The proteasome inhibitor bortezomib depletes plasma cells and protects mice with lupus-like disease from nephritis
The proteasome inhibitor bortezomib depletes plasma cells and protects mice with lupus-like disease from nephritis
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DOI：
10.1038/nm1763
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发表时间：
2008-07-01
期刊：
影响因子：
82.9
通讯作者：
Voll, Reinhard E.
中科院分区：
文献类型：
--
作者：
Neubert, Kirsten;Meister, Silke;Voll, Reinhard E.
自身抗体介导的疾病，如重症肌无力，自身免疫性溶血性贫血和系统性红斑狼疮代表了治疗的挑战。特别是，产生自身抗体的长寿浆细胞抵抗当前的治疗和实验方法。最近，我们发现骨髓瘤细胞对蛋白酶体抑制剂的敏感性与它们的免疫球蛋白合成速率直接相关。因此，我们假设正常的浆细胞也对蛋白酶体抑制高度敏感，因为它们的蛋白质生物合成量极高。在这里，我们表明，蛋白酶体抑制剂硼替佐米，这是批准用于治疗多发性骨髓瘤，消除短寿命和长寿命的浆细胞通过激活终端未折叠的蛋白质反应。硼替佐米治疗耗尽浆细胞产生抗体的双链DNA，消除自身抗体的产生，改善肾小球肾炎和延长生存的两个小鼠品系狼疮样疾病，NZB/WF 1和MRL/lpr小鼠。因此，通过蛋白酶体抑制剂消除自身反应性浆细胞可能代表抗体介导的疾病的新治疗策略。
Autoantibody-mediated diseases like myasthenia gravis, autoimmune hemolytic anemia and systemic lupus erythematosus represent a therapeutic challenge. In particular, long-lived plasma cells producing autoantibodies resist current therapeutic and experimental approaches. Recently, we showed that the sensitivity of myeloma cells toward proteasome inhibitors directly correlates with their immunoglobulin synthesis rates. Therefore, we hypothesized that normal plasma cells are also hypersensitive to proteasome inhibition owing to their extremely high amount of protein biosynthesis. Here we show that the proteasome inhibitor bortezomib, which is approved for the treatment of multiple myeloma, eliminates both short- and long-lived plasma cells by activation of the terminal unfolded protein response. Treatment with bortezomib depleted plasma cells producing antibodies to double-stranded DNA, eliminated autoantibody production, ameliorated glomerulonephritis and prolonged survival of two mouse strains with lupus-like disease, NZB/W F1 and MRL/lpr mice. Hence, the elimination of autoreactive plasma cells by proteasome inhibitors might represent a new treatment strategy for antibody-mediated diseases.