Department of Biomedicine & Health Sciences, The Catholic University Liver Research Center, College of Medicine, POSTECH-Catholic Biomedical Engineering Institute, Seoul, Republic of Korea.
The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
Liver Transpl. 2024 Sep 1;30(9):877-886. doi: 10.1097/LVT.0000000000000378. Epub 2024 Apr 17.
While steroid therapy is the preferred treatment for severe alcohol-associated hepatitis, the role of effector regulatory T (eTreg) cells and their association with steroid response and clinical outcomes in these patients remains to be elucidated. We prospectively enrolled 47 consecutive patients with alcohol-associated hepatitis, consisting of severe alcohol-associated hepatitis treated with steroids (n=18; steroid-treated group) and mild alcohol-associated hepatitis (n=29; nontreated group). After isolating peripheral blood mononuclear cells from the patients at enrollment and again 7 days later, the frequency of eTreg cells was examined using flow cytometry. Single-cell RNA sequencing analysis was conducted using paired peripheral blood mononuclear cells. In vitro experiments were also performed to assess phenotype changes and the suppressive function of Treg cells following steroid treatment. The steroid-treated group exhibited significantly higher Model for End-Stage Liver Disease scores than the nontreated group ( p < 0.01). Within the steroid-treated group, the proportion of eTreg cells significantly expanded in the steroid responders (n=13; p = 0.01). Furthermore, a significant positive correlation was observed between the decrease in the Model for End-Stage Liver Disease score and the increase in eTreg cells ( p < 0.05). Single-cell RNA sequencing using paired peripheral blood mononuclear cells (pre-steroid and post-steroid therapy) from a steroid responder revealed gene expression changes in T cells and monocytes, suggesting enhancement of Treg cell function. In vitro results showed an elevation in the proportion of eTreg cells after steroid therapy. In conclusion, our findings suggest that the efficacy of steroid therapy in patients with severe alcohol-associated hepatitis is mediated by an increase in the number of eTreg cells.
虽然类固醇治疗是治疗严重酒精性肝炎的首选方法，但效应调节性 T（eTreg）细胞的作用及其与这些患者的类固醇反应和临床结局的关系仍有待阐明。我们前瞻性地纳入了 47 例连续的酒精性肝炎患者，包括接受类固醇治疗的严重酒精性肝炎患者（n=18；类固醇治疗组）和轻度酒精性肝炎患者（n=29；未治疗组）。在入组时和 7 天后从患者中分离外周血单核细胞，使用流式细胞术检测 eTreg 细胞的频率。使用配对的外周血单核细胞进行单细胞 RNA 测序分析。还进行了体外实验，以评估类固醇治疗后 Treg 细胞的表型变化和抑制功能。类固醇治疗组的终末期肝病模型评分明显高于未治疗组（p<0.01）。在类固醇治疗组中，类固醇应答者（n=13；p=0.01）的 eTreg 细胞比例显著增加。此外，终末期肝病模型评分的降低与 eTreg 细胞的增加呈显著正相关（p<0.05）。使用类固醇应答者的配对外周血单核细胞（类固醇治疗前和治疗后）进行单细胞 RNA 测序显示 T 细胞和单核细胞的基因表达变化，提示 Treg 细胞功能增强。体外结果显示类固醇治疗后 eTreg 细胞比例升高。总之，我们的研究结果表明，类固醇治疗严重酒精性肝炎患者的疗效是通过增加 eTreg 细胞的数量来介导的。
