Bortezomib treatment induces a higher mortality rate in lupus model mice with a higher disease activity.
Bortezomib treatment induces a higher mortality rate in lupus model mice with a higher disease activity.
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DOI：
10.1186/s13075-017-1397-7
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发表时间：
2017-08-11
影响因子：
4.9
通讯作者：
Harigae H
中科院分区：
文献类型：
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作者：
Ikeda T;Fujii H;Nose M;Kamogawa Y;Shirai T;Shirota Y;Ishii T;Harigae H
硼替佐米（Bz）是一种蛋白酶体抑制剂，直接靶向产生抗体的浆细胞。我们最近报道了第一个随机对照试验，评估了Bz在系统性红斑狼疮（SLE）患者中的作用。在该研究中，我们证明了Bz治疗与难治性疾病患者的许多不良反应相关。在本研究中，我们研究了Bz对具有严重疾病活动的MRL/MpJ-lpr/lpr（MRL/lpr）小鼠的治疗和毒性作用。用磷酸盐缓冲盐水（PBS）（n = 19）、Bz（750 μg/kg，每周两次）（n = 27）或环磷酰胺（Cyc）（1 mg/只，2周一次）（n = 20）处理10周龄和14周龄的雌性MRL/lpr小鼠。然后在22周龄时分析细胞亚群、血清免疫球蛋白、抗双链DNA（抗dsDNA）抗体滴度和肾小球肾炎的病理指数。比较10周龄和14周龄Bz处理组的存活曲线。Bz治疗后1周测量血细胞计数、肌酐、肝酶和血清细胞因子水平。将来自Bz和Cyc处理小鼠的脾脏的基因表达谱与来自对照小鼠的基因表达谱进行比较。14周龄小鼠的抗dsDNA抗体水平显著高于10周龄小鼠，表明14周龄时疾病活动性更高。在Bz处理和Cyc-treated小鼠中观察到脾细胞数量和肾小球肾炎指数显著降低。Bz，而不是Cyc，显着降低血清免疫球蛋白和抗dsDNA抗体滴度水平。存活曲线分析显示，14周龄的死亡率显著高于10周龄的Bz治疗组和对照组。两次注射Bz后，14周龄小鼠的血清IL-6和TNF-α水平显著高于10周龄小鼠。潜在的免疫原性分子，如热休克蛋白，在Bz处理的小鼠的脾脏中特征性地上调，而不是Cyc-treated小鼠。尽管Bz治疗具有治疗效果，但在疾病活动度较高的小鼠中，Bz治疗具有与促炎细胞因子水平升高相关的更多毒性作用。了解Bz的毒性机制并制定相应的预防措施对Bz在SLE中的安全应用具有重要意义。本文的在线版本（doi：10.1186/s13075-017-1397-7）包含补充材料，可供授权用户使用。
Bortezomib (Bz) is a proteasome inhibitor that directly targets antibody-producing plasma cells. We recently reported the first randomized control trial that evaluated the effects of Bz in patients with systemic lupus erythematosus (SLE). In that study, we demonstrated that Bz treatment is associated with many adverse reactions in patients with refractory disease. In the present study, we examine the therapeutic and toxic effects of Bz on MRL/MpJ-lpr/lpr (MRL/lpr) mice with severe disease activity. Female MRL/lpr mice at 10 and 14 weeks of age were treated with phosphate buffered saline (PBS) (n = 19), Bz (750 μg/kg twice weekly) (n = 27), or cyclophosphamide (Cyc) (1 mg/body, once in 2 weeks) (n = 20). Cellular subsets, serum immunoglobulin, anti-double-stranded DNA (anti-dsDNA) antibody titer, and a pathological index of glomerulonephritis were then analyzed at 22 weeks of age. Survival curves of the 10-week-old and 14-week-old Bz-treated groups were compared. Blood counts, creatinine, liver enzymes, and serum cytokine levels were measured 1 week after Bz treatment. Gene expression profiling of spleens from Bz and Cyc treatment mice were compared with those from control mice. The anti-dsDNA antibody levels were significantly higher in 14-week-old than in 10-week-old mice, indicating a higher disease activity at 14 weeks. A significant decrease in the number of splenic cells and glomerulonephritis index was observed in Bz-treated and Cyc-treated mice. Bz, but not Cyc, significantly decreased serum immunoglobulin and anti-dsDNA antibody titer levels. Survival curve analysis revealed a significantly higher mortality rate in 14-week-old than in 10-week-old Bz-treated and control groups. Following two injections of Bz, serum IL-6 and TNF-α levels were significantly more elevated in 14-week-old than in 10-week-old mice. Potentially immunogenic molecules, such as heat shock proteins, were characteristically upregulated in spleens of Bz-treated but not Cyc-treated mice. In spite of its therapeutic effect, Bz treatment had more toxic effects associated with increased proinflammatory cytokine levels in mice with a higher disease activity. Understanding the mechanism of the toxicity and developing preventive strategies against it is important for the safe clinical application of Bz in human SLE. The online version of this article (doi:10.1186/s13075-017-1397-7) contains supplementary material, which is available to authorized users.
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影响因子：
3.7
作者：
Khodadadi L;Cheng Q;Alexander T;Sercan-Alp Ö;Klotsche J;Radbruch A;Hiepe F;Hoyer BF;Taddeo A
通讯作者：
Taddeo A
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通讯作者：
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