Induction of regulatory T cells and efficacy of low-dose interleukin-2 in systemic sclerosis: interventional open-label phase 1–phase 2a study

IF 5.1 2区医学 Q1 RHEUMATOLOGY

RMD Open Pub Date : 2024-04-01 DOI:10.1136/rmdopen-2023-003500

François Barde, Roberta Lorenzon, Eric Vicaut, Sébastien Rivière, Patrice Cacoub, Carlotta Cacciatore, Michelle Rosenzwajg, Anne Daguenel-Nguyen, Olivier Fain, David Klatzmann, Arsène Mekinian

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引用次数: 0

Abstract

Background Systemic sclerosis (SSc) is a chronic autoimmune disease, with impaired immune response, increased fibrosis and endothelial dysfunction. Regulatory T cells (Tregs), which are essential to control inflammation, tissue repair and autoimmunity, have a decreased frequency and impaired function in SSc patients. Low-dose interleukin-2 (IL-2LD) can expand and activate Tregs and has, therefore, a therapeutic potential in SSc. Objective We aimed to assess the safety and biological efficacy of IL-2LD in patients with SSc. Methods As part of the TRANSREG open-label phase IIa basket trial in multiple autoimmune diseases, we studied nine patients with SSc without severe organ involvement. Patients received 1 million international units (MIU)/day of IL-2 for 5 days, followed by fortnightly injections for 6 months. Laboratory and clinical evaluations were performed between baseline and month 6. Results At day 8, the primary endpoint (Treg frequency) was reached with a 1.8±0.5-fold increase of Treg levels among CD4+ T lymphocytes (p=0.0015). There were no significant changes in effector T cells nor in B cells. IL-2LD was well tolerated, and no serious adverse events related to treatment occurred. There was a globally stable measurement in the modified Rodnan skin score and Valentini score at month 6. Disease activity and severity measures, the quality of life evaluated by EuroQL-5D-5L and pulmonary function test parameters remained stable during the study period. Conclusion IL-2LD at a dosage of 1 MIU/day safely and selectively activates and expands Tregs. Clinical signs remain stable during the study period. This opens the door to properly powered phase II efficacy trials investigating IL-2LD therapeutic efficacy in SSc. Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as online supplemental information.

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诱导调节性 T 细胞和低剂量白细胞介素-2 对系统性硬化症的疗效：介入性开放标签 1 期和 2a 期研究

背景系统性硬化症（SSc）是一种慢性自身免疫性疾病，伴有免疫反应受损、纤维化加重和内皮功能障碍。调节性 T 细胞（Tregs）对控制炎症、组织修复和自身免疫至关重要，但在 SSc 患者中，Tregs 的数量减少，功能受损。低剂量白细胞介素-2（IL-2LD）可扩增和激活调节性 Tregs，因此具有治疗 SSc 的潜力。目的我们旨在评估 IL-2LD 在 SSc 患者中的安全性和生物学疗效。方法作为针对多种自身免疫性疾病的 TRANSREG 开放标签 IIa 期篮子试验的一部分，我们研究了九名无严重器官受累的 SSc 患者。患者每天接受 100 万国际单位（MIU）的 IL-2 注射，连续注射 5 天，之后每两周注射一次，持续 6 个月。从基线到第 6 个月期间进行了实验室和临床评估。结果第8天，CD4+ T淋巴细胞中的Treg水平增加了1.8±0.5倍（p=0.0015），达到了主要终点（Treg频率）。效应 T 细胞和 B 细胞均无明显变化。IL-2LD 的耐受性良好，没有发生与治疗相关的严重不良事件。在第 6 个月时，改良罗德南皮肤评分和瓦伦蒂尼评分总体稳定。在研究期间，疾病的活动性和严重程度、通过 EuroQL-5D-5L 评估的生活质量以及肺功能测试参数均保持稳定。结论 IL-2LD 的剂量为 1 MIU/天，能安全、选择性地激活和扩增 Tregs。临床症状在研究期间保持稳定。这为研究IL-2LD在SSc中的疗效的II期疗效试验打开了大门。如有合理要求，可提供相关数据。与该研究相关的所有数据均包含在文章中或作为在线补充信息上传。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

RMD Open RHEUMATOLOGY-

CiteScore

7.30

自引率

6.50%

发文量

205

审稿时长

14 weeks

期刊介绍： RMD Open publishes high quality peer-reviewed original research covering the full spectrum of musculoskeletal disorders, rheumatism and connective tissue diseases, including osteoporosis, spine and rehabilitation. Clinical and epidemiological research, basic and translational medicine, interesting clinical cases, and smaller studies that add to the literature are all considered.