Immunosuppression with FTY720 is insufficient to prevent secondary progressive neurodegeneration in experimental autoimmune encephalomyelitis
Immunosuppression with FTY720 is insufficient to prevent secondary progressive neurodegeneration in experimental autoimmune encephalomyelitis
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DOI：
10.1177/1352458511400476
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发表时间：
2011-08-01
影响因子：
5.8
通讯作者：
Baker, David
中科院分区：
文献类型：
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作者：
Al-Izki, Sarah;Pryce, Gareth;Baker, David
工作背景：从实验性自身免疫性脑脊髓炎（EAE）（多发性硬化症（MS）的动物模型）到MS的治疗中使用免疫抑制剂的转化一直很差。这可能是由于大多数EAE研究检查了预防性的预治疗方案，这些方案被证明在长期建立的，通常是进行性的，MS.FTY720（芬戈莫德/Gilenya）是一种鞘氨醇-1-磷酸受体调节剂。这是一种新的口服药物，与目前批准的注射药物（如β干扰素）相比，可显著减少MS患者的复发次数。FTY720具有抗淋巴细胞的活性，但也可能影响少突胶质细胞，因此可能有潜力影响进行性MS，通过促进remyelination.Methods：FTY720的效果进行了评估，在复发进行性EAE小鼠。结果：早期干预复发EAE期间可以完全抑制随后的复发，抑制神经变性的积累，促进运动恢复。然而，当检查在继发性进行性EAE，从复发性疾病的赤字积累后，长期治疗FTY720未能减缓恶化时，启动后期（4个月）到疾病course.Conclusions：这项研究表明，早期干预免疫抑制剂可能会抑制神经退行性微环境的产生，这是不再响应于有效的免疫抑制。然而，如果治疗开始得太晚，进行性神经系统疾病会持续下去。这表明免疫抑制不足以控制动物的继发性进展，如迄今为止在MS中发现的情况，并且可能需要FTY 720的早期干预以获得最佳治疗益处。
Background: There has been poor translation for the use of immunosuppressive agents from experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), into the treatment of MS. This may be due to the fact that most EAE studies examine prophylactic, pre-treatment regimes that prove to be therapeutically-ineffective in long-established, often progressive, MS. FTY720 (fingolimod/Gilenya) is a sphingosine-1-phosphate receptor modulator. This is a new oral agent that markedly reduces the number of relapses in people with MS, compared with currently licensed injectable agents such as the beta interferons. FTY720 has activity against lymphocytes but may also influence oligodendroglia and could therefore have the potential to influence progressive MS, by promoting remyelination.Methods: The effect of FTY720 was assessed in relapsing-progressive EAE in mice.Results: Early intervention during relapsing EAE could completely inhibit subsequent relapses, inhibited the accumulation of neurodegeneration, and facilitated motor recovery. However, when examined in secondary progressive EAE, that develops after the accumulation of deficit from relapsing disease, long-term treatment with FTY720 failed to slow deterioration when initiated late (4 months) into the disease course.Conclusions: This study indicates that early intervention with immunosuppressive agents may inhibit the generation of the neurodegenerative microenvironment, which is no longer responsive to potent immunosuppression. However, if treatment is initiated too late, progressive, neurological-disease continues unabated. This suggests that immunosuppression is insufficient to control secondary progression in animals, as has been found so far to be the case in MS, and may warrant early intervention with FTY720 for optimal treatment benefit.