Treatment with a neutralizing anti‐murine interleukin‐17 antibody after the onset of collagen‐induced arthritis reduces joint inflammation, cartilage destruction, and …

E Lubberts, MI Koenders… - … : Official Journal of …, 2004 - Wiley Online Library
E Lubberts, MI Koenders, B Oppers‐Walgreen, L Van Den Bersselaar, CJJ Coenen‐de Roo…
Arthritis & Rheumatism: Official Journal of the American College …, 2004Wiley Online Library
Abstract Objective Interleukin‐17 (IL‐17) is a proinflammatory cytokine that is expressed in
the synovium of rheumatoid arthritis (RA) patients. This T cell cytokine is implicated in the
initiation phase of arthritis. However, the role of IL‐17 during the effector phase of arthritis
has still not been identified; this was the objective of the present study. Methods Mice with
collagen‐induced arthritis (CIA) were treated with polyclonal rabbit anti‐murine IL‐17 (anti–
IL‐17) antibody–positive serum or normal rabbit serum after the first signs of arthritis. In …
Objective
Interleukin‐17 (IL‐17) is a proinflammatory cytokine that is expressed in the synovium of rheumatoid arthritis (RA) patients. This T cell cytokine is implicated in the initiation phase of arthritis. However, the role of IL‐17 during the effector phase of arthritis has still not been identified; this was the objective of the present study.
Methods
Mice with collagen‐induced arthritis (CIA) were treated with polyclonal rabbit anti‐murine IL‐17 (anti–IL‐17) antibody–positive serum or normal rabbit serum after the first signs of arthritis. In addition, during a later stage of CIA mice were selected and treated with anti–IL‐17 antibody or control serum. Arthritis was monitored visually, and joint pathology was examined radiologically and histologically. Systemic IL‐6 levels were measured by enzyme‐linked immunosorbent assay, and local synovial IL‐1 and receptor activator of NF‐κB ligand (RANKL) expression was analyzed using specific immunohistochemistry.
Results
Treatment with a neutralizing anti–IL‐17 antibody after the onset of CIA significantly reduced the severity of CIA. Radiographic analysis revealed marked suppression of joint damage in the knee and ankle joints. Histologic analysis confirmed the suppression of joint inflammation and showed prevention of cartilage and bone destruction after anti–IL‐17 antibody therapy. Systemic IL‐6 levels were significantly reduced after anti–IL‐17 antibody treatment. Moreover, fewer IL‐1β–positive and RANKL‐positive cells were detected in the synovium after treatment with neutralizing IL‐17. Interestingly, initiation of anti–IL‐17 antibody therapy during a later stage of CIA, using mice with higher clinical arthritis scores, still significantly slowed the progression of the disease.
Conclusion
IL‐17 plays a role in early stages of arthritis, but also later during disease progression. Systemic IL‐6 was reduced and fewer synovial IL‐1–positive and RANKL‐positive cells were detected after neutralizing endogenous IL‐17 treatment, suggesting both IL‐1–dependent and IL‐1–independent mechanisms of action. Our data strongly indicate that IL‐17 neutralization could provide an additional therapeutic strategy for RA, particularly in situations in which elevated IL‐17 may attenuate the response to anti–tumor necrosis factor/anti–IL‐1 therapy.
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