Gut：IFN-λ3诱导有望成为抗乙肝病毒治疗新途径

MP4

http://www.alabmed.com/content-134-3732-1.html

MP4

来自日本的早期研究表明，对于慢性乙型肝炎病毒（HBV）感染患者来说，诱导干扰素（IFN）-λ3的产生或许是一种有希望的治疗策略。

据该发表于Gut杂志上的研究表明，在慢乙肝患者中IFN-λ3是由核苷酸而不是核苷类似物选择性诱导产生的，而反过来IFN-λ3又刺激IFN刺激因子的产生进而抑制乙型肝炎表面抗原（HBsAg）的产生。

研究人员在文中写到：“这种机制的发现对于HBV的治疗来说是一个新进展，提示抗乙肝病毒治疗或可通过开发针对IFN-λ3诱导的方法来实现。”

通过使用定制的内部测定，研究人员分析了142名处于HBV感染各个阶段患者的血清IFN-λ3水平，包括接受核苷酸类似物治疗的80名慢性肝炎，22名肝硬化，40名肝细胞癌患者。

在用核苷酸类似物（阿德福韦或替诺福韦酯富马酸盐[TDF]）治疗的25名患者中，IFN-λ3的血清水平显着高于117名给予核苷类似物（拉米夫定或恩替卡韦）治疗的患者，中位数为27.2 VS 1.4pg / mL（p <0.001）。

这个研究发现在另一项研究中获得重复，新研究是在19名使用阿德福韦治疗，1名使用替诺福韦（TDF）治疗，另有20名患者使用拉米夫定和/或恩替卡韦治疗中进行的，研究人员对他们的血清IFN-λ3水平分析时发现，使用核苷酸类似物患者的IFN-λ3水平要较核苷类似物要高。因此，研究人员认为“这强烈提示核苷酸类似物本身或具有诱导IFN-λ3产生的作用。”

此外，研究人员注意到，在用核苷酸类似物处理的结肠癌细胞系WiDr和HT-29的上清液中检测到IFN-λ3的表达，并且该上清液“强烈上调”IFN调节因子并抑制各种肝源细胞系HBsAg的产生。

通过给予重组IFN-λ3，PLC / PRF / 5肝癌细胞系的HBsAg产生也被抑制，并且该抑制呈现剂量依赖性。

尽管核苷酸类似物的这种额外作用，显然单药治疗还不足以诱导HBsAg的消失，因为TDF和恩替卡韦都可以使得 HBsAg 在一小部分患者中的消失，观察研究人员。他们建议将核苷酸类似物与聚乙二醇干扰素（PEG-IFNα）联合用药“在理论上可能是一种有希望的治疗方法。”

事实上，以前已有报道表明当PEG-IFN与阿德福韦或TDF联用时HBsAg丢失的概率更高，而联合拉米夫定治疗观察到的效果跟单独给予PEF-IFNα效果相似。

Masashi Mizokami（国立全球健康和医学中心，Ichikawa）和团队在研究结论结论中认为：“在核苷酸类似物单药或联合PEG-IFN-α的治疗过程中，我们预计IFN刺激因子在肝脏中会出现上调的情形，其与HBsAg变化的或具有相关性，显然我们的这项研究证实了我们的假设。”


英文原文
IFN-λ3 induction shows potential as anti-HBV therapy


Early research from Japan suggests that induction of interferon (IFN)-λ3 could be a promising therapeutic strategy in patients with hepatitis B virus (HBV) infection.

IFN-λ3 production was induced selectively by nucleotide, but not nucleoside, analogs in HBV patients, which in turn, induced IFN-stimulated genes and suppressed hepatitis B surface antigen (HBsAg) production, the investigators report in Gut.

“The discovery of this mechanism is a new advancement for HBV treatment, suggesting the possibility of developing an anti-HBV treatment targeting IFN-λ3 induction,” they write.

Using a custom in-house assay, they analyzed serum IFN-λ3 levels among 142 individuals at various stages of HBV infection – including 80 patients with chronic hepatitis, 22 with liver cirrhosis, and 40 with hepatocellular carcinoma – who had received nucleos(t)ide analog therapy.

Serum levels of IFN-λ3 were significantly higher among the 25 patients treated with the nucleotide analogs (adefovir or tenofovir disoproxil fumarate [TDF]) than among the 117 given nucleoside analogs (lamivudine or entecavir), at a median of 27.2 versus 1.4 pg/mL (p<0.001).

These findings were replicated in an analysis of serial serum samples from 19 adefovir-treated participants, one individual given TDF alone, and 20 patients treated with lamivudine and/or entecavir, such that IFN-λ3 levels rose during nucleotide, but not nucleoside therapy, and “strongly suggested that the nucleotide analogues are themselves responsible for the induction of IFN-λ3,” say the study authors.

Furthermore, they note that IFN-λ3 expression was detected in the supernatant of the colon cancer cell lines WiDr and HT-29 treated with the nucleotide analogs, and this supernatant “robustly upregulated” IFN-regulated genes and inhibited the production of HBsAg in various cell lines of hepatic origin.

HBsAg production by the PLC/PRF/5 hepatoma cell line was also suppressed by the administration of recombinant IFN-λ3, and this inhibition was dose-dependent.

Despite this additional effect of nucleotide analogs, clearly single-agent treatment is not sufficient to induce HBsAg loss, as TDF and entecavir both lead to HBsAg loss in a small proportion of patients, observe the researchers. They propose that combining nucleotide analogs with pegylated (PEG)-IFNα “could theoretically be a promising treatment method.”

Indeed, previous reports have suggested a high probability of HBsAg loss when PEG-IFN is co-administered with adefovir or TDF, whereas simultaneous treatment with lamivudine leads to findings similar to those in patients given PEF-IFNα alone.

Masashi Mizokami (National Center for Global Health and Medicine, Ichikawa) and team conclude that “[p]rospective studies to demonstrate the upregulation of [IFN-stimulated genes] in the liver and its association with HBsAg changes during treatment with nucleotide analogues or combination with PEG-IFN-α would be warranted to confirm our hypothesis.”

MP4

福韦