Spiegelmer inhibition of CCL2/MCP-1 ameliorates lupus nephritis in MRL-(Fas)lpr mice
Spiegelmer inhibition of CCL2/MCP-1 ameliorates lupus nephritis in MRL-(Fas)lpr mice
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DOI：
10.1681/asn.2006121348
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发表时间：
2007-08-01
影响因子：
13.6
通讯作者：
Anders, Hans-Joachim
中科院分区：
文献类型：
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作者：
Kulkarni, Onkar;Pawar, Rahul D.;Anders, Hans-Joachim
单核细胞趋化蛋白CCL2对于单核细胞和T细胞从血管募集到炎症部位的血管外腔室至关重要。CCL2在人狼疮肾炎中表达，并被证明介导实验性狼疮；因此，CCL2拮抗剂可能对治疗有益。本研究描述了l -对映体RNA寡核苷酸mNOX-E36，一种所谓的Spiegelmer，高亲和力结合小鼠CCL2并在体外和体内中和其作用。Spiegelmer的镜像结构具有核酸酶抗性，因此具有优异的生物稳定性。mNOX-E36不通过toll样受体-7或细胞质RNA受体诱导I型IFN，最近对某些合成的D-RNA的研究表明。自身免疫易感的MRL Ipr/Ipr小鼠在14 - 24周龄期间接受聚乙二醇形式的mNOX-E36治疗，显示出与狼疮肾炎、支气管周围炎症和狼疮样炎症性皮肤病变显著改善相关的生存延长。因此，基于mnox - e36的CCL2抑制代表了一种治疗自身免疫性组织损伤（如狼疮肾炎）的新策略。
The monocyte chemoattractant protein CCL2 is crucial for monocyte and T cell recruitment from the vascular to the extravascular compartment at sites of inflammation. CCL2 is expressed in human lupus nephritis and was shown to mediate experimental lupus; therefore, CCL2 antagonists may be beneficial for therapy. This study describes the L-enantiomeric RNA oligonucleotide mNOX-E36, a so-called Spiegelmer that binds murine CCL2 with high affinity and neutralizes its action in vitro and in vivo. The mirror image configuration of the Spiegelmer confers nuclease resistance and thus excellent biostability. mNOX-E36 does not induce type I IFN via Toll-like receptor-7 or cytosolic RNA receptors, as recently shown for certain synthetic D-RNA. Autoimmune-prone MRL Ipr/Ipr mice that were treated with a polyethylene glycol form of mNOX-E36 from weeks 14 to 24 of age showed prolonged survival associated with a robust improvement of lupus nephritis, peribronchial inflammation, and lupus-like inflammatory skin lesions. Thus, mNOX-E36-based inhibition of CCL2 represents a novel strategy for the treatment of autoimmune tissue injury, such as lupus nephritis.