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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 plays a critical role in the arthritis flare-up reaction.In C57BL/6 mice, antigen-induced arthritis (AIA) was induced. Four weeks after the induction of AIA either IgG control or anti-IL-23p19 was administrated intra-peritoneally weekly for 5 weeks. One day after the final injection mice were given an intra-articular injection with mBSA to induce a flare-up or were left untreated. (A) Twenty-four hours later, knee joints were assessed macroscopically on a 0–2 scale. Each symbol represents data from an individual knee joint and the horizontal line depicts the median. Data are from n = 5 mice per group assessing both knee joints. *P<0.05; **P<0.01; ***P<0.001 by Mann-Whitney U test. (B) Cells from the knee-joints were isolated, RNA was extracted and gene expression for the indicated genes was quantified by quantitative RT-PCR and normalized for GAPDH. Data are the mean+SEM from 5 mice per group.
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pone-0057553-g005: IL-23 plays a critical role in the arthritis flare-up reaction.In C57BL/6 mice, antigen-induced arthritis (AIA) was induced. Four weeks after the induction of AIA either IgG control or anti-IL-23p19 was administrated intra-peritoneally weekly for 5 weeks. One day after the final injection mice were given an intra-articular injection with mBSA to induce a flare-up or were left untreated. (A) Twenty-four hours later, knee joints were assessed macroscopically on a 0–2 scale. Each symbol represents data from an individual knee joint and the horizontal line depicts the median. Data are from n = 5 mice per group assessing both knee joints. *P<0.05; **P<0.01; ***P<0.001 by Mann-Whitney U test. (B) Cells from the knee-joints were isolated, RNA was extracted and gene expression for the indicated genes was quantified by quantitative RT-PCR and normalized for GAPDH. Data are the mean+SEM from 5 mice per group.

Mentions: CIA pathology is initiated by CII-specific helper T and B cells which in turn lead to the generation of anti-CII-specific IgG producing plasma cells and the formation of pathogenic immune-complexes (ICs) [10]. To further dissect the role of IL-23 on reactivation of memory T cell mediated pathology, we utilized the mBSA-driven antigen-induced arthritis (AIA) flare-up model. Mice were immunized with mBSA/CFA and one week later an intra-articular injection with mBSA was given to induce a primary mono-arthritis which typically lasts for 3 weeks. After recovery from the primary arthritis, mice received five weekly injections with a murine anti-murine IL-23p19 antibody or isotype control antibody. One day after the last antibody injection, a local arthritic flare-up was induced by a second intra-articular injection with mBSA and the following day mice were sacrificed and the arthritis severity was assessed macroscopically. Mice treated with anti-IL-23p19 developed significantly lower arthritis scores compared with control (Figure 5A). To gain insight in the effect of IL-23 neutralization, RNA from knee-infiltrating cells was isolated and gene transcription was determined by quantitative RT-PCR. Synovial IL-17A and IL-22 expression was lower in anti-IL-23p19 treated mice compared to control, although not reaching statistical significance (Figure 5B). In contrast, synovial IFN-γ expression was similar between the two groups (Figure 5B). These data show that anti-IL-23p19 treatment significantly suppressed antigen-induced flare-up arthritis.


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 plays a critical role in the arthritis flare-up reaction.In C57BL/6 mice, antigen-induced arthritis (AIA) was induced. Four weeks after the induction of AIA either IgG control or anti-IL-23p19 was administrated intra-peritoneally weekly for 5 weeks. One day after the final injection mice were given an intra-articular injection with mBSA to induce a flare-up or were left untreated. (A) Twenty-four hours later, knee joints were assessed macroscopically on a 0–2 scale. Each symbol represents data from an individual knee joint and the horizontal line depicts the median. Data are from n = 5 mice per group assessing both knee joints. *P<0.05; **P<0.01; ***P<0.001 by Mann-Whitney U test. (B) Cells from the knee-joints were isolated, RNA was extracted and gene expression for the indicated genes was quantified by quantitative RT-PCR and normalized for GAPDH. Data are the mean+SEM from 5 mice per group.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3585376&req=5

pone-0057553-g005: IL-23 plays a critical role in the arthritis flare-up reaction.In C57BL/6 mice, antigen-induced arthritis (AIA) was induced. Four weeks after the induction of AIA either IgG control or anti-IL-23p19 was administrated intra-peritoneally weekly for 5 weeks. One day after the final injection mice were given an intra-articular injection with mBSA to induce a flare-up or were left untreated. (A) Twenty-four hours later, knee joints were assessed macroscopically on a 0–2 scale. Each symbol represents data from an individual knee joint and the horizontal line depicts the median. Data are from n = 5 mice per group assessing both knee joints. *P<0.05; **P<0.01; ***P<0.001 by Mann-Whitney U test. (B) Cells from the knee-joints were isolated, RNA was extracted and gene expression for the indicated genes was quantified by quantitative RT-PCR and normalized for GAPDH. Data are the mean+SEM from 5 mice per group.
Mentions: CIA pathology is initiated by CII-specific helper T and B cells which in turn lead to the generation of anti-CII-specific IgG producing plasma cells and the formation of pathogenic immune-complexes (ICs) [10]. To further dissect the role of IL-23 on reactivation of memory T cell mediated pathology, we utilized the mBSA-driven antigen-induced arthritis (AIA) flare-up model. Mice were immunized with mBSA/CFA and one week later an intra-articular injection with mBSA was given to induce a primary mono-arthritis which typically lasts for 3 weeks. After recovery from the primary arthritis, mice received five weekly injections with a murine anti-murine IL-23p19 antibody or isotype control antibody. One day after the last antibody injection, a local arthritic flare-up was induced by a second intra-articular injection with mBSA and the following day mice were sacrificed and the arthritis severity was assessed macroscopically. Mice treated with anti-IL-23p19 developed significantly lower arthritis scores compared with control (Figure 5A). To gain insight in the effect of IL-23 neutralization, RNA from knee-infiltrating cells was isolated and gene transcription was determined by quantitative RT-PCR. Synovial IL-17A and IL-22 expression was lower in anti-IL-23p19 treated mice compared to control, although not reaching statistical significance (Figure 5B). In contrast, synovial IFN-γ expression was similar between the two groups (Figure 5B). These data show that anti-IL-23p19 treatment significantly suppressed antigen-induced flare-up arthritis.

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