Biopathologie de la Myéline, Neuroprotection et Stratégies Thérapeutiques, INSERM U1119/Université de Strasbourg, Faculté de Médecine, 11 rue Humann, 67085, Strasbourg, France.
Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France.
J Neuroinflammation. 2019 Mar 2;16(1):54. doi: 10.1186/s12974-019-1441-4.
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an autoimmune-mediated inflammatory disease of the peripheral nervous system characterized by a response directed against certain myelin proteins and for which therapies are limited. Previous studies have suggested a beneficial role of FTY720, a sphingosine 1-phosphate (S1P) receptor agonist, known to deplete lymphocytes from the peripheral blood by sequestering them into lymph nodes, in the treatment of experimental autoimmune neuritis (EAN). Therefore, we investigated whether FTY720 is also beneficial in chronic experimental autoimmune neuritis (c-EAN), a recently developed rat model mimicking human CIDP.
c-EAN was induced in Lewis rats by immunization with S-palm P0(180-199) peptide. Rats were treated with FTY720 (1 mg/kg) or vehicle intraperitoneally once daily from the onset of clinical signs for 18 days; clinical signs were assessed daily until 60 days post-immunization (dpi). Electrophysiological and histological features were examined at different time points. We also evaluated the serum levels of different pro- and anti-inflammatory cytokines by ELISA or flow cytometry at 18, 40, and 60 dpi.
Our data demonstrate that FTY720 decreased the severity and abolished the chronicity of the disease in c-EAN rats. Therapeutic FTY720 treatment reversed electrophysiological and histological anomalies, suggesting that myelinated fibers were subsequently preserved, it inhibited macrophage and IL-17 cell infiltration in PNS, and it significantly reduced circulating pro-inflammatory cytokines.
FTY720 treatment has beneficial effects on c-EAN, a new animal model mimicking human CIDP. We have shown that FTY720 is an effective immunomodulatory agent, improving the disease course of c-EAN, preserving the myelinated fibers, attenuating the axonal degeneration, and decreasing the number of infiltrated inflammatory cells in peripheral nerves. These data confirm the interest of testing FTY720 or molecules targeting S1P in human peripheral neuropathies.
慢性炎症性脱髓鞘性多发性神经病（CIDP）是一种自身免疫介导的周围神经系统炎症性疾病，其特征是针对某些髓鞘蛋白的反应，而针对该疾病的治疗方法有限。先前的研究表明，鞘氨醇 1-磷酸（S1P）受体激动剂 FTY720 通过将淋巴细胞隔离到淋巴结中来耗尽外周血中的淋巴细胞，在治疗实验性自身免疫性神经炎（EAN）中具有有益作用。因此，我们研究了 FTY720 对慢性实验性自身免疫性神经炎（c-EAN）是否也有益，c-EAN 是一种最近开发的模拟人类 CIDP 的大鼠模型。
通过用 S-棕榈 P0（180-199）肽免疫诱导 Lewis 大鼠发生 c-EAN。大鼠从出现临床症状开始，每天腹膜内给予 FTY720（1mg/kg）或载体 18 天；在免疫后 60 天（dpi）之前每天评估临床症状。在不同时间点检查电生理学和组织学特征。我们还通过 ELISA 或流式细胞术在 18、40 和 60 dpi 时评估血清中不同的促炎和抗炎细胞因子的水平。
我们的数据表明，FTY720 降低了 c-EAN 大鼠疾病的严重程度并消除了其慢性期。治疗性 FTY720 治疗逆转了电生理学和组织学异常，表明随后保留了有髓纤维，它抑制了 PNS 中的巨噬细胞和 IL-17 细胞浸润，并显著降低了循环促炎细胞因子。
FTY720 治疗对模拟人类 CIDP 的新型动物模型 c-EAN 具有有益作用。我们已经表明，FTY720 是一种有效的免疫调节药物，可改善 c-EAN 的疾病进程，保留有髓纤维，减轻轴突变性，并减少周围神经中浸润的炎性细胞数量。这些数据证实了在人类周围神经病变中测试 FTY720 或靶向 S1P 的分子的兴趣。
