Gomez Alejandro M, Vrolix Kathleen, Martínez-Martínez Pilar, Molenaar Peter C, Phernambucq Marko, van der Esch Eline, Duimel Hans, Verheyen Fons, Voll Reinhard E, Manz Rudolf A, De Baets Marc H, Losen Mario
Neuroimmunology Group, Department of Neuroscience, School of Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.
J Immunol. 2011 Feb 15;186(4):2503-13. doi: 10.4049/jimmunol.1002539. Epub 2011 Jan 14.
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.
硼替佐米，一种蛋白酶体抑制剂，据报道可降低自身抗体滴度，并改善患有狼疮样疾病小鼠的临床状况。硼替佐米可耗尽短期和长期存活的浆细胞；而后者通常能在针对T细胞和B细胞的标准免疫抑制治疗中存活下来。这些发现促使我们测试硼替佐米在重症肌无力实验性自身免疫性重症肌无力（EAMG）模型中是否能有效缓解症状，重症肌无力是一种以针对骨骼肌乙酰胆碱受体（AChR）的自身抗体为特征的疾病。在为期8周的实验期的第一周，将Lewis大鼠用生理盐水（对照组，n = 36）或在弗氏完全佐剂中的电鳐AChR（EAMG组，n = 54）进行免疫。免疫后，大鼠每周接受两次皮下注射硼替佐米（0.2 mg/kg溶于生理盐水）或生理盐水注射。硼替佐米诱导骨髓细胞凋亡，并使骨髓中浆细胞数量减少多达81%。在EAMG动物中，硼替佐米有效降低了抗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，并减轻了肌无力症状。因此，本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进行治疗的潜力。
