降低HBV的复制延长对IFN-α治疗的早期免疫反应

StephenW

Reduction of HBV replication prolongs the early immunological response to IFNα therapy

    Anthony T. Tana, 1,
    Long Truong Hoangb, 1,
    Daniel Chin c,
    Erik Rasmussen c,
    Uri Lopatin c,
    Stefan Hart c,
    Hans Bitter c,
    Tom Chu c,
    Lore Gruenbaum c,
    Palani Ravindran c,
    Hua Zhong c,
    Ed Gane d,
    Seng Gee Lim e,
    Wan Cheng Chow f,
    Pei-Jer Chen g,
    Rosemary Petric c,
    Antonio Bertolettia, h, 1, Corresponding author contact information, E-mail the corresponding author, E-mail the corresponding author,
    Martin Lloyd Hibberdb, 1

    a Singapore Institute for Clinical Sciences, A∗STAR, Singapore
    b Genome Institute of Singapore, A∗STAR, Singapore
    c Hoffmann-La Roche
    d Auckland City Hospital, Auckland, New Zealand
    e National University Hospital, Singapore
    f Singapore General Hospital, Singapore
    g National Taiwan University Hospital, Taipei, Taiwan
    h Program in Emerging Infectious Disease, Duke-NUS Graduate Medical School, Singapore

Abstract
Background and Aims

The interaction between HBV replication and immune modulatory effects mediated by IFNα therapy is not well understood. We characterized the impact of HBV DNA replication on the early IFNα-induced immunomodulatory mechanisms.
Methods

We interrogated the transcriptional, serum cytokine/chemokine and cellular immune profiles of 28 patients with HBeAg+ chronic HBV infection (CHB) randomly assigned to one of 4 treatment cohorts (untreated n=5, weekly dosing of 360μg Pegasys® [Peg-IFNα] n=11, daily dose of 300mg Viread® [tenofovir disoproxil fumarate, TDF] n=6, or a combination of both n=6). Samples were characterized at multiple early time points through day 14 of therapy, after which all patients were given standard of care (180μg Pegasys® injected subcutaneously, weekly).
Results

Peg-IFNα induced a distinct and rapid up-regulation of IFN signaling pathway that coincided with increase detection of distinct serum cytokines/chemokines (IL-15, IL-6, and CXCL-10) and the up-regulation of the frequency of proliferating NK and activated total CD8+ T cells. IFNα treatment alone did not result in rapid decay of HBV replication and was not able to restore the defective HBV-specific T-cell response present in CHB patients. In addition, the IFNα immune-stimulatory effects diminished after the first dose, but this refractory effect was reduced in patients where HBV replication was simultaneously inhibited with TDF.
Conclusions

We present here the first comprehensive description of the early effects of IFNα treatment on immune and viral biomarkers in HBeAg+ CHB patients. Our results show that Peg-IFNα-induced innate immune activation directly benefits from the suppression of HBV replication

StephenW

背景和目的

HBV复制之间的相互作用介导的IFNα治疗和免疫调节作用还不是很清楚。我们的特点的影响HBV DNA复制的早期IFNα诱导免疫调节机制。
方法

我们审问的转录，血清细胞因子/趋化因子和细胞免疫型材的28例患者的HBeAg +慢性乙肝病毒感染（CHB）随机分配一个4治疗同伙（未经处理的Ñ = 5 ，每周剂量360μg派罗欣® [穿心- IFNα ] Ñ = 11时，每日剂量为300mg的Viread ®富马酸替诺福韦TDF ] N = 6，或组合两个n = 6 ） 。多个早期时间点的样品进行了表征，通过14天的治疗后，所有患者均给予标准的护理（每次180μg派罗欣®皮下注射，每周） 。
结果

聚乙二醇化IFN-α诱导的一个独特的和快速上调IFN信号转导通路的同时增加检测不同的血清细胞因子/趋化因子（ IL-15， IL -6， CXCL - 10 ）和增殖的频率上调NK细胞和活化的CD8 + T细胞。 IFNα治疗本身并不导致乙肝病毒复制迅速衰减，无法恢复故障CHB患者的HBV特异性T细胞反应。此外，首次剂量后IFNα免疫刺激效应减弱，但这种难治性的效果，减少患者同时抑制HBV的复制与TDF 。
结论

我们在座的IFNα治疗大三阳+ CHB患者的免疫和病毒的生物标志物的早期影响的第一个全面的描述。我们的研究结果表明， PEG - IFNα诱导先天免疫激活抑制HBV复制的直接利益