Proteasome Inhibition with Bortezomib Depletes Plasma Cells and Autoantibodies in Experimental Autoimmune Myasthenia Gravis
Proteasome Inhibition with Bortezomib Depletes Plasma Cells and Autoantibodies in Experimental Autoimmune Myasthenia Gravis
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DOI：
10.4049/jimmunol.1002539
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发表时间：
2011-02-15
影响因子：
4.4
通讯作者：
Losen, Mario
中科院分区：
文献类型：
--
作者：
Gomez, Alejandro M.;Vrolix, Kathleen;Losen, Mario
硼替佐米是一种蛋白酶体抑制剂，据报道可降低自身抗体滴度并改善狼疮样疾病小鼠的临床状况。硼替佐米消耗短寿命和长寿命的浆细胞;后者通常在针对T和B细胞的标准免疫抑制剂治疗中存活。这些发现鼓励我们测试硼替佐米是否有效缓解重症肌无力的实验性自身免疫性重症肌无力（EAMG）模型中的症状，重症肌无力是一种以针对骨骼肌的乙酰胆碱受体（AChR）的自身抗体为特征的疾病。刘易斯大鼠在8周实验期的第一周用盐水（对照，n = 36）或电鳐AChR（EAMG，n = 54）在CFA中免疫。免疫后，大鼠每周接受两次s.c.注射硼替佐米（0.2mg/kg，在盐水中）或盐水注射。硼替佐米诱导骨髓细胞凋亡，并使骨髓中浆细胞的数量减少高达81%。在EAMG动物中，硼替佐米有效地降低了抗AChR自身抗体滴度的升高，防止了突触后膜的超微结构损伤，改善了神经肌肉传递，并减少了肌无力症状。因此，这项研究强调了蛋白酶体抑制剂在抗体介导的自身免疫性疾病中靶向浆细胞的治疗用途的潜力。免疫学杂志，2011，186：2503-2513。
Bortezomib, an inhibitor of proteasomes, has been reported to reduce autoantibody titers and to improve clinical condition in mice suffering from lupus-like disease. Bortezomib depletes both short- and long-lived plasma cells; the latter normally survive the standard immunosuppressant treatments targeting T and B cells. These findings encouraged us to test whether bortezomib is effective for alleviating the symptoms in the experimental autoimmune myasthenia gravis (EAMG) model for myasthenia gravis, a disease that is characterized by autoantibodies against the acetylcholine receptor (AChR) of skeletal muscle. Lewis rats were immunized with saline (control, n = 36) or Torpedo AChR (EAMG, n = 54) in CFA in the first week of an experimental period of 8 wk. After immunization, rats received twice a week s.c. injections of bortezomib (0.2 mg/kg in saline) or saline injections. Bortezomib induced apoptosis in bone marrow cells and reduced the amount of plasma cells in the bone marrow by up to 81%. In the EAMG animals, bortezomib efficiently reduced the rise of anti-AChR autoantibody titers, prevented ultrastructural damage of the postsynaptic membrane, improved neuromuscular transmission, and decreased myasthenic symptoms. This study thus underscores the potential of the therapeutic use of proteasome inhibitors to target plasma cells in Ab-mediated autoimmune diseases. The Journal of Immunology, 2011, 186: 2503-2513.