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

IF 8.8 2区 医学 Q1 IMMUNOLOGY
Marion Leboyer , Marianne Foiselle , Nicolas Tchitchek , Ryad Tamouza , Roberta Lorenzon , Jean-Romain Richard , Raphaele Arrouasse , Philippe Le Corvoisier , Katia Le Dudal , Eric Vicaut , Pierre Ellul , Michelle Rosenzwajg , David Klatzmann
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引用次数: 0

Abstract

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-2LD in 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-2LD assessed 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, number NCT04133233. 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-2LD expanding 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-2LD treated 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-2LD as an adjunct treatment of major mood disorders.

针对双相抑郁症患者的低剂量白细胞介素-2:第二阶段随机双盲安慰剂对照试验。
在双相情感障碍(BD)中,尤其是在抑郁期间,已观察到包括调节性T细胞(Treg)不足和血液中炎症标志物增加在内的免疫异常。由于Tregs在控制炎症方面起着关键作用,因此通过低剂量IL-2(IL-2LD)刺激Treg可能会对双相抑郁症产生治疗效果。我们在双相抑郁症患者中开展了一项随机、双盲、安慰剂对照(2 项活性:1 项安慰剂)的附加 IL-2LD 概念验证试验。患者接受安慰剂或IL-2LD(1MIU)治疗,每天一次,共5天,然后从第2周开始每周一次,共4周。首要目标是证明IL-2LD的生物Treg反应,评估指标是CD4 +细胞的Treg百分比从基线到第5天的增加倍数。次要目标包括整个研究期间的安全性评估和情绪改善。该试验已在 ClinicalTrials.gov 注册,编号为 NCT04133233。14名双相抑郁症患者参与了该试验,其中4人接受安慰剂治疗,10人接受IL-2LD治疗。各组的基线临床和生物学特征均衡。结果符合主要评估标准,IL-2LD的治疗效果为1.17 [95 % CI 1.01-1.34] vs 1.01 [95 % CI 0.90-1.12] (p = 0.0421),并激活了Tregs。IL-2LD治疗患者的抑郁症状和整体功能自第15天起显著改善,符合二级评估标准。治疗耐受性良好,未出现与治疗相关的严重不良事件。这项概念验证试验表明,刺激双相抑郁症患者体内的Tregs是安全的,并能改善临床症状。这支持了炎症在双相抑郁症中的病理生理作用,值得继续评估IL-2LD作为重性情绪障碍辅助治疗的效果。
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来源期刊
CiteScore
29.60
自引率
2.00%
发文量
290
审稿时长
28 days
期刊介绍: Established in 1987, Brain, Behavior, and Immunity proudly serves as the official journal of the Psychoneuroimmunology Research Society (PNIRS). This pioneering journal is dedicated to publishing peer-reviewed basic, experimental, and clinical studies that explore the intricate interactions among behavioral, neural, endocrine, and immune systems in both humans and animals. As an international and interdisciplinary platform, Brain, Behavior, and Immunity focuses on original research spanning neuroscience, immunology, integrative physiology, behavioral biology, psychiatry, psychology, and clinical medicine. The journal is inclusive of research conducted at various levels, including molecular, cellular, social, and whole organism perspectives. With a commitment to efficiency, the journal facilitates online submission and review, ensuring timely publication of experimental results. Manuscripts typically undergo peer review and are returned to authors within 30 days of submission. It's worth noting that Brain, Behavior, and Immunity, published eight times a year, does not impose submission fees or page charges, fostering an open and accessible platform for scientific discourse.
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