Low-dose interleukin 2 in patients with type 1 diabetes: a phase 1/2 randomised, double-blind, placebo-controlled trial
Low-dose interleukin 2 in patients with type 1 diabetes: a phase 1/2 randomised, double-blind, placebo-controlled trial
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DOI：
10.1016/s2213-8587(13)70113-x
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发表时间：
2013-12-01
影响因子：
44.5
通讯作者：
Klatzmann, David
中科院分区：
文献类型：
--
作者：
Hartemann, Agnes;Bensimon, Gilbert;Klatzmann, David
调节性/效应性T（T-reg/T-eff）细胞的不平衡是自身免疫性疾病（包括1型糖尿病）发展的核心。我们以前的研究表明，低剂量的白细胞介素2（IL 2）诱导的T-reg细胞扩增和激活和临床改善丙型肝炎病毒引起的血管炎患者。我们的目的是确定哪种低剂量的IL 2是安全的，并在1型糖尿病患者中诱导T-reg细胞，考虑到：（1）1型糖尿病可能与IL 2/IL 2 R活化途径的改变有关;（2）IL 2激活致病性T-eff细胞可加重疾病;和（3）低剂量IL 2在1型糖尿病中的安全性尚不清楚。方法这是一项单中心1/2期研究。24例成人患者入选了18-55岁的确诊胰岛素依赖型1型糖尿病和至少一种糖尿病相关自身抗体的患者，（1：1：1）1比值，通过计算机生成的随机化列表，区组大小为4）与安慰剂或IL 2（0.33 MIU/天，1 MIU/天，或3 MIU/d，疗程5天，随访60天。所有研究者和参与者均对分配设盲。主要结果是从第1天到第60天，通过流式细胞术测量的T-reg细胞的变化，并表示为CD 4 + T细胞的百分比。该试验在ClinicalTrials.gov注册，编号NCT 01353833。结果在2011年6月1日至2012年2月3日期间，将6名患者分配至每组。IL 2在所有剂量下均耐受良好，无严重不良事件。然而，在治疗阶段（第1-6天），非严重不良事件存在剂量反应相关性;安慰剂组1例患者、0.33 MIU组3例患者、1 MIU组5例患者和3 MIU组6例患者发生非严重不良事件。治疗期最常见的不良事件为注射部位反应（安慰剂组无患者vs 3例患者，0.33 MIU和1 MIU vs 2例患者，3 MIU）和流感样综合征（安慰剂组无患者vs 1例患者，0.33 MIU和1 MIU vs 4例患者，3 MIU）。治疗期后，不良事件在两组之间没有差异。IL-2没有诱导葡萄糖代谢变量的有害变化。IL 2诱导Treg细胞比例的剂量依赖性增加，与安慰剂相比在所有剂量下均显著（安慰剂平均增加0.5% [SD 0.4]; 0.33 MIU 2.8% [1.2]，p= 0.0039; 1 MIU 39%[1.8]，p= 0.0039;解释我们已经定义了用于1型糖尿病治疗和预防的耐受性良好且免疫学有效的IL 2剂量范围，这可能与其中Treg细胞增加将是期望的其它病症相关。
Background An improper balance of regulatory/effector T (T-reg/T-eff) cells is central to the development of autoimmune diseases, including type 1 diabetes. We previously showed that low-dose interleukin 2 (IL2) induced T-reg cell expansion and activation and clinical improvement in patients with hepatitis-C-virus-induced vasculitis. We aimed to establish which low doses of IL2 would be safe and induce T-reg cells in patients with type 1 diabetes, considering that: (1) type 1 diabetes might be linked to alteration of the IL2/IL2R activation pathway; (2) activation of pathogenic T-eff cells by IL2 could exacerbate disease; and (3) the safety of low-dose IL2 is not known in type 1 diabetes.Methods This was a single-centre phase 1/2 study. 24 adult patients (18-55 years) with established insulin-dependent type 1 diabetes and at least one diabetes-related autoantibody were enrolled and randomly assigned (in a 1: 1: 1: 1 ratio, by computer-generated randomisation list, with block size four) to placebo or IL2 at 0.33 MIU/day, 1 MIU/day, or 3 MIU/day for a 5-day course and were followed up for 60 days. All investigators and participants were masked to assignment. The primary outcome was change in T-reg cells, measured by flow cytometry, and expressed as a percentage of CD4+ T cells, from day 1 to day 60. This trial is registered with ClinicalTrials.gov, number NCT01353833.Findings Six patients were assigned to each group between June 1, 2011, and Feb 3, 2012. IL2 was well tolerated at all doses, with no serious adverse events. However, there was a dose-response association for non-serious adverse events during the treatment phase (days 1-6); one patient in the placebo group, three patients in the 0.33 MIU group, five patients in the 1 MIU group, and six patients in the 3 MIU group had non-serious adverse events. The most common adverse events in the treatment phase were injection-site reaction (no patients with placebo vs three patients with 0.33 MIU and 1 MIU vs two patients with 3 MIU) and influenza-like syndrome (no patients with placebo vs one patient with 0.33 MIU and 1 MIU vs four patients with 3 MIU). After the treatment phase, adverse events did not differ between groups. IL2 did not induce deleterious changes in glucose-metabolism variables. IL2 induced a dose-dependent increase in the proportion of Treg cells, significant at all doses compared with placebo (placebo mean increase 0.5% [SD 0.4]; 0.33 MIU 2.8% [1.2], p=00039; 1 MIU 3 9% [1.8], p= 0.0039; 3 MIU 4 8% [1.9] p=0.0039).Interpretation We have defined a well-tolerated and immunologically effective dose range of IL2 for application to type 1 diabetes therapy and prevention, which could be relevant to other disorders in which a Treg cell increase would be desirable.