Kupffer细胞清除聚乙二醇化干扰素会限制NK细胞激活和HBV感染

StephenW

Clearance of pegylated interferon by Kupffer cells limits NK cell activation and therapy response of patients with HBV infection
Akira Nishio  1 , Fabian J Bolte  1 , Kazuyo Takeda  2 , Nana Park  1 , Zu-Xi Yu  2 , Heiyoung Park  1 , Kristin Valdez  3 , Marc G Ghany  3 , Barbara Rehermann  4
Affiliations
Affiliations

    1
    Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD 20892, USA.
    2
    Pathology Core, National Heart, Lung and Blood Institute, National Institutes of Health, DHHS, Bethesda, MD 20892, USA.
    3
    Clinical Research Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD 20892, USA.
    4
    Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD 20892, USA. [email protected].

    PMID: 33790025 DOI: 10.1126/scitranslmed.aba6322

Abstract

Pegylated interferon-α (PEG-IFN-α), where IFN-α is attached to polyethylene glycol (PEG), is an approved treatment for chronic hepatitis B virus (HBV) infection, a disease that causes liver-related morbidity and mortality in 257 million people worldwide. It is unknown why only a minority of patients respond to PEG-IFN-α. Using sequential blood samples and liver biopsies of patients with chronic HBV infection before, during, and after PEG-IFN-α treatment, we find that patients with early natural killer (NK) cell activation after PEG-IFN-α injection experienced greater liver inflammation, lysis of HBV-infected hepatocytes, and hepatitis B surface antigen (HBsAg) decline than those without. NK cell activation was associated with induction of interferon-stimulated genes and determined by PEG-IFN-α pharmacokinetics. Patients with delayed increases in PEG-IFN-α concentrations had greater amounts of PEG-specific immunoglobulin M (IgM) immune complexes in the blood and more PEG and IgM detected in the liver than patients with rapid increase in PEG-IFN-α concentration. This was associated with reduced NK cell activation. These results indicate that the immunomodulatory functions of PEG-IFN-α, particularly activation of NK cells, play a pivotal role in the response to treatment and further demonstrate that these functions are affected by PEG-IFN-α pharmacokinetics. Accelerated clearance of antibody-complexed pegylated drugs by Kupffer cells may be important beyond the field of HBV therapeutics. Thus, these findings may contribute to improving the efficacy of pegylated drugs that are now being developed for other chronic diseases and cancer.

Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

StephenW

Kupffer细胞清除聚乙二醇化干扰素会限制NK细胞激活和HBV感染患者的治疗反应
西尾晃1，Fabian J Bolte 1，武田和代2，娜娜公园1，余祖希2，黑英公园1，克里斯汀·瓦尔迪兹3，马克·加尼3，芭芭拉·雷赫曼4
隶属关系
隶属关系

    1个
    美国国立卫生部国立卫生研究院糖尿病与消化及肾脏疾病研究所肝病科免疫学科，美国贝塞斯达，医学博士20892。
    2个
    美国国立卫生研究院国立卫生研究院国家心脏，肺和血液研究所病理学核心，美国贝塞斯达，医学博士20892。
    3
    美国国立卫生部国立卫生研究院糖尿病与消化与肾脏疾病研究所肝病科临床研究科，美国贝塞斯达，医学博士20892。
    4
    美国国立卫生部国立卫生研究院糖尿病与消化及肾脏疾病研究所肝病科免疫学科，美国贝塞斯达，医学博士20892。 [email protected]。

    PMID：33790025 DOI：10.1126 / scitranslmed.aba6322

抽象的

聚乙二醇化干扰素-α（PEG-IFN-α）（其中IFN-α与聚乙二醇（PEG）相连）是一种批准的慢性乙型肝炎病毒（HBV）感染的治疗方法，这种疾病会导致肝脏相关的发病率和死亡率全球有2.57亿人。尚不清楚为什么只有少数患者对PEG-IFN-α产生反应。使用序贯的血液样本和PEG-IFN-α治疗之前，期间和之后的慢性HBV感染患者的肝活检，我们发现PEG-IFN-α注射后具有早期自然杀伤（NK）细胞活化作用的患者发生了更大的肝脏炎症HBV感染肝细胞的裂解，乙肝表面抗原（HBsAg）下降。 NK细胞活化与干扰素刺激基因的诱导有关，并由PEG-IFN-α药代动力学确定。与PEG-IFN-α浓度快速升高的患者相比，PEG-IFN-α浓度延迟升高的患者血液中的PEG特异性免疫球蛋白M（IgM）免疫复合物数量更多，在肝脏中检测到更多的PEG和IgM。这与减少的NK细胞活化有关。这些结果表明，PEG-IFN-α的免疫调节功能，特别是NK细胞的激活，在对治疗的反应中起关键作用，并且进一步证明这些功能受PEG-IFN-α的药代动力学影响。 Kupffer细胞对抗体复合的聚乙二醇化药物的加速清除可能在HBV治疗领域之外很重要。因此，这些发现可能有助于改善目前正在开发用于其他慢性疾病和癌症的聚乙二醇化药物的功效。

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