Low-dose interleukin-2 selectively corrects regulatory T cell defects in patients with systemic lupus erythematosus
Low-dose interleukin-2 selectively corrects regulatory T cell defects in patients with systemic lupus erythematosus
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DOI：
10.1136/annrheumdis-2015-207776
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发表时间：
2016-07-01
影响因子：
27.4
通讯作者：
Humrich, Jens Y.
中科院分区：
文献类型：
--
作者：
von Spee-Mayer, Caroline;Siegert, Elise;Humrich, Jens Y.
目的调节性T细胞（Treg）生物学缺陷与系统性红斑狼疮（SLE）等系统性自身免疫性疾病有关。然而，这种Treg缺陷的起源及其在SLE的发病机制和治疗中的意义仍然知之甚少。方法采用多色流式细胞术检测61例SLE患者和52例健康人外周血单个核细胞（PBMC）及体外IL-2刺激的PBMC。5例难治性SLE患者每天皮下注射150万IU的人IL-2（阿地白介素）连续5天，PBMC进行了流式细胞仪分析。结果SLE患者发展的进行性稳态失衡之间的Treg和常规的CD 4 + T细胞与疾病活动和平行显示的Treg上的CD 25表达大幅减少。这些Treg缺陷类似于IL-2缺乏的标志，并导致功能和代谢活性Treg的可用性显著降低。体外实验表明，CD 4 + T细胞缺乏IL-2产生导致SLE Treg中CD 25表达丧失，这可以通过低剂量IL-2刺激选择性逆转。因此，治疗SLE患者与低剂量IL-2方案选择性地纠正Treg缺陷也在体内和强烈扩大Treg population.Conclusions Treg缺陷与SLE患者与IL-2缺乏症，并可以纠正与低剂量的IL-2。因此，通过低剂量IL-2治疗恢复免疫耐受的内源性机制，提出了一种选择性生物治疗策略，直接解决了SLE的病理生理学。
Objectives Defects in regulatory T cell (Treg) biology have been associated with human systemic autoimmune diseases, such as systemic lupus erythematosus (SLE). However, the origin of such Treg defects and their significance in the pathogenesis and treatment of SLE are still poorly understood.Methods Peripheral blood mononuclear cells (PBMC) from 61 patients with SLE and 52 healthy donors and in vitro IL-2 stimulated PBMC were characterised by multicolour flow cytometry. Five patients with refractory SLE were treated daily with subcutaneous injections of 1.5 million IU of human IL-2 (aldesleukin) for five consecutive days, and PBMC were analysed by flow cytometry.Results Patients with SLE develop a progressive homeostatic dysbalance between Treg and conventional CD4+ T cells in correlation with disease activity and in parallel display a substantial reduction of CD25 expression on Treg. These Treg defects resemble hallmarks of IL-2 deficiency and lead to a markedly reduced availability of functionally and metabolically active Treg. In vitro experiments revealed that lack of IL-2 production by CD4+ T cells accounts for the loss of CD25 expression in SLE Treg, which could be selectively reversed by stimulation with low doses of IL-2. Accordingly, treatment of patients with SLE with a low-dose IL-2 regimen selectively corrected Treg defects also in vivo and strongly expanded the Treg population.Conclusions Treg defects in patients with SLE are associated with IL-2 deficiency, and can be corrected with low doses of IL-2. The restoration of endogenous mechanisms of immune tolerance by low-dose IL-2 therapy, thus, proposes a selective biological treatment strategy, which directly addresses the pathophysiology in SLE.