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Abstract：
To investigate the regulation of T follicular regulatory (Tfr) and T follicular (Tfh) cell subtypes by low-dose IL-2 in systemic lupus erythematosus (SLE) in a randomized, double-blind, placebo-controlled clinical trial.
A post hoc analysis was performed in a randomized cohort of SLE patients (n=60) receiving low-dose IL-2 therapy (n=30) or placebo (n=30), along with the standard of care treatment. The primary endpoint was the attainment of SLE responder index-4 (SRI-4) at week 12 in the trial. Twenty-three healthy controls were enrolled for T cell subset detection at the same time as the trial. The t-stochastic neighbor embedding (tSNE) analysis of CD4 T subsets based on immune cells flow cytometry markers was performed to distinguish Tfh, Tfh1, Tfh2, Tfh17, and Tfr cell subsets.
Compared with HC, the frequency of Tfr (CXCR5+PD-1low Treg and CXCR5+PD-1high Treg) cells was significantly reduced, while the pro-inflammatory Tfh cells were increased in patients with SLE. The imbalanced Tfh cell was associated with several pathogenic factors (anti-dsDNA antibodies (r=0.309, P=0.027) and serum IL-17 (r=0.328, P=0.021)) and SLE Disease Activity Index (SLEDAI) score (r=0.273, P=0.052). Decreased CXCR5+PD-1low Treg/Tfh and CXCR5+PD-1low Treg/Tfh17 were both associated with increased immunoglobulin M (IgM) (r=-0.448, P=0.002 and r=-0.336, P=0.024, respectively). Efficacy of low-dose IL-2 therapy was associated with a restored Tfr/Tfh cell balance.
These data support the hypothesis that promotion of Tfr is associated with decreased disease activities and that low-dose IL-2 therapy can recover Tfr/Tfh immune balance.
ClinicalTrials.gov Registries ( NCT02465580 ).
A post hoc analysis was performed in a randomized cohort of SLE patients (n=60) receiving low-dose IL-2 therapy (n=30) or placebo (n=30), along with the standard of care treatment. The primary endpoint was the attainment of SLE responder index-4 (SRI-4) at week 12 in the trial. Twenty-three healthy controls were enrolled for T cell subset detection at the same time as the trial. The t-stochastic neighbor embedding (tSNE) analysis of CD4 T subsets based on immune cells flow cytometry markers was performed to distinguish Tfh, Tfh1, Tfh2, Tfh17, and Tfr cell subsets.
Compared with HC, the frequency of Tfr (CXCR5+PD-1low Treg and CXCR5+PD-1high Treg) cells was significantly reduced, while the pro-inflammatory Tfh cells were increased in patients with SLE. The imbalanced Tfh cell was associated with several pathogenic factors (anti-dsDNA antibodies (r=0.309, P=0.027) and serum IL-17 (r=0.328, P=0.021)) and SLE Disease Activity Index (SLEDAI) score (r=0.273, P=0.052). Decreased CXCR5+PD-1low Treg/Tfh and CXCR5+PD-1low Treg/Tfh17 were both associated with increased immunoglobulin M (IgM) (r=-0.448, P=0.002 and r=-0.336, P=0.024, respectively). Efficacy of low-dose IL-2 therapy was associated with a restored Tfr/Tfh cell balance.
These data support the hypothesis that promotion of Tfr is associated with decreased disease activities and that low-dose IL-2 therapy can recover Tfr/Tfh immune balance.
ClinicalTrials.gov Registries ( NCT02465580 ).
摘要：
探讨低剂量IL-2对系统性红斑狼疮(SLE)T滤泡调节(Tfr)和T滤泡(Tfh)细胞亚型的影响。双盲,安慰剂对照临床试验。
在接受低剂量IL-2治疗（n=30）或安慰剂（n=30）的SLE患者（n=60）的随机队列中进行了事后分析，以及护理治疗的标准。主要终点是在试验第12周达到SLE反应指数-4(SRI-4)。在试验的同时,23个健康对照被登记用于T细胞亚群检测。进行基于免疫细胞流式细胞术标志物的CD4T亚群的t-随机邻居嵌入(tSNE)分析以区分Tfh,Tfh1、Tfh2、Tfh17和Tfr细胞亚群。
与HC相比，Tfr(CXCR5+PD-1lowTreg和CXCR5+PD-1highTreg)细胞频率显著降低,而SLE患者的促炎Tfh细胞增加。Tfh细胞失衡与多种致病因素（抗dsDNA抗体（r=0.309，P=0.027）和血清IL-17（r=0.328，P=0.021））和SLE疾病活动指数（SLEDAI）评分（r=0.273，P=0.052）有关。CXCR5+PD-1lowTreg/Tfh和CXCR5+PD-1lowTreg/Tfh17均与免疫球蛋白M(IgM)升高相关(r=-0.448,P=0.002,r=-0.336,P=0.024)。低剂量IL-2治疗的功效与恢复的Tfr/Tfh细胞平衡相关。
这些数据支持以下假设：Tfr的促进与疾病活动减少有关，低剂量IL-2治疗可以恢复Tfr/Tfh免疫平衡。
ClinicalTrials.gov登记处（NCT02465580）。
在接受低剂量IL-2治疗（n=30）或安慰剂（n=30）的SLE患者（n=60）的随机队列中进行了事后分析，以及护理治疗的标准。主要终点是在试验第12周达到SLE反应指数-4(SRI-4)。在试验的同时,23个健康对照被登记用于T细胞亚群检测。进行基于免疫细胞流式细胞术标志物的CD4T亚群的t-随机邻居嵌入(tSNE)分析以区分Tfh,Tfh1、Tfh2、Tfh17和Tfr细胞亚群。
与HC相比，Tfr(CXCR5+PD-1lowTreg和CXCR5+PD-1highTreg)细胞频率显著降低,而SLE患者的促炎Tfh细胞增加。Tfh细胞失衡与多种致病因素（抗dsDNA抗体（r=0.309，P=0.027）和血清IL-17（r=0.328，P=0.021））和SLE疾病活动指数（SLEDAI）评分（r=0.273，P=0.052）有关。CXCR5+PD-1lowTreg/Tfh和CXCR5+PD-1lowTreg/Tfh17均与免疫球蛋白M(IgM)升高相关(r=-0.448,P=0.002,r=-0.336,P=0.024)。低剂量IL-2治疗的功效与恢复的Tfr/Tfh细胞平衡相关。
这些数据支持以下假设：Tfr的促进与疾病活动减少有关，低剂量IL-2治疗可以恢复Tfr/Tfh免疫平衡。
ClinicalTrials.gov登记处（NCT02465580）。
