FTY720 (fingolimod) modulates the severity of viral-induced encephalomyelitis and demyelination.
FTY720 (fingolimod) modulates the severity of viral-induced encephalomyelitis and demyelination.
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FTY720（芬戈莫德）可调节病毒引起的脑脊髓炎和脱髓鞘的严重程度。
DOI：
10.1186/s12974-014-0138-y
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发表时间：
2014-08-20
影响因子：
9.3
通讯作者：
Lane TE
中科院分区：
文献类型：
--
作者：
Blanc CA;Rosen H;Lane TE
FTY720（芬戈莫德）是美国食品和药物管理局批准的第一个口服药物，用于治疗复发缓解型人类脱髓鞘疾病多发性硬化症患者。有证据表明，FTY720 的治疗益处是通过阻止淋巴细胞从淋巴结流出，从而抑制致病淋巴细胞浸润到中枢神经系统 (CNS) 来实现的。我们假设 FTY720 治疗会影响淋巴细胞向中枢神经系统的迁移，并影响病毒引起的神经系统疾病小鼠模型的疾病严重程度。小鼠颅内感染了嗜神经型小鼠肝炎病毒 JHM 株。受感染的动物接受增加剂量（1、3 和 10 mg/kg）的 FTY720 治疗，并记录发病率和死亡率。使用流式细胞术测定 FTY720 治疗小鼠 CNS 中炎性病毒特异性 T 细胞的浸润（四聚体染色）。还确定了 FTY720 治疗对病毒特异性 T 细胞增殖、细胞因子产生和溶细胞活性的影响。分别通过流式细胞术和组织病理学检查 FTY720 治疗小鼠脊髓中神经炎症和脱髓鞘的严重程度。对感染 JHMV 的小鼠施用 FTY720 导致临床疾病严重程度和死亡率增加。这些结果与感染后第 7 天和第 14 天中枢神经系统内控制病毒复制的能力受损 (P<0.05) 相关，这与中枢神经系统中病毒特异性 CD4+ 和 CD8+ T 细胞的积累减少 (P<0.05) 相关。 FTY720治疗小鼠神经炎症的减少与引流颈部淋巴结内T淋巴细胞保留的增加相关（P<0.05）。 FTY720 治疗不影响病毒特异性 T 细胞增殖、IFN-γ、TNF-α 表达或细胞溶解活性。 FTY720 治疗的小鼠表现出与神经炎症抑制相关的脱髓鞘严重程度的降低。这些发现表明，在急性病毒诱发的脑脊髓炎期间，FTY720 通过影响中枢神经系统内病毒特异性 T 细胞的迁移和积累来抑制有效的抗病毒免疫反应。 FTY720治疗通过限制致病淋巴细胞进入中枢神经系统来降低神经炎症介导的脱髓鞘的严重程度，但在该模型中与病毒复发无关。
FTY720 (fingolimod) is the first oral drug approved by the Food and Drug Administration for treatment of patients with the relapsing-remitting form of the human demyelinating disease multiple sclerosis. Evidence suggests that the therapeutic benefit of FTY720 occurs by preventing the egress of lymphocytes from lymph nodes thereby inhibiting the infiltration of disease-causing lymphocytes into the central nervous system (CNS). We hypothesized that FTY720 treatment would affect lymphocyte migration to the CNS and influence disease severity in a mouse model of viral-induced neurologic disease. Mice were infected intracranially with the neurotropic JHM strain of mouse hepatitis virus. Infected animals were treated with increasing doses (1, 3 and 10 mg/kg) of FTY720 and morbidity and mortality recorded. Infiltration of inflammatory virus-specific T cells (tetramer staining) into the CNS of FTY720-treated mice was determined using flow cytometry. The effects of FTY720 treatment on virus-specific T cell proliferation, cytokine production and cytolytic activity were also determined. The severity of neuroinflammation and demyelination in FTY720-treated mice was examined by flow cytometry and histopathologically, respectively, in the spinal cords of the mice. Administration of FTY720 to JHMV-infected mice resulted in increased clinical disease severity and mortality. These results correlated with impaired ability to control viral replication (P < 0.05) within the CNS at days 7 and 14 post-infection, which was associated with diminished accumulation of virus-specific CD4+ and CD8+ T cells (P < 0.05) into the CNS. Reduced neuroinflammation in FTY720-treated mice correlated with increased retention of T lymphocytes within draining cervical lymph nodes (P < 0.05). Treatment with FTY720 did not affect virus-specific T cell proliferation, expression of IFN-γ, TNF-α or cytolytic activity. FTY720-treated mice exhibited a reduction in the severity of demyelination associated with dampened neuroinflammation. These findings indicate that FTY720 mutes effective anti-viral immune responses through impacting migration and accumulation of virus-specific T cells within the CNS during acute viral-induced encephalomyelitis. FTY720 treatment reduces the severity of neuroinflammatory-mediated demyelination by restricting the access of disease-causing lymphocytes into the CNS but is not associated with viral recrudescence in this model.
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影响因子：
11.2
作者：
JOHNSON, RT
通讯作者：
JOHNSON, RT
影响因子：
4.4
作者：
Glass, WG;Hickey, MJ;Lane, TE
通讯作者：
Lane, TE
影响因子：
11.2
作者：
Hauser, Stephen L.;Chan, Jonah R.;Oksenberg, Jorge R.
通讯作者：
Oksenberg, Jorge R.
影响因子：
3.7
作者：
Glass, WG;Lane, TE
通讯作者：
Lane, TE
影响因子：
5.1
作者：
Cusick MF;Libbey JE;Fujinami RS
通讯作者：
Fujinami RS