Treatment with a neutralizing anti-murine interleukin-17 antibody after the onset of collagen-induced arthritis reduces joint inflammation, cartilage destruction, and bone erosion
Treatment with a neutralizing anti-murine interleukin-17 antibody after the onset of collagen-induced arthritis reduces joint inflammation, cartilage destruction, and bone erosion
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DOI：
10.1002/art.20001
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发表时间：
2004-02-01
影响因子：
--
通讯作者：
van den Berg, WB
中科院分区：
文献类型：
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作者：
Lubberts, E;Koenders, MI;van den Berg, WB
目标。白介素17(IL-17)是一种在类风湿关节炎(RA)患者滑膜中表达的促炎细胞因子。这种T细胞因子与关节炎的初始阶段有关。然而，IL-17在关节炎效应期中的作用仍未明确，这正是本研究的目的。胶原性关节炎(CIA)小鼠出现关节炎症状后，用兔抗鼠IL-17抗体阳性血清或正常兔血清治疗。另外，在CIA的后期阶段，选择小鼠，用抗IL-17抗体或对照血清进行治疗。对关节炎进行目视监测，并对关节病理进行放射学和组织学检查。用酶联免疫吸附试验检测滑膜局部IL-6水平，用免疫组织化学方法检测滑膜局部IL-1和核因子-kappaB受体激活物配体(RANKL)的表达。CIA发病后使用中和抗IL-17抗体治疗可显著减轻CIA的严重程度。放射学分析显示膝关节和踝关节的关节损伤明显受到抑制。组织学分析证实，抗IL-17抗体治疗后关节炎症得到抑制，软骨和骨破坏得到预防。经抗IL-17抗体治疗后，全身IL-6水平明显降低。此外，经中和IL-17处理后，滑膜中检测到较少的IL-1β和RANKL阳性细胞。有趣的是，在CIA的后期阶段，使用临床关节炎评分较高的小鼠，开始抗IL-17抗体治疗，仍然显著减缓了疾病的进展。IL-17在关节炎的早期阶段发挥作用，但也在疾病进展的后期发挥作用。中和内源性IL-17后，滑膜IL-6水平降低，滑膜IL-1阳性细胞和RANKL阳性细胞减少，提示IL-1依赖和IL-1非依赖的作用机制。我们的数据有力地表明，IL-17的中和可以为RA提供一种额外的治疗策略，特别是在IL-17升高可能会减弱抗肿瘤坏死因子/抗IL-1治疗的反应的情况下。
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-kappaB ligand (RANKL) expression was analyzed using specific inummohistochemistry.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-1beta-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.