PDF(Pubmed)
Abstract：
Multiple sclerosis (MS) onset at an advanced age is associated with a higher risk of developing progressive forms and a greater accumulation of disability for which there are currently no effective disease-modifying treatments. Immunosenescence is associated with the production of the senescence-associated secretory phenotype (SASP), with IL-6 being one of the most prominent cytokines. IL-6 is a determinant for the development of autoimmunity and neuroinflammation and is involved in the pathogenesis of MS. Herein, we aimed to preclinically test the therapeutic inhibition of IL-6 signaling in experimental autoimmune encephalomyelitis (EAE) as a potential age-specific treatment for elderly MS patients. Young and aged mice were immunized with myelin oligodendrocyte protein (MOG)35-55 and examined daily for neurological signs. Mice were randomized and treated with anti-IL-6 antibody. Inflammatory infiltration was evaluated in the spinal cord and the peripheral immune response was studied. The blockade of IL-6 signaling did not improve the clinical course of EAE in an aging context. However, IL-6 inhibition was associated with an increase in the peripheral immunosuppressive response as follows: a higher frequency of CD4 T cells producing IL-10, and increased frequency of inhibitory immune check points PD-1 and Tim-3 on CD4+ T cells and Lag-3 and Tim-3 on CD8+ T cells. Our results open the window to further studies aimed to adjust the anti-IL-6 treatment conditions to tailor an effective age-specific therapy for elderly MS patients.
摘要：
多发性硬化症（MS）在高龄时发病与发展为进行性形式的高风险和更大的残疾积累有关，目前尚无有效的疾病改善治疗方法。免疫衰老与衰老相关分泌表型（SASP）的产生有关，IL-6是最突出的细胞因子之一。IL-6是自身免疫和神经炎症发展的决定因素，并参与MS的发病机理。在这里，我们旨在临床前测试实验性自身免疫性脑脊髓炎(EAE)中IL-6信号传导的治疗抑制作用,作为老年MS患者的潜在年龄特异性治疗方法.年轻和老年小鼠用髓磷脂少突胶质细胞蛋白(MOG)35-55免疫,并每天检查神经体征。将小鼠随机化并用抗IL-6抗体处理。评估脊髓中的炎症浸润，并研究外周免疫反应。IL-6信号传导的阻断不能改善衰老背景下EAE的临床过程。然而,IL-6抑制与外周免疫抑制反应的增加相关如下:产生IL-10的CD4T细胞的频率更高,以及CD4+T细胞上的抑制性免疫检查点PD-1和Tim-3以及CD8+T细胞上的Lag-3和Tim-3的频率增加。我们的结果为进一步的研究打开了窗口，旨在调整抗IL-6治疗条件，为老年MS患者量身定制有效的年龄特异性疗法。
