Jung S, Zielasek J, Köllner G, Donhauser T, Toyka K, Hartung H P
Department of Neurology, Julius-Maximilians Universität Würzburg, Germany.
J Neuroimmunol. 1996 Aug;68(1-2):1-11. doi: 10.1016/0165-5728(96)00051-3.
Experimental autoimmune encephalomyelitis (EAE) in Lewis rats, an animal model mimicking some aspects of multiple sclerosis, was treated with the type IV-specific phosphodiesterase inhibitor Rolipram. Actively induced EAE evoked by immunization with myelin basic protein (MBP) in complete Freund's adjuvant was delayed but only slightly ameliorated in its maximal severity by preventive treatment with Rolipram (2 x 3 mg/kg per day) starting on the day of immunization. Therapeutic administration of Rolipram (2 x 5 mg/kg per day) was begun within hours after onset of first clinical signs of EAE but could not modify the further course of the disease. Both doses had significant side effects. Injection of 5 mg Rolipram/kg provoked transient slackening and unsteady gait while chronic application of 6 mg/kg/day strongly accelerated the weight gain in adolescent rats. EAE adoptively transferred by injection of encephalitogenic T line blasts was shortened and significantly suppressed in its severity by application of Rolipram (2 x 5 mg/kg per day) starting on the day of cell transfer. In corresponding lumbar spinal cord sections density of inflammatory infiltration by T cells and macrophages was reduced. Rolipram did not prevent generation of an antigen-specific immune response in vivo. In vitro the drug inconsistently inhibited MBP-induced activation of encephalitogenic T cells. TNF-alpha secretion by encephalitogenic T cells was limited only when T cell proliferation was also affected. In contrast, TNF-alpha production by LPS-activated macrophages was consistently and markedly suppressed by Rolipram. However, since the encephalitogenic T line cells produced at least 100 times more TNF-alpha than the same number of Rolipram-sensitive macrophages, the impact of Rolipram on the total amount of TNF-alpha synthesized in EAE may be limited. Together with our histological findings, the data suggest that relevant immunosuppressive mechanisms of Rolipram may be the inhibition of migration of leukocytes into the central nervous system and to some extent its inhibitory effect on T cell proliferation and macrophage activity. The downregulatory effects of Rolipram may be partially counteracted by its augmenting impact on the production of nitric oxide by macrophages.
实验性自身免疫性脑脊髓炎（EAE）是一种模仿多发性硬化症某些方面的动物模型，在Lewis大鼠中用IV型特异性磷酸二酯酶抑制剂咯利普兰进行治疗。在完全弗氏佐剂中用髓鞘碱性蛋白（MBP）免疫诱导的主动型EAE，通过从免疫当天开始预防性给予咯利普兰（每天2×3mg/kg），其发作延迟，但最大严重程度仅略有改善。在EAE首次出现临床症状后的数小时内开始给予咯利普兰治疗（每天2×5mg/kg），但无法改变疾病的进一步发展进程。两种剂量都有明显的副作用。注射5mg咯利普兰/kg会引起短暂的松弛和步态不稳，而长期应用6mg/kg/天则会显著加速青春期大鼠的体重增加。通过注射致脑炎T系母细胞过继转移的EAE，从细胞转移当天开始应用咯利普兰（每天2×5mg/kg）后，病程缩短且严重程度显著降低。在相应的腰段脊髓切片中，T细胞和巨噬细胞的炎性浸润密度降低。咯利普兰不能阻止体内抗原特异性免疫反应的产生。在体外，该药物对MBP诱导的致脑炎T细胞活化的抑制作用不稳定。只有当T细胞增殖也受到影响时，致脑炎T细胞分泌的肿瘤坏死因子-α（TNF-α）才会受到限制。相比之下，咯利普兰能持续且显著地抑制脂多糖激活的巨噬细胞产生TNF-α。然而，由于致脑炎T系细胞产生的TNF-α比相同数量对咯利普兰敏感的巨噬细胞至少多100倍，咯利普兰对EAE中合成的TNF-α总量的影响可能有限。结合我们的组织学研究结果，数据表明咯利普兰相关的免疫抑制机制可能是抑制白细胞向中枢神经系统的迁移，以及在一定程度上对T细胞增殖和巨噬细胞活性的抑制作用。咯利普兰的下调作用可能会因其对巨噬细胞产生一氧化氮的增强作用而部分抵消。
