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

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.

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.

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.

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.

ClinicalTrials.gov: NCT02424396; EU Clinical trials Register: 2014-000088-42.