IFN-α 治疗后无反应患者通过序贯低剂量 IL-2 治疗恢复 HBV 特

StephenW

IFN-α 治疗后无反应患者通过序贯低剂量 IL-2 治疗恢复 HBV 特异性 CD8 + T 细胞反应
王冬瑶#1 2 , 付斌庆#1 2 , 沈晓坤1 2 , 郭创1 2 , 刘艳艳3 , 张俊飞3 , 孙瑞1 2 , 叶英3 , 李家斌4 , 田志刚5 6 , 魏海明7 8
隶属关系
隶属关系

    1
    中国科学技术大学基础医学院与医学中心免疫学研究所及中国科学院先天免疫与慢性病重点实验室，安徽合肥230001。
    2
    中国科学技术大学合肥微尺度物质科学国家实验室，安徽合肥，230001。
    3
    安徽医科大学第一附属医院感染科，安徽 合肥 230027
    4
    安徽医科大学第一附属医院感染科，安徽 合肥 230027 [email protected]。
    5
    中国科学技术大学基础医学院与医学中心免疫学研究所及中国科学院先天免疫与慢性病重点实验室，安徽合肥230001。 [email protected]。
    6
    中国科学技术大学合肥微尺度物质科学国家实验室，安徽合肥，230001。 [email protected]。
    7
    中国科学技术大学基础医学院与医学中心免疫学研究所及中国科学院先天免疫与慢性病重点实验室，安徽合肥230001。 [email protected]。
    8
    中国科学技术大学合肥微尺度物质科学国家实验室，安徽合肥，230001。 [email protected]。

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同等贡献。

    PMID：34737296 DOI：10.1038/s41392-021-00776-0

抽象的

接受干扰素 (IFN)-α 治疗的慢性乙型肝炎 (CHB) 患者通常表现出较差的 HBeAg 血清学反应。因此，对针对 CHB 的新疗法存在未满足的需求。该研究包括两项临床试验，包括 130 名未接受过治疗的 CHB 患者；首先，92 名患者在接受 Peg-IFN-α-2b 治疗后进行了体外白细胞介素 2 受体 (IL-2R) 表达和抑制性分子表达的系统分析。在我们的第二项临床试验中，38 名 IFN-α 治疗失败的无反应患者接受或不接受低剂量 IL-2 治疗 24 周。然后我们检查了这些患者的乙型肝炎病毒 (HBV) 特异性 CD8+ T 细胞反应和临床结果。尽管接受 Peg-IFN-α-2b 治疗的大多数参与者是无反应者，但我们观察到他们的 CD4+ T 细胞上 CD25 表达下降，这表明 IFN-α 治疗可能为序贯 IL-2 治疗提供了一个基本原理，而无需增加调节性 T 细胞 (Tregs)。在用 IL-2 进行序贯治疗后，我们证明无反应者的 Treg 数量和程序性细胞死亡蛋白 1 (PD-1) 表达减少。此外，连续 IL-2 给药挽救了有效的免疫功能，涉及信号转导和转录激活因子 1 (STAT1) 的激活。重要的是，IL-2 治疗显着增加了 HBV 特异性 CD8+ T 细胞的频率和功能，这在无反应的 CHB 患者中转化为改善的临床结果，包括 HBeAg 血清学转换。我们的研究结果表明，序贯 IL-2 治疗显示出挽救难治性 CHB 无反应患者免疫功能的功效。

© 2021。作者。

StephenW

Restoration of HBV-specific CD8 + T-cell responses by sequential low-dose IL-2 treatment in non-responder patients after IFN-α therapy
Dongyao Wang #  1   2 , Binqing Fu #  1   2 , Xiaokun Shen  1   2 , Chuang Guo  1   2 , Yanyan Liu  3 , Junfei Zhang  3 , Rui Sun  1   2 , Ying Ye  3 , Jiabin Li  4 , Zhigang Tian  5   6 , Haiming Wei  7   8
Affiliations
Affiliations

    1
    Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medicine and Medical Center, University of Science and Technology of China, Hefei, Anhui, 230001, China.
    2
    Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui, 230001, China.
    3
    Department of Infectious Diseases, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230027, China.
    4
    Department of Infectious Diseases, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230027, China. [email protected].
    5
    Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medicine and Medical Center, University of Science and Technology of China, Hefei, Anhui, 230001, China. [email protected].
    6
    Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui, 230001, China. [email protected].
    7
    Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medicine and Medical Center, University of Science and Technology of China, Hefei, Anhui, 230001, China. [email protected].
    8
    Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui, 230001, China. [email protected].

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Contributed equally.

    PMID: 34737296 DOI: 10.1038/s41392-021-00776-0

Abstract

Patients with chronic hepatitis B (CHB) undergoing interferon (IFN)-α-based therapies often exhibit a poor HBeAg serological response. Thus, there is an unmet need for new therapies aimed at CHB. This study comprised two clinical trials, including 130 CHB patients, who were treatment-naïve; in the first, 92 patients were systematically analyzed ex vivo for interleukin-2 receptor (IL-2R) expression and inhibitory molecules expression after receiving Peg-IFN-α-2b therapy. In our second clinical trial, 38 non-responder patients, in whom IFN-α therapy had failed, were treated with or without low-dose IL-2 for 24 weeks. We then examined the hepatitis B virus (HBV)-specific CD8+ T-cell response and the clinical outcome, in these patients. Although the majority of the participants undergoing Peg-IFN-α-2b therapy were non-responders, we observed a decrease in CD25 expression on their CD4+ T cells, suggesting that IFN-α therapy may provide a rationale for sequential IL-2 treatment without increasing regulatory T cells (Tregs). Following sequential therapy with IL-2, we demonstrated that the non-responders experienced a decrease in the numbers of Tregs and programmed cell death protein 1 (PD-1) expression. In addition, sequential IL-2 administration rescued effective immune function, involving signal transducer and activator of transcription 1 (STAT1) activation. Importantly, IL-2 therapy significantly increased the frequency and function of HBV-specific CD8+ T cells, which translated into improved clinical outcomes, including HBeAg seroconversion, among the non-responder CHB patients. Our findings suggest that sequential IL-2 therapy shows efficacy in rescuing immune function in non-responder patients with refractory CHB.

© 2021. The Author(s).

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