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 singl...

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Published inJournal of neurology Vol. 270; no. 9; pp. 4403 - 4414
Main Authors Louapre, C., Rosenzwajg, M., Golse, M., Roux, A., Pitoiset, F., Adda, L., Tchitchek, N., Papeix, C., Maillart, E., Ungureanu, A., Charbonnier-Beaupel, F., Galanaud, D., Corvol, J. C., Vicaut, E., Lubetzki, C., Klatzmann, D.
Format Journal Article
LanguageEnglish
Published Berlin/Heidelberg Springer Berlin Heidelberg 01.09.2023
Springer Nature B.V
Springer Verlag
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Abstract 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.
AbstractList 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.
BACKGROUNDMultiple sclerosis (MS) is associated with regulatory T cells (Tregs) insufficiency while low-dose interleukin-2 (IL2LD) activates Tregs and reduces disease activity in autoimmune diseases.METHODSWe aimed at addressing whether IL2LD 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.RESULTSUnlike previous trials of IL2LD in more than 20 different autoimmune diseases, Tregs were not expanded at day-5 in IL2LD group, but only at day-15 (median [IQR] fold change from baseline: 1.26 [1.21-1.33] in IL2LD 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 IL2LD 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 IL2LD group (p < 0.001). Number of new active brain lesions and of relapses tended to be reduced in IL2LD treated patients, but the difference did not reach significance in this trial not powered to detect clinical efficacy.CONCLUSIONThe effect of IL2LD 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 IL2LD efficacy in amyotrophic lateral sclerosis, warrants larger studies of IL2LD in MS, notably with increased dosages and/or modified modalities of administration.TRIAL REGISTRATION INFORMATIONClinicalTrials.gov: NCT02424396; EU Clinical trials Register: 2014-000088-42.
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.
Author Rosenzwajg, M.
Vicaut, E.
Papeix, C.
Maillart, E.
Corvol, J. C.
Tchitchek, N.
Roux, A.
Klatzmann, D.
Louapre, C.
Charbonnier-Beaupel, F.
Golse, M.
Pitoiset, F.
Lubetzki, C.
Adda, L.
Ungureanu, A.
Galanaud, D.
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ISSN 0340-5354
IngestDate Fri Dec 13 06:42:55 EST 2024
Wed Dec 04 09:47:19 EST 2024
Mon Dec 09 21:50:56 EST 2024
Thu Nov 21 23:55:17 EST 2024
Sat Nov 02 12:29:14 EDT 2024
Sat Dec 16 12:04:32 EST 2023
IsPeerReviewed true
IsScholarly true
Issue 9
Keywords Tolerance
Neuroinflammation
Immunosuppression
Neurodegeneration
Immunoregulation
Immunotherapy
NCT02424396
EU Clinical trials Register: 2014-000088-42 Neuroinflammation
EU Clinical trials Register: 2014-000088-42 Neuroinflammation Neurodegeneration Immunoregulation Immunosuppression Tolerance Immunotherapy
Language English
License 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.
Distributed under a Creative Commons Attribution 4.0 International License: http://creativecommons.org/licenses/by/4.0
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Snippet Background Multiple sclerosis (MS) is associated with regulatory T cells (Tregs) insufficiency while low-dose interleukin-2 (IL2 LD ) activates Tregs and...
Multiple sclerosis (MS) is associated with regulatory T cells (Tregs) insufficiency while low-dose interleukin-2 (IL2 ) activates Tregs and reduces disease...
BackgroundMultiple sclerosis (MS) is associated with regulatory T cells (Tregs) insufficiency while low-dose interleukin-2 (IL2LD) activates Tregs and reduces...
BACKGROUNDMultiple sclerosis (MS) is associated with regulatory T cells (Tregs) insufficiency while low-dose interleukin-2 (IL2LD) activates Tregs and reduces...
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SubjectTerms Adult
Amyotrophic lateral sclerosis
Autoimmune diseases
CD25 antigen
Clinical trials
Cytokines
Double-Blind Method
Double-blind studies
Effector cells
Female
Humans
Immunological diseases
Immunology
Immunoregulation
Interleukin 2
Interleukin-2 - therapeutic use
Life Sciences
Lymphocytes T
Male
Medicine
Medicine & Public Health
Multiple Sclerosis
Multiple Sclerosis, Relapsing-Remitting - diagnostic imaging
Multiple Sclerosis, Relapsing-Remitting - drug therapy
Myelination
NCT
NCT02424396
Neurology
Neuroradiology
Neurosciences
Original Communication
Patients
Phenotypes
Placebos
Treatment Outcome
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Title A randomized double-blind placebo-controlled trial of low-dose interleukin-2 in relapsing–remitting multiple sclerosis
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