TLR7激动剂增加乙型肝炎病毒特异性T细胞和天然杀伤细胞对慢

StephenW

Gastroenterology. 2018 Jan 26. pii: S0016-5085(18)30072-6. doi: 10.1053/j.gastro.2018.01.030. [Epub ahead of print]
TLR7 Agonist Increases Responses Of HBV-Specific T Cells And Natural Killer Cells In Patients With Chronic Hepatitis B Treated With Nucleos(T)Ide Analogues.Boni C1, Vecchi A1, Rossi M1, Laccabue D1, Giuberti T1, Alfieri A1, Lampertico P2, Grossi G2, Facchetti F2, Brunetto MR3, Coco B3, Cavallone D3, Mangia A4, Santoro R4, Piazzolla V4, Lau A5, Gaggar A5, Subramanian GM5, Ferrari C6.
Author information
1Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda-Ospedaliero-Universitaria of Parma, Parma, Italy.2Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Università degli Studi di Milano, Italy.3Hepatology Unit and Liver Physiopathology Laboratory and Department of Clinical and Experimental Medicine, University Hospital of Pisa, Italy.4Liver Unit, IRCCS, "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Foggia, Italy.5Gilead Sciences, Inc. Foster City, CA, United States.6Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda-Ospedaliero-Universitaria of Parma, Parma, Italy. Electronic address: [email protected].

AbstractBACKGROUND & AIMS: The oral TLR7 agonist GS-9620 has anti-viral effects in woodchuck and chimpanzee models of chronic hepatitis B virus (HBV) infection. We investigated in a clinical trial the capacity of this agent to reconstitute protective immunity in patients with chronic HBV infection.
METHODS: We performed a prospective study of 28 patients with suppression of HBV infection by nucleos(t)ide analogue therapy who tested negative for HB e antigen at 4 medical centers in Italy. Patients were randomly assigned (1:3:3:3) to groups given placebo or different doses of GS-9620 (1, 2, and 4 mg, weekly for 12 weeks). We added data from 8 patients receiving nucleos(t)ide analogue therapy to the placebo group (controls); 13 treatment-naive patients with chronic HBV infection and 15 subjects who spontaneously recovered from an acute HBV infection served as additional controls. Peripheral blood mononuclear cells were collected at baseline, during administration of GS-9620 or placebo, and 12 weeks afterward. Phenotype and function of natural killer (NK) and HBV-specific T cells were analyzed by flow cytometry. T cells were expanded by incubation with peptides from the entire HBV proteome and studied after overnight or 10 days culture. NK cell inhibition of T-cell responses was measured by assessing cytokine production by T cells stimulated with peptides in the presence or absence of NK cells.
RESULTS: T cells collected at baseline before addition of GS-9620, when patients were receiving only nucleos(t)ide therapy, had greater responses to HBV than T cells from treatment-naïve patients, based on cytokine production in response to HBV peptides. However, during or after administration of GS-9620 T cells produced higher levels of cytokines compared to baseline. NK cell activation and function increased after patients were given GS-9620, but the ability of NK cells to suppress T-cell responses was lower during GS-9620 therapy than before. Changes in T-cell or NK cell function did not correlate with levels of HBsAg. Serum levels of HBsAg did not decrease significantly compared to baseline in patients given any dose of GS-9620.
CONCLUSIONS: Twelve weeks administration of GS-9620 had no significant effect on serum HBsAg levels but did appear to increase T-cell and NK cell responses and reduce the ability of NK to suppress T cells. GS-9620 might therefore be included in therapies to increase the immune response to HBV.

Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.

KEYWORDS: T-cell inhibition; clinical trial; immune regulation; viral hepatitis treatment

PMID:29378197DOI:10.1053/j.gastro.2018.01.030

StephenW

消化内科。 2018年1月26日。pii：S0016-5085（18）30072-6。 doi：10.1053 / j.gastro.2018.01.030。 [电子版提前打印]
TLR7激动剂增加乙型肝炎病毒特异性T细胞和天然杀伤细胞对慢性乙型肝炎治疗核苷（T）的类似物的反应。
Boni C1，Vecchi A1，Rossi M1，Laccabue D1，Giuberti T1，Alfieri A1，Lampertico P2，Grossi G2，Facchetti F2，Brunetto MR3，Coco B3，Cavallone D3，Mangia A4，Santoro R4，Piazzolla V4，Lau A5，Gaggar A5 ，Subramanian GM5，法拉利C6。
作者信息

1
    病毒免疫病理学实验室，感染性疾病和肝病学单位，意大利帕尔马帕尔马的Azienda-Ospedaliero-Universitaria。
2
    意大利米兰大学医学院，胃肠病学和肝病学系，Fondazione IRCCS Ca'Granda，Ospedale Maggiore Policlinico。
3
    意大利比萨大学附属医院肝病科和肝病理生理学实验室及临床和实验医学系。
4
    IRCCS肝脏部，意大利福贾San Giovanni Rotondo的“Casa Sollievo della Sofferenza”。
五
    吉列德科学公司福斯特城，加利福尼亚州，美国。
6
    病毒免疫病理学实验室，感染性疾病和肝病学单位，意大利帕尔马帕尔马的Azienda-Ospedaliero-Universitaria。电子地址：[email protected]。

抽象
背景与目的：

口服TLR7激动剂GS-9620在慢性乙型肝炎病毒（HBV）感染的土拨鼠和黑猩猩模型中具有抗病毒作用。我们在临床试验中调查了这种药物在慢性HBV感染患者中重建保护性免疫的能力。
方法：

我们对意大利4个医疗中心HBe抗原检测阴性的核苷（酸）类似物治疗的28例HBV感染抑制患者进行了前瞻性研究。将患者随机分配（1：3：3：3）给予安慰剂组或不同剂量的GS-9620（1,2和4mg，每周12周）。我们将8名接受核苷（酸）类似物治疗的患者的数据添加到安慰剂组（对照）。慢性HBV感染的13名初治患者和15名从急性HBV感染中自发恢复的受试者作为另外的对照。在基线，GS-9620或安慰剂给药期间和12周后收集外周血单核细胞。通过流式细胞术分析自然杀伤（NK）和HBV特异性T细胞的表型和功能。通过与来自整个HBV蛋白质组的肽孵育来扩增T细胞，并在过夜或培养10天后进行研究。通过评估在存在或不存在NK细胞的情况下用肽刺激的T细胞的细胞因子产生来测量NK细胞对T细胞应答的抑制。
结果：

T细胞在加入GS-9620之前收集，当患者仅接受核苷（酸）治疗时，基于对HBV肽的应答产生细胞因子，其对HBV的应答比治疗初治患者的T细胞更高。然而，在施用GS-9620T细胞期间或之后，与基线相比，产生更高水平的细胞因子。 GS-9620治疗后NK细胞激活和功能增加，但GS-9620治疗期间NK细胞抑制T细胞应答的能力降低。 T细胞或NK细胞功能的变化与HBsAg水平不相关。给予任何剂量的GS-9620的患者血清HBsAg水平与基线相比没有显着降低。
结论：

GS-9620的12周给药对血清HBsAg水平没有显着影响，但似乎增加了T细胞和NK细胞应答，降低了NK抑制T细胞的能力。 GS-9620因此可能被包括在治疗中以增加对HBV的免疫应答。

版权所有©2018 AGA研究所。由Elsevier Inc.出版。保留所有权利。
关键词：

T细胞抑制;临床试验;免疫调节;病毒性肝炎治疗

结论：
    29378197
DOI：
    10.1053 / j.gastro.2018.01.030