Suppression of Indoleamine 2,3-Dioxygenase Enhances Immune Responses to the Therapeutic Vaccine for Chronic Hepatitis B

IF 3.7 3区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

Hepatology Research Pub Date : 2026-07-07 Epub Date: 2026-03-21 DOI:10.1111/hepr.70165

Yohei Shirakami, Soranobu Ninomiya, Takayasu Ideta, Ayumu Kanbe, Toshihide Maeda, Daisuke Minowa, Daisuke Taguchi, Masaya Kubota, Hiroyasu Sakai, Kenji Imai, Yasuko Yamamoto, Hiroyasu Ito, Kuniaki Saito, Osamu Yoshida, Yoichi Hiasa, Masahito Shimizu

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Abstract

Aim

Chronic hepatitis B virus (HBV) infection remains a major cause of liver cirrhosis and hepatocellular carcinoma. NASVAC is a therapeutic vaccine containing hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (HBcAg), which has shown clinical potential to induce loss of HBsAg and acquisition of anti-HBs antibodies. Indoleamine 2,3-dioxygenase (IDO), an enzyme that degrades tryptophan into kynurenine, plays a key role in viral persistence by suppressing effector T cell activity and promoting immunoregulatory pathways. This study aimed to elucidate the role of IDO in modulating immune responses to NASVAC.

Methods

Wild-type and IDO knockout (KO) mice were immunized with NASVAC, and some wild-type mice received an IDO inhibitor. Serum amino acids and anti-HBc and anti-HBs titers, cellular immune responses, splenic CD4/CD8 T cell ratios, and IL-2 production from splenocytes were assessed. Additionally, pretreatment and posttreatment serum samples from NASVAC clinical trial were analyzed for tryptophan and kynurenine levels to assess their association with the efficacy of vaccination.

Results

Genetic deletion of IDO markedly enhanced NASVAC-induced humoral and cellular immune responses in mice, whereas pharmacological inhibition partially increased cellular responses. NASVAC treatment modulated the splenic CD4/CD8 ratio, with more pronounced effects in IDO-KO mice. In human participants, lower pretreatment serum kynurenine level was associated with successful acquisition of anti-HBs following NASVAC administration.

Conclusions

These findings suggest that IDO activity negatively regulates both humoral and cellular immune responses to NASVAC. Modulation or suppression of IDO may potentially enhance the therapeutic efficacy of NASVAC, and serum kynurenine may represent a predictive biomarker for treatment outcomes in chronic HBV infection.

Registry and the Registration No. of the study/trial

The clinical trial was registered in the UMIN Clinical Trials Registry (no. UMIN000027442) and the Japan Registry of Clinical Trials (no. jRCTs061180100).

Abstract Image

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抑制吲哚胺2,3-双加氧酶可增强慢性乙型肝炎治疗性疫苗的免疫应答。

目的：慢性乙型肝炎病毒（HBV）感染仍然是肝硬化和肝细胞癌的主要原因。NASVAC是一种含有乙型肝炎表面抗原（HBsAg）和乙型肝炎核心抗原（HBcAg）的治疗性疫苗，已显示出诱导乙型肝炎表面抗原（HBsAg）丢失和获得抗乙型肝炎抗体的临床潜力。吲哚胺2,3-双加氧酶（IDO）是一种将色氨酸降解为犬尿氨酸的酶，通过抑制效应T细胞活性和促进免疫调节途径在病毒持久性中起关键作用。本研究旨在阐明IDO在调节NASVAC免疫应答中的作用。方法：用NASVAC免疫野生型和IDO敲除（KO）小鼠，部分野生型小鼠注射IDO抑制剂。评估血清氨基酸、抗hbc和抗hbs滴度、细胞免疫应答、脾CD4/CD8 T细胞比率和脾细胞IL-2生成。此外，还分析了NASVAC临床试验前、后血清样本的色氨酸和犬尿氨酸水平，以评估其与疫苗接种效果的关系。结果：IDO基因缺失显著增强了小鼠nasvac诱导的体液和细胞免疫反应，而药物抑制部分增加了细胞反应。NASVAC治疗可调节脾CD4/CD8比值，在IDO-KO小鼠中效果更为明显。在人类受试者中，较低的预处理血清犬尿氨酸水平与服用NASVAC后成功获得抗hbs相关。结论：这些发现提示IDO活性负调控对NASVAC的体液和细胞免疫反应。调节或抑制IDO可能潜在地增强NASVAC的治疗效果，血清犬尿氨酸可能代表慢性HBV感染治疗结果的预测性生物标志物。注册表及注册编号研究/试验的情况：该临床试验已在UMIN临床试验注册中心注册(注册号：UMIN000027442)和日本临床试验注册中心(no。jRCTs061180100)。

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来源期刊

Hepatology Research 医学-胃肠肝病学

CiteScore

8.30

自引率

14.30%

发文量

124

审稿时长

1 months

期刊介绍： Hepatology Research (formerly International Hepatology Communications) is the official journal of the Japan Society of Hepatology, and publishes original articles, reviews and short comunications dealing with hepatology. Reviews or mini-reviews are especially welcomed from those areas within hepatology undergoing rapid changes. Short communications should contain concise definitive information.