The universal effects of low-dose interleukin-2 across 13 autoimmune diseases in a basket clinical trial

Lorenzon, Roberta; Ribet, Claire; Pitoiset, Fabien; Aractingi, Selim; Banneville, Beatrice; Beaugerie, Laurent; Berenbaum, Francis; Cacoub, Patrice; Champey, Julien; Chazouilleres, Olivier; Corpechot, Christophe; Fautrel, Bruno; Mekinian, Arsène; Regnier, Elodie; Saadoun, David; Salem, Joe-Elie; Sellam, Jérémie; Seksik, Philippe; Vicaut, Eric; Rosenzwajg, Michelle; Klatzmann, David

doi:10.1016/j.jaut.2024.103172

Cited by 14 publications

(2 citation statements)

References 24 publications

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“…In contrast to study in other diseases (Humrich et al, 2022;Rosenzwajg et al, 2020), there was no correlation between Treg numbers, percentages, or activation markers and the clinical response, which we attribute to the known variability in Treg measurements (Hartemann et al, 2013) and the small size of the study. Despite, we are confident that the antidepressant add-on effect of IL-2LD is related to the Treg activation, given the concomitant increase of all the makers of Treg activation and efficiency (Louapre et al, 2023;Rosenzwajg et al, 2015bRosenzwajg et al, , 2019Rosenzwajg et al, , 2020Humrich et al, 2022;Lorenzon et al, 2024).…”

Section: Discussionmentioning

confidence: 82%

“…Indeed, IL-2 is the main cytokine driving Treg development, activation, and proliferation. At low dose, IL-2 is a specific and safe Treg activator, as demonstrated in numerous clinical trials (Saadoun et al, 2011;Koreth et al, 2011;Hartemann et al, 2013;Rosenzwajg et al, 2015aRosenzwajg et al, , 2015aHe et al, 2016;Rosenzwajg et al, 2019Rosenzwajg et al, , 2020Camu et al, 2020;Humrich et al, 2022;Nigel Leigh et al, 2023;Lorenzon et al, 2024;Barde et al, 2024). These effects are due to the exquisite sensitivity of Tregs to IL-2 that are explained by (i) the constitutive expression of the IL-2 high affinity receptor; (ii) the 20-40 fold higher sensitivity to IL-2 for STAT5 phosphorylation between Tregs and other T cells; (iii) the >100 fold higher sensitivity of Tregs for the gene activation program downstream phosphorylated STAT5 (Rosenzwajg et al, 2015a;Yu et al, 2015) , .…”

Section: Introductionmentioning

confidence: 99%

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Low-dose interleukin-2 in patients with bipolar depression: a phase 2 randomised double-blind placebo-controlled trial

Leboyer,

Foiselle,

Tchitchek

et al. 2024

Preprint

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Immune abnormalities including an insufficiency of regulatory T cells (Treg) and increased blood-based inflammatory markers have been observed in bipolar disorders (BD), particularly during depression. As Tregs are pivotal to control inflammation, Treg stimulation by low-dose IL-2 (IL-2LD) could have a therapeutic impact on bipolar depression. We performed a randomized, double-blind, placebo-controlled (2 active: 1 placebo) proof-of-concept trial of add-on IL-2LDin patients with bipolar depression. Patients received a placebo or IL-2LD(1MIU) once a day for 5 days, and then once a week for 4 weeks starting on week 2. The primary objective was to demonstrate a biological Treg response to IL-2LDassessed by fold increase in Treg percentage of CD4+ cells from baseline to day 5. Secondary objectives included safety assessment and mood improvement throughout the study period. This trial is registered with ClinicalTrials.gov, numberNCT04133233. Fourteen patients with bipolar depression were included, with 4 receiving placebo and 10 IL-2LD. Baseline clinical and biological characteristics were balanced between groups. The primary evaluation criterion was met, with IL-2LDexpanding 1.17 [95% CI 1.01-1.34] vs 1.01 [95% CI 0.90 - 1.12] (p=0.0421) and activating Tregs. Secondary evaluation criteria were also met with significant improvements of depressive symptoms and global functioning from day-15 onwards in the IL-2LDtreated patients. The treatment was well-tolerated, with no serious adverse events related to treatment. This proof-of-concept trial shows that stimulating Tregs in patients with bipolar depression is safe and associated with clinical improvements. This supports a pathophysiological role of inflammation in BD and warrants pursuing the evaluation of IL-2LDas an adjunct treatment of major mood disorders.

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Section: Discussionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Low-dose interleukin-2 in patients with bipolar depression: a phase 2 randomised double-blind placebo-controlled trial

Leboyer,

Foiselle,

Tchitchek

et al. 2024

Preprint

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In vitro modulation of T cells in myasthenia gravis by low‐dose IL‐2

Çebi,

Çakar,

Durmuş

et al. 2024

Eur J Immunol

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Follicular helper (Tfh), peripheral helper (Tph), and regulatory (Treg) T cells are involved in myasthenia gravis (MG) pathogenesis, an autoimmune disorder arising from autoantibodies targeting neuromuscular junction proteins. This study explores the impact of low‐dose IL‐2 on Tfh, Tph, and Treg cells in vitro in MG. Acetylcholine‐receptor antibody‐positive MG (AChR‐MG), muscle‐specific kinase antibody‐positive MG (MuSK‐MG) patients, and healthy controls (HC) were studied. Blood cells were cultured with/without IL‐2 and compared by the ratios of IL‐2 stimulated/unstimulated cultures. In both AChR‐MG and MuSK‐MG patients, CD25+FoxP3+Tregs were lower, while CXCR5+PD‐1+ or ICOS+Tfh and CXCR5−PD‐1+ or ICOS+Tph cells were higher compared with HC. Among the MG group, the FoxP3+ Treg cells in AChR‐MG patients were even lower compared with MuSK‐MG patients. In vitro IL‐2 stimulation increased Tregs in all groups while decreasing PD‐1+/ICOS+Tfh and PD‐1+/ICOS+Tph populations. The fold‐increase ratio of Tregs and the fold‐decrease ratio of PD‐1+ or ICOS+Tfh and ICOS+Tph cells in AChR‐MG and MuSK‐MG patients were greater than in HCs. Low‐dose IL‐2 treatment may balance Tfh, Tph, and Treg cells in MG patients, offering a potential opportunity for disease modulation.

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