A randomized double-blind placebo-controlled trial of low-dose interleukin-2 in relapsing–remitting multiple sclerosis

Background Multiple sclerosis (MS) is associated with regulatory T cells (Tregs) insufficiency while low-dose interleukin-2 (IL2 LD ) activates Tregs and reduces disease activity in autoimmune diseases. Methods We aimed at addressing whether IL2 LD 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. Results Unlike previous trials of IL2 LD in more than 20 different autoimmune diseases, Tregs were not expanded at day-5 in IL2 LD group, but only at day-15 (median [IQR] fold change from baseline: 1.26 [1.21–1.33] in IL2 LD 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 LD 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 LD group (p < 0.001). Number of new active brain lesions and of relapses tended to be reduced in IL2 LD treated patients, but the difference did not reach significance in this trial not powered to detect clinical efficacy. Conclusion The effect of IL2 LD 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 LD efficacy in amyotrophic lateral sclerosis, warrants larger studies of IL2 LD in MS, notably with increased dosages and/or modified modalities of administration. Trial registration information ClinicalTrials.gov: NCT02424396; EU Clinical trials Register: 2014-000088-42.