Corna D, Morigi M, Facchinetti D, Bertani T, Zoja C, Remuzzi G
Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
Kidney Int. 1997 May;51(5):1583-9. doi: 10.1038/ki.1997.217.
Classical immunosuppressants like cyclophosphamide give excellent results in human lupus nephritis. However, they augment malignancies and viral infections. Here we investigated the effect of the new immunosuppressant agent, mycophenolate mofetil (MMF), in New Zealand Black x New Zealand White (NZBxW) F1 hybrid mice, a model of genetically determined immune complex disease that mimics systemic lupus in humans. MMF has a selective antiproliferative effect on T- and B-lymphocytes, inhibits antibody formation and blocks the glycosylation of lymphocyte glycoproteins involved in the adhesion of leukocytes to endothelial cells. Two groups of NZBxW mice were used: group 1 (N = 20) given daily MMF (60 mg/kg p.o.) and group 2 (N = 15) given daily vehicle alone. Treatment started at three months of age and lasted until the death of the animals. Results showed that percentage of proteinuric mice was significantly reduced by MMF treatment and serum BUN levels were also lower than vehicle. MMF had a suppressive effect on autoantibody production and protected animals from leukopenia and anemia. Life survival of MMF treated lupus mice was significantly improved in respect to untreated animals. Thus, MMF delayed renal function deterioration and prolonged life survival in murine lupus nephritis. MMF has been already recognized as reasonably well tolerated in renal transplant patients and despite its gastrointestinal toxicity its overall safety profile appears superior to azathioprine. Human studies are needed to establish whether MMF may function as a steroid-sparing drug in lupus nephritis.
像环磷酰胺这样的传统免疫抑制剂在治疗人类狼疮性肾炎方面效果显著。然而，它们会增加患恶性肿瘤和病毒感染的风险。在此，我们研究了新型免疫抑制剂霉酚酸酯（MMF）对新西兰黑鼠与新西兰白鼠（NZBxW）F1杂交小鼠的影响，该小鼠模型是一种由基因决定的免疫复合物疾病，可模拟人类的系统性红斑狼疮。MMF对T淋巴细胞和B淋巴细胞具有选择性抗增殖作用，可抑制抗体形成，并阻断参与白细胞与内皮细胞黏附的淋巴细胞糖蛋白的糖基化。我们使用了两组NZBxW小鼠：第1组（N = 20）每日给予MMF（口服60 mg/kg），第2组（N = 15）每日仅给予赋形剂。治疗从三个月龄开始，持续至动物死亡。结果显示，MMF治疗显著降低了蛋白尿小鼠的比例，血清尿素氮水平也低于赋形剂组。MMF对自身抗体产生具有抑制作用，并保护动物免受白细胞减少和贫血的影响。与未治疗的动物相比，接受MMF治疗的狼疮小鼠的生存时间显著延长。因此，MMF延缓了小鼠狼疮性肾炎的肾功能恶化并延长了生存时间。MMF在肾移植患者中已被认为耐受性较好，尽管存在胃肠道毒性，但其总体安全性似乎优于硫唑嘌呤。需要进行人体研究以确定MMF是否可作为狼疮性肾炎中的一种类固醇替代药物发挥作用。
