Suppression of Glomerulonephritis in Lupus-Prone NZB x NZW Mice by RN486, a Selective Inhibitor of Bruton's Tyrosine Kinase
Suppression of Glomerulonephritis in Lupus-Prone NZB x NZW Mice by RN486, a Selective Inhibitor of Bruton's Tyrosine Kinase
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DOI：
10.1002/art.38047
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发表时间：
2013-08-01
影响因子：
--
通讯作者：
Xu, Daigen
中科院分区：
文献类型：
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作者：
Mina-Osorio, Paola;LaStant, Jacob;Xu, Daigen
目的布鲁顿酪氨酸激酶（BTK）在B细胞发育和功能中起重要作用。我们最近描述了一种选择性BTK抑制剂RN 486，其阻断B细胞受体（BCR）和Fc受体信号传导，并且在关节炎动物模型中有效。本研究的目的是使用自发性SLE的NZB x NZW小鼠模型来检查BTK在系统性红斑狼疮（SLE）中的潜在功效。从32周龄开始，以30 mg/kg的终浓度（在食物中给药）给药8周。如通过肾小球肾炎的组织学和功能分析所确定的。该功效与对B细胞活化的显着抑制有关，正如BCR交联反应中CD 69表达的显着减少所证明的那样。RN 486显着减少IgG抗双链DNA（抗dsDNA）分泌的分泌，如通过酶联免疫吸附和酶联免疫斑点测定。流式细胞术分析表明脾脏中CD 138（高）B220（低）浆细胞耗竭。RN 486抑制IgG抗dsDNA而非IgM抗dsDNA的分泌，表明BTK的药理学阻断类似于所报道的B细胞中低水平内源性BTK的转基因表达。此外，RN 486还可能影响自身抗体的效应子功能，如通过在体外显著减少免疫复合物介导的人单核细胞活化和下调巨噬细胞相关基因和干扰素诱导基因在治疗小鼠的肾脏和脾脏中的表达所证明的。因此构成了这种疾病的有希望的治疗选择。
Objective Bruton's tyrosine kinase (BTK) plays a critical role in B cell development and function. We recently described a selective BTK inhibitor, RN486, that blocks B cell receptor (BCR) and Fc receptor signaling and is efficacious in animal models of arthritis. The aim of this study was to examine the potential efficacy of BTK in systemic lupus erythematosus (SLE), using an NZB x NZW mouse model of spontaneous SLE.Methods Mice received RN486 or its vehicle (administered in chow) at a final concentration of 30 mg/kg for 8 weeks, starting at 32 weeks of age.Results The administration of RN486 completely stopped disease progression, as determined by histologic and functional analyses of glomerular nephritis. The efficacy was associated with striking inhibition of B cell activation, as demonstrated by a significant reduction in CD69 expression in response to BCR crosslinking. RN486 markedly reduced the secretion of IgG anti-double-stranded DNA (anti-dsDNA) secretion, as determined by enzyme-linked immunosorbent and enzyme-linked immunospot assays. Flow cytometric analysis demonstrated depletion of CD138(high)B220(low) plasma cells in the spleen. RN486 inhibited secretion of IgG anti-dsDNA but not IgM anti-dsDNA, suggesting that pharmacologic blockade of BTK resembles the reported transgenic expression of low levels of endogenous BTK in B cells. In addition, RN486 may also impact the effector function of autoantibodies, as evidenced by a significant reduction in immune complex-mediated activation of human monocytes in vitro and down-regulation of the expression of macrophage-related and interferon-inducible genes in both the kidneys and spleens of treated mice.Conclusion Collectively, our data suggest that BTK inhibitors may simultaneously target autoantibody-producing and effector cells in SLE, thus constituting a promising therapeutic alternative for this disease.