Targeting of Gr-l+,CCR2+ monocytes in collagen-induced arthritis
Targeting of Gr-l+,CCR2+ monocytes in collagen-induced arthritis
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DOI：
10.1002/art.22854
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发表时间：
2007-09-01
影响因子：
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通讯作者：
Mack, Matthias
中科院分区：
文献类型：
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作者：
Bruehl, Hilke;Cihak, Josef;Mack, Matthias
Objective.趋化因子受体CCR 2在单核细胞上高度表达，被认为是治疗类风湿性关节炎的有希望的靶点。然而，在胶原诱导的关节炎的进展期间用单克隆抗体（mAb）阻断CCR 2导致疾病的严重恶化。在这项研究中，我们研究了为什么CCR 2抗体具有促炎作用，如何避免这些作用，以及CCR 2+单核细胞是否是治疗关节炎的有用靶点。用11型胶原免疫DBA/1小鼠诱导关节炎。在不同时间点用抗CCR 2（MC-21）、IgE或同种型对照抗体的mAb处理小鼠。通过荧光活化细胞分选仪分析和酶联免疫吸附测定法测定嗜碱性粒细胞的活化和单核细胞亚群的耗竭。CCR 2的交联活化嗜碱性粒细胞以释放白细胞介素-6（IL-6）和IL-4。在体内，IL-6的释放仅发生在暴露于高剂量的MC-21后，而应用低剂量的mAb则避免了IL-6的释放。无论使用的剂量水平如何，抗体MC-21有效地从DBA/1小鼠的滑膜组织、外周血和脾脏中耗尽Gr-1 +、CCR 2+单核细胞。用高剂量的MC-21或抗IgE抗体激活嗜碱性粒细胞导致胶原诱导的关节炎显著加重和IL-6释放增加。相比之下，在这种治疗环境中用MC-21进行低剂量治疗对IL-6没有影响，并导致关节炎的显著改善。这些结果表明，清除CCR 2+单核细胞可能被证明是炎性关节炎的一种治疗选择，只要考虑到CCR 2 mAb的剂量依赖性促炎作用。
Objective. The chemokine receptor CCR2 is highly expressed on monocytes and considered a promising target for treatment of rheumatoid arthritis. However, blockade of CCR2 with a monoclonal antibody (mAb) during progression of collagen -induced arthritis results in a massive aggravation of the disease. In this study we investigated why CCR2 antibodies have proin-flammatory effects, how these effects can be avoided, and whether CCR2+ monocytes are useful targets in the treatment of arthritis.Methods. Arthritis was induced in DBA/1 mice by immunization with type 11 collagen. Mice were treated with mAb against CCR2 (MC-21), IgE, or isotype control antibodies at various time points. Activation of basophils and depletion of monocyte subsets were determined by fluorescence- activated cell sorter analysis and enzyme-linked immunosorbent assay.Results. Crosslinkage of CCR2 activated basophils to release interieukin-6 (IL-6) and IL-4. In vivo, IL-6 release occurred only after exposure to high doses of MC-21, whereas application of low doses of the mAb circumvented the release of IL-6. Regardless of the dose level used, the antibody MC-21 efficiently depleted Gr-1 +,CCR2 + monocytes from the synovial tissue, peripheral blood, and spleen of DBA/1 mice. Activation of basophils with high doses of MC-21 or with antibodies against IgE resulted in a marked aggravation of collagen -induced arthritis and an increased release of IL-6. In contrast, low-dose treatment with MC-21 in this therapeutic setting had no effect on IL-6 and led to marked improvement of arthritis.Conclusion. These results show that depletion of CCR2+ monocytes may prove to be a therapeutic option in inflammatory arthritis, as long as the dose-dependent proinflammatory effects of CCR2 mAb are taken into account.