Serpero Laura D, Filaci Gilberto, Parodi Alessia, Battaglia Florinda, Kalli Francesca, Brogi Davide, Mancardi Giovanni Luigi, Uccelli Antonio, Fenoglio Daniela
Center of Excellence for Biomedical Research, University of Genova, Viale Benedetto XV, 6, 16132, Genoa, Italy.
J Neuroimmune Pharmacol. 2013 Dec;8(5):1106-13. doi: 10.1007/s11481-013-9465-5. Epub 2013 May 7.
Multiple sclerosis (MS) is a complex neurological disease where, in genetically predisposed individuals, the unbalanced interplay between pathogenic and regulatory T cells will result in the progression of the autoimmune assault to neural antigens. Fingolimod (FTY720), an oral sphingosine 1-phosphate modulator recently approved for the treatment of MS, inhibits the egress of T cells from lymph nodes acting specifically on naïve and memory T cells and sparing effector T cells. Here we characterized IL-17 and IFNγ producing effector CD4 and CD8 positive T cells as well as CD4 positive CD25(high)CD127(low) regulatory T cells in MS patients before and 1 month after treatment was started. We observed that fingolimod did not significantly affect the percentage of CCR6 and CD161 positive T cells in both CD4 and CD8 compartments. In contrast, it significantly reduced the levels of both CD4+ CCR6+ CD161+ and CD8+ CCR6+ CD161+ producing IFNγ alone or in combination with IL-17. The percentage of IL-17 secreting cells in both subsets was affected by the treatment to a lesser extent. Finally, we observed that CD4+ CD25(high)CD127(low) regulatory T cells were decreased in MS patients compared to healthy controls and fingolimod significantly increased their frequencies. All together these findings demonstrate that fingolimod functionally modulates the ability of potentially pathogenic effector cells to produce relevant pro-inflammatory cytokines and increases the number of circulating regulatory T cells possibly contributing in restoring a balance between these populations.
多发性硬化症（MS）是一种复杂的神经系统疾病，在具有遗传易感性的个体中，致病性T细胞和调节性T细胞之间的不平衡相互作用会导致针对神经抗原的自身免疫攻击的进展。芬戈莫德（FTY720）是一种最近被批准用于治疗MS的口服鞘氨醇-1-磷酸调节剂，它抑制T细胞从淋巴结逸出，特异性作用于初始T细胞和记忆T细胞，而不影响效应T细胞。在这里，我们对MS患者治疗开始前和开始治疗1个月后的产生白细胞介素-17（IL-17）和干扰素γ（IFNγ）的效应性CD4和CD8阳性T细胞以及CD4阳性CD25（高）CD127（低）调节性T细胞进行了表征。我们观察到，芬戈莫德对CD4和CD8亚群中CCR6和CD161阳性T细胞的百分比没有显著影响。相比之下，它显著降低了单独产生IFNγ或与IL-17联合产生IFNγ的CD4+CCR6+CD161+和CD8+CCR6+CD161+的水平。两个亚群中分泌IL-17的细胞百分比受治疗的影响较小。最后，我们观察到，与健康对照相比，MS患者的CD4+CD25（高）CD127（低）调节性T细胞减少，而芬戈莫德显著增加了它们的频率。所有这些发现表明，芬戈莫德在功能上调节潜在致病性效应细胞产生相关促炎细胞因子的能力，并增加循环调节性T细胞的数量，这可能有助于恢复这些细胞群体之间的平衡。
