FRI0005 Combination Blocking of IL-22 and IL-17 During Experimental Arthritis Potently Reduces TH17-Driven Disease Progression
Debbie RoeleveldRebecca RogierBirgitte WalgreenM.M. HelsenLiduine van den BersselaarWim B. van den BergP.M. van der KraanMarije I. Koenders
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Abstract:
Background
Rheumatoid arthritis (RA) patients show elevated levels of IL-22 and IL-22-producing T helper cells that correlate to erosive disease, suggesting a role for this cytokine in the pathogenesis of RA. Interestingly, IL-22 is a dual cytokine with pro- and anti-inflammatory properties, and its effects might be regulated by cooperation and crosstalk with IL-17.Objectives
The purpose of this study was to elucidate the role of IL-22 in the development of a spontaneous model of experimental arthritis by using IL-1Ra knockout mice. Additionally, we aimed to investigate the therapeutic potential of combined IL-22/IL-17 blocking during experimental arthritis.Methods
IL-1Ra-deficient mice develop spontaneous arthritis due to excess IL-1 signaling, and we previously demonstrated the importance of IL-17 and Th17 cells in this model1. To investigate the role of IL-22 in this arthritis model, we compared IL-1Ra-/- x IL-22+/+ mice to IL-1Ra-/- mice lacking IL-22 expression. Paw joint swelling was scored weekly, and mice were sacrificed at the age of fifteen weeks. In addition, arthritic IL-1Ra-/- x IL-22-/- mice were treated with anti-IL-17 antibodies to determine the therapeutic potency of this combined blocking strategy during experimental arthritis.Results
IL-1Ra-/- mice that also lack IL-22 showed strongly reduced arthritis development, reaching a disease incidence of only 54% at the age of 15 weeks compared to 93% in IL-1Ra-/- x IL-22+/+ mice. In addition, arthritis severity of the mice that did develop arthritis was significantly reduced by 30.6% in the absence of IL-22. Interestingly, combined blocking of IL-22 and IL-17 using IL-1Ra-/- x IL-22-/- mice treated with neutralizing anti-IL-17 antibodies after the onset of arthritis demonstrated clear additive effects compared to blocking these single cytokines alone, thereby potently reducing progression of this Th17-driven arthritis model.Conclusions
These findings suggest that IL-22 plays an important role both in the initiation and augmentation of Th17-dependent experimental arthritis, and that targeting IL-22, especially in combination with IL-17 therefore seems an interesting, potent strategy in RA treatment.References
Koenders MI, Devesa I, Marijnissen RJ, Abdollahi-Roodsaz S, Boots AM, Walgreen B, di Padova FE, Nicklin MJ, Joosten LA, van den Berg WB. Interleukin-1 drives pathogenic Th17 cells during spontaneous arthritis in interleuking-1 receptor antagonist-deficient mice. Arthritis Rheum. 58(11): 3461-70, 2008.Disclosure of Interest
None declaredThe paper studied the effect of three different treatments for patients with rheumatoid arthritis on indicators functional activity of phagocytic cells. The study participated 89 patients with rheumatoid arthritis that were rozprydilenni into three groups depending on the type of treatment, and 20 healthy individuals. It was found that in response to microbial antigens kept functional activity of phagocytic cells in patients with minimal active rheumatoid arthritis receiving methotrexate and in patients with rheumatoid arthritis III degree of activity that received combined treatment Remikeydom and methotrexate compared with a group of patients with rheumatoid arthritis III the degree of activity treated with methotrexate alone.
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IL-17 is a pro-inflammatory factor which is involved in autoimmune diseases,such as rheumatoid arthritis and systemic lupus erythematosus.It is mainly released by Th17 cell-a subtype of CD4+T cell.At present,the effect of IL-17 on the patholagical process of rheumatoid arthritis has been widely paid attention attention.Anti-IL-17A antibodies,which are used for the treatment of rheumatoid arthritis,psoriatic arthritis and other diseases,have been produced and entered clinical trials.But the role of IL-17 on pathological processes still needs to be further studied,and its effects also need to be further investigated.This article mainly reviews the expression,regulation,biological functions of the IL-17 family and the relationship with rheumatoid arthritis to supply new ideas to the treatment of rheumatiod arthritis.
Rheumatoid factor
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Objectives : BALB/c mice were administered with JeEoTmg extract after rheumatoid arthritis elicitation were observed to investigate the mitigative effect of JeEoTang for rheumatoid arthritis. Methods : The JeEoTang extract(3.3 ml/kg/day) was daily administered for 14 days to mice suffered from rheumatoid arthritis induced by LPS(300 pt/kg). These specimens were decalcificated in EDTA solution for 4 Weeks. Results : All parameters involved in the rheumatoid arthritis of synovial membrane - hyperplasia of synoviocytes, fibrosis, angiogensis. and infiltration of inflammatory cells - were dramatically decreased in JeEoTmg extract administered mice. The number of NK-1.1, IL-lP, IL-2R-a, and ICAM-1 positive cells in synovial membrane was also remarkably diminished in JeEoTmg extract administered mice and apoptotic cell was decreased. Conclusions : These results indicate that the immnue suppression of JeEoTmg work on the mitigation of synovial damages in mice with rheumatoid arthritis, subsequently JeEoTung may play a role as a cure for rheumatoid arthritis.
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Radiosynoviorthese, a new method for the treatment of patients with rheumatoid arthritis, was developed. Altogether 260 patients with rheumatoid arthritis were treated. The therapeutic activity of radioactive colloid Au was administered intra-articularly to all the patients. Indications and contraindications for radiation therapy of rheumatoid arthritis were developed. Good short- and long-term results were noted in most of the patients after radiation therapy. Radiosynoviorthese as a method of local active therapy of affected joints with colloid Au in the multiple modality treatment of rheumatoid arthritis is effective; its prolonged stable therapeutic effect in patients is observed.
Therapeutic effect
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Delphi Method
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Rheumatoid Arthritis is found to be very effective in alleviating the symptoms in the hapless victims of rheumatoid arthritis as stipulated in ashtanga hridaya. This paper deals with the role of asteracantha longifolia in the treatment of Rheumatoid arthritis. But in the initial stages the paneeya made out of kokilasha (Asteracantha longifolia) is found to be very effective in alleviating the symptoms in the hapless victims of rheumatoid arthritis as stipulated in ashtanga hridaya. This paper deals with the role of asteracantha longifolia in the treatment of Rheumatoid arthritis.
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Objective Th17 has been shown to have a pivotal role in the development of arthritis. However, the role of IL-17 in the T cell-independent effector phase has not fully been examined. We investigated whether IL-17 is involved in the effector phase of arthritis by using K/BxN serum-induced arthritis model. Methods K/BxN serum was transferred into IL-17 knockout (KO) mice, SCID mice and their control mice, and arthritis was evaluated over time. In order to clarify the source of IL-17 in the effector phase, neutrophils or CD4+ T cells collected from IL-17 KO or control mice were injected into IL-17 KO recipient mice together with K/BxN serum. To examine if neutrophils secrete IL-17 upon stimulation, neutrophils were stimulated with immune complex in vitro and IL-17 in the supernatant was measured by ELISA. Results K/BxN serum-induced arthritis was much less severe in IL-17 KO mice than in WT mice. Since K/BxN serum-transferred SCID mice developed severe arthritis with high serum IL-17 concentration, we speculated neutrophils are the responsible player as an IL-17 source. When wild type (WT) but not IL-17 KO neutrophils were co-injected with K/BxN serum into IL-17 KO mice, arthritis was exacerbated, whereas co-injection of WT CD4+ T cells had no effect. In vitro, stimulation of neutrophils with immune complexcaused IL-17 secretion. Conclusions Neutrophils are essential as a source of IL-17 in the effector phase of arthritis. The trigger of secreting IL-17 from neutrophils may be immune complex.
Inflammatory arthritis
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Intestinal microbiota are associated with the development of inflammatory arthritis. The aim of this study was to dissect intestinal mucosal immune responses in the preclinical phase of arthritis and determine whether the presence of Th17 cells, beyond involvement of the cytokine interleukin-17 (IL-17), is required for arthritis development, and whether the involvement of Th17 cells in arthritis depends on the composition of the host microbiota.Mucosal T cell production of IL-17, interferon-γ, tumor necrosis factor α (TNFα), IL-22, and granulocyte-macrophage colony-stimulating factor (GM-CSF) was analyzed by flow cytometry and Luminex assay before arthritis onset in mice immunized to develop collagen-induced arthritis (CIA). Pathogenic features of arthritis in mice with CIA and mice with antigen-induced arthritis were compared between Th17 cell-deficient (CD4-Cre+ Rorcflox/flox ) and Th17 cell-sufficient (CD4-Cre- Rorcflox/flox ) mice. In addition, the impact of intestinal microbiota on the Th17 cell dependence of CIA was assessed.Lamina propria CD4 T cells were activated before the onset of arthritis in mice with CIA, with marked up-regulation of several cytokines, including IL-17A, TNFα, and GM-CSF. CD4-Cre+ Rorcflox/flox mice showed a specific reduction in intestinal mucosal levels of Th17 cells and partially reduced levels of IL-17-producing CD8 T cells. However, total levels of IL-17A, mostly produced by γδ T cells and neutrophils, were unaffected. The severity of arthritis was significantly reduced in Th17 cell-deficient mice, suggesting that Th17 cells have additional, IL-17A-independent roles in inflammatory arthritis. Accordingly, antigen-stimulated T cells from Th17 cell-deficient mice produced less IL-17A, IL-17F, and GM-CSF. Importantly, the dependence of CIA on the involvement of Th17 cells was mitigated in the presence of an alternative microbiome.These data from murine models suggest that activation of mucosal immunity precedes the development of arthritis, and also that Th17 cells have a microbiota-dependent role in arthritis. Therefore, a microbiome-guided stratification of patients might improve the efficacy of Th17-targeted therapies.
Inflammatory arthritis
Collagen-induced arthritis
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Objective To study the comprehensive surgical method for rheumatoid arthritis of knee.Methods 38 cases of total knee replacement for rheumatoid arthritis were analyzed using the John.N.lnsall(HSS) score system.Results The result showed that the joint function improvement were excellent in 86.9%,especially in deformity relief.Conclusion The patient with rheumatoid arthritis has lots of complications,comprehensive surgical method is an effective method for treating rheumatoid arthritis.
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