Regulatory T-Cell Responses to Low-Dose Interleukin-2 in HCV-Induced Vasculitis
Regulatory T-Cell Responses to Low-Dose Interleukin-2 in HCV-Induced Vasculitis
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DOI：
10.1056/nejmoa1105143
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发表时间：
2011-12-01
影响因子：
158.5
通讯作者：
Klatzmann, David
中科院分区：
文献类型：
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作者：
Saadoun, David;Rosenzwajg, Michelle;Klatzmann, David
背景丙型肝炎病毒（HCV）引起的血管炎患者的调节性T细胞（TcR）水平降低。HCV感染的消退与血管炎的治愈和Treg水平的恢复相关。我们的理由是，白细胞介素-2，一种细胞因子，促进Treg的生存和功能，可能是有益的血管炎患者，是耐HCV therapy.MethodsWe调查的安全性和免疫效果的管理低剂量白细胞介素-2在一个前瞻性的开放标签，1期-2A期研究。10例HCV诱导的血管炎患者，对常规抗病毒治疗、利妥昔单抗治疗或两者均难治，且未接受糖皮质激素或免疫抑制剂治疗，接受1个疗程的白细胞介素-2（150万IU/天），持续5天，随后在第3、6和9周接受3个疗程，每天300万IU，持续5天。治疗的安全性和有效性进行了评估，后者通过监测Treg反应和HCV vasculitis.ResultsNo不良事件的临床体征达到高于1级的水平。治疗未诱导效应T细胞活化、血管炎发作或HCV病毒血症增加。我们观察到10名患者中有9名的冷球蛋白血症减少，10名患者中有8名的血管炎改善。给予低剂量白细胞介素-2后，所有受试者中具有强效抑制活性的CD 4+、CD 25（高）、叉头盒P3（FOXP 3+）T细胞百分比[E-max（最大值）除以基线值x 100 = 420%]增加，同时边缘区B细胞比例降低。外周血单个核细胞的转录组研究表明，白细胞介素-2诱导的炎症和氧化应激mediator.ConclusionsThe试验表明，低剂量的白细胞介素-2的签名全球衰减与不良反应，并导致Treg恢复和伴随的临床改善HCV引起的血管炎，自身免疫性疾病的患者。（由法国艾滋病和病毒性肝炎研究机构[ANRS]和其他机构资助。
BackgroundPatients with vasculitis induced by the hepatitis C virus (HCV) have reduced levels of regulatory T cells (Tregs). Resolution of HCV infection correlates with cure of vasculitis and the recovery of Treg levels. We reasoned that interleukin-2, a cytokine that promotes Treg survival and function, could be beneficial for patients with vasculitis that is resistant to HCV therapy.MethodsWe investigated the safety and immunologic effects of the administration of low-dose interleukin-2 in a prospective open-label, phase 1-phase 2a study. Ten patients with HCV-induced vasculitis that was refractory to conventional antiviral therapy, rituximab therapy, or both and who were not receiving glucocorticoid or immunosuppressant therapy, received one course of interleukin-2 (1.5 million IU per day) for 5 days, followed by three 5-day courses of 3 million IU per day at weeks 3, 6, and 9. Both the safety of the treatment and its effectiveness were evaluated, the latter by monitoring the Treg response and the clinical signs of HCV vasculitis.ResultsNo adverse events reached a level higher than grade 1. The treatment did not induce effector T-cell activation, vasculitis flare, or increased HCV viremia. We observed a reduction in cryoglobulinemia in 9 of 10 patients and improvement of vasculitis in 8 of 10. Administration of low-dose interleukin-2 was followed by an increase in the percentage of CD4+, CD25(high), forkhead box P3 (FOXP3+) Tregs [E-max (maximum value) divided by baseline value x 100 = 420%] with potent suppressive activity in all subjects and by a concomitantly decreased proportion of marginal-zone B cells. Transcriptome studies of peripheral-blood mononuclear cells revealed that interleukin-2 induced a global attenuation of the signatures for inflammation and oxidative stress mediators.ConclusionsThe trial showed that low-dose interleukin-2 was not associated with adverse effects and led to Treg recovery and concomitant clinical improvement in patients with HCV-induced vasculitis, an autoimmune condition. (Funded by the French Agency for Research on AIDS and Viral Hepatitis [ANRS] and others.)