Sorbonne University, Paris Brain Institute - ICM, Assistance Publique Hôpitaux de Paris, Inserm, CNRS, Hôpital de la Pitié Salpêtrière, Department of Neurology, CIC neurosciences, Paris, France.
Immunology-Immunopathology-Immunotherapy (i3)-UMRS_959, Sorbonne Université- INSERM, Paris, France.
J Neurol. 2023 Sep;270(9):4403-4414. doi: 10.1007/s00415-023-11690-6. Epub 2023 May 28.
Multiple sclerosis (MS) is associated with regulatory T cells (Tregs) insufficiency while low-dose interleukin-2 (IL2) activates Tregs and reduces disease activity in autoimmune diseases.
We aimed at addressing whether IL2 improved Tregs from MS patients. MS-IL2 was a single-center double-blind phase-2 study. Thirty patients (mean [SD] age 36.8 years [8.3], 16 female) with relapsing-remitting MS with new MRI lesions within 6 months before inclusion were randomly assigned in a 1:1 ratio to placebo or IL-2 at 1 million IU, daily for 5 days and then fortnightly for 6 months. The primary endpoint was change in Tregs at day-5.
Unlike previous trials of IL2 in more than 20 different autoimmune diseases, Tregs were not expanded at day-5 in IL2 group, but only at day-15 (median [IQR] fold change from baseline: 1.26 [1.21-1.33] in IL2 group; 1.01 [0.95-1.05] in placebo group, p < 0.001). At day-5, however, Tregs had acquired an activated phenotype (fold change of CD25 expression in Tregs: 2.17 [1.70-3.55] in IL2 versus 0.97 [0.86-1.28] in placebo group, p < 0.0001). Regulator/effector T cells ratio remained elevated throughout treatment period in the IL2 group (p < 0.001). Number of new active brain lesions and of relapses tended to be reduced in IL2 treated patients, but the difference did not reach significance in this trial not powered to detect clinical efficacy.
The effect of IL2 on Tregs in MS patients was modest and delayed, compared to other auto-immune diseases. This, together with findings that Tregs improve remyelination in MS models and recent reports of IL2 efficacy in amyotrophic lateral sclerosis, warrants larger studies of IL2 in MS, notably with increased dosages and/or modified modalities of administration.
ClinicalTrials.gov: NCT02424396; EU Clinical trials Register: 2014-000088-42.
多发性硬化症（MS）与调节性 T 细胞（Tregs）不足有关，而低剂量白细胞介素 2（IL2）可激活 Tregs 并降低自身免疫性疾病的疾病活动度。
我们旨在探讨白细胞介素 2（IL2）是否能改善 MS 患者的 Tregs。MS-IL2 是一项单中心、双盲、二期研究。30 例（平均[标准差]年龄 36.8[8.3]岁，16 名女性）复发缓解型 MS 患者，在纳入前 6 个月内有新的 MRI 病变，随机分为 1:1 比例接受安慰剂或 IL-2（100 万 IU），每天 5 天，然后每两周 6 个月。主要终点是第 5 天 Tregs 的变化。
与 IL2 在 20 多种不同自身免疫性疾病中的以往试验不同，IL2 组在第 5 天 Tregs 没有扩增，而是在第 15 天扩增（与基线相比的中位数[IQR]倍数变化：IL2 组 1.26[1.21-1.33]；安慰剂组 1.01[0.95-1.05]，p<0.001）。然而，在第 5 天，Tregs 获得了激活表型（Tregs 中 CD25 表达的倍数变化：IL2 组 2.17[1.70-3.55]；安慰剂组 0.97[0.86-1.28]，p<0.0001）。在 IL2 组，调节性/效应性 T 细胞比值在整个治疗期间均升高（p<0.001）。接受 IL2 治疗的患者新发活动脑病变和复发的数量趋于减少，但在这项未达到检测临床疗效的功效的试验中，差异无统计学意义。
与其他自身免疫性疾病相比，IL2 对 MS 患者 Tregs 的影响较小且延迟。这一点，加上 Tregs 可改善 MS 模型中的髓鞘再生以及最近关于 IL2 在肌萎缩侧索硬化症中的疗效的报告，表明需要对 IL2 在 MS 中的作用进行更大规模的研究，特别是增加剂量和/或改变给药方式。
ClinicalTrials.gov：NCT02424396；欧盟临床试验注册：2014-000088-42。
