. At days 10 (CFA and CFA/CII) and 25 (CFA/CII) post-immunization, splenocytes were isolated and assessed for intracellular expression of IL-17A and IFN-γ. Numbers in quadrant indicate percentage positive cells in that quadrant. Plots are representative of n = 3–6 per group. (B) IL-17A and IFN-γ secretion levels after antigen (CII) specific restimulation of purified splenic CD4+ T cells with irradiated APCs in the absence (−) or presence of exogenous IL-23. Data are the mean +SEM from n = 3 mice per group and *P<0.05; **P<0.01; ***P<0.001 as calculated by Mann-Whitney U test.

Mentions: To profile the kinetics of Th1 and Th17 cells during collagen-induced arthritis (CIA), splenocytes were isolated from type II collagen (CII)-immunized DBA/1 mice at various time points post-immunization (p.i.) and assessed for intracellular cytokines by flow cytometry. At day 10 p.i. the highest proportions of total IL-17A+ and IL-17A+IFNγ- CD4+ T cells were observed as compared to naïve (non-immunized) mice as well as to mice 25 days p.i and CIA-diseased mice (Figure 1A). However, injection of CFA only also induced a clear population of IL-17+IFNγ- CD4+ T cells though lower than that observed in CII/CFA-immunized mice. This shows the generation of CD4+ IL-17A-expressing T cells during 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)

IL-23 does not enhance CII-specific IL-17A production.(A) DBA/1 mice were immunized with CFA only, with CII/CFA or left untreated. At days 10 (CFA and CFA/CII) and 25 (CFA/CII) post-immunization, splenocytes were isolated and assessed for intracellular expression of IL-17A and IFN-γ. Numbers in quadrant indicate percentage positive cells in that quadrant. Plots are representative of n = 3–6 per group. (B) IL-17A and IFN-γ secretion levels after antigen (CII) specific restimulation of purified splenic CD4+ T cells with irradiated APCs in the absence (−) or presence of exogenous IL-23. Data are the mean +SEM from n = 3 mice per group and *P<0.05; **P<0.01; ***P<0.001 as calculated by Mann-Whitney U test.
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Related In: Results  -  Collection

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pone-0057553-g001: IL-23 does not enhance CII-specific IL-17A production.(A) DBA/1 mice were immunized with CFA only, with CII/CFA or left untreated. At days 10 (CFA and CFA/CII) and 25 (CFA/CII) post-immunization, splenocytes were isolated and assessed for intracellular expression of IL-17A and IFN-γ. Numbers in quadrant indicate percentage positive cells in that quadrant. Plots are representative of n = 3–6 per group. (B) IL-17A and IFN-γ secretion levels after antigen (CII) specific restimulation of purified splenic CD4+ T cells with irradiated APCs in the absence (−) or presence of exogenous IL-23. Data are the mean +SEM from n = 3 mice per group and *P<0.05; **P<0.01; ***P<0.001 as calculated by Mann-Whitney U test.
Mentions: To profile the kinetics of Th1 and Th17 cells during collagen-induced arthritis (CIA), splenocytes were isolated from type II collagen (CII)-immunized DBA/1 mice at various time points post-immunization (p.i.) and assessed for intracellular cytokines by flow cytometry. At day 10 p.i. the highest proportions of total IL-17A+ and IL-17A+IFNγ- CD4+ T cells were observed as compared to naïve (non-immunized) mice as well as to mice 25 days p.i and CIA-diseased mice (Figure 1A). However, injection of CFA only also induced a clear population of IL-17+IFNγ- CD4+ T cells though lower than that observed in CII/CFA-immunized mice. This shows the generation of CD4+ IL-17A-expressing T cells during 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