Fingolimod attenuates experimental autoimmune neuritis and contributes to Schwann cell-mediated axonal protection.
Fingolimod attenuates experimental autoimmune neuritis and contributes to Schwann cell-mediated axonal protection.
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DOI：
10.1186/s12974-017-0864-z
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发表时间：
2017-04-26
影响因子：
9.3
通讯作者：
Gold R
中科院分区：
文献类型：
--
作者：
Ambrosius B;Pitarokoili K;Schrewe L;Pedreiturria X;Motte J;Gold R
芬戈莫德是一种 1-磷酸鞘氨醇受体调节剂，具有广泛描述的涉及外周免疫细胞运输的免疫调节特性，是第一个被批准用于治疗复发缓解型多发性硬化症的口服药物。慢性周围自身免疫性神经病缺乏类似的免疫调节治疗方案。我们在 Lewis 大鼠实验性自身免疫性神经炎动物模型中测试了芬戈莫德。用P2肽对六至八周大的雌性大鼠进行免疫，并从当天开始用芬戈莫德进行治疗。对坐骨神经进行组织学分析，以分析 T 细胞和巨噬细胞计数、细胞间粘附分子 (ICAM) 和淀粉样前体蛋白 (APP) 表达以及凋亡雪旺细胞计数。使用 0.1 mg/kg 至 3 mg/kg 芬戈莫德溶解在菜籽油中每日一次进行预防性口服治疗，可完全改善临床神经炎症状。它减少了循环外周血 T 细胞以及坐骨神经中的浸润 T 细胞和巨噬细胞，同时保持了血神经屏障的不渗透性。最重要的是，芬戈莫德在致病过程中显示出有益的特性，如凋亡雪旺细胞较少和淀粉样前体蛋白含量较低（表明病程高峰期的轴突损伤）。综上所述，口服低剂量芬戈莫德在实验性自身免疫性神经炎大鼠模型中显示出令人印象深刻的免疫调节作用。我们目前的观察结果表明，芬戈莫德对于神经炎患者来说是一种有吸引力的治疗选择。
Fingolimod, a sphingosine-1-phosphate receptor modulator with well-described immunomodulatory properties involving peripheral immune cell trafficking, was the first oral agent approved for the treatment of relapsing remitting multiple sclerosis. Analogous immunomodulatory treatment options for chronic peripheral autoimmune neuropathies are lacking. We tested fingolimod in the animal model of experimental autoimmune neuritis in Lewis rat. Six to eight-week-old female rats were immunized with P2 peptide and from this day on treated with fingolimod. Histology of the sciatic nerve was done to analyze T cell and macrophage cell count, intercellular adhesion molecule (ICAM) and amyloid precursor protein (APP) expression, as well as apoptotic Schwann cell counts. Preventive oral treatment with 0.1 mg/kg up to 3 mg/kg fingolimod once daily dissolved in rapeseed oil completely ameliorated clinical neuritis signs. It reduced circulating peripheral blood T cells and infiltrating T cells and macrophages in the sciatic nerve, whereas at the same time, it preserved blood-nerve barrier impermeability. Most importantly, fingolimod showed beneficial properties on the pathogenic process as indicated by fewer apoptotic Schwann cells and a lower amount of amyloid precursor protein indicative of axonal damage at the peak of disease course. Taken together, orally administered low-dose fingolimod showed an impressive immunomodulatory effect in the rat model of experimental autoimmune neuritis. Our current observations introduce fingolimod as an attractive treatment option for neuritis patients.