Department of Medical Microbiology and Immunology, University of Pecs, Medical School, 12 Szigeti Street, Pecs, 7624, Hungary.
Janos Szentagothai Research Centre, Pecs, Hungary.
Clin Exp Med. 2020 May;20(2):219-230. doi: 10.1007/s10238-020-00618-3. Epub 2020 Feb 27.
Chronic hepatitis C (CHC) infection is associated with increased TIM-3, PD-1 immune checkpoint receptors expression that inhibits adaptive T cells and increases NK cell cytotoxicity against T helper cells, both resulting T cell exhaustion. Elimination of the virus with direct-acting antivirals (DAAs) may modify host immune response via altering these immune checkpoint receptors' expression. We conducted a prospective study to analyze changes in TIM-3, PD-1 and their ligands galectin-9, PD-L1 expression by peripheral blood T cell subpopulations, NK cell subpopulations, and monocytes by multicolor flow cytometry in 14 CHC patients successfully treated with 12 weeks of dasabuvir, ombitasvir, and paritaprevir/ritonavir plus ribavirin. Blood samples were collected before, at the end of treatment, and 12 and 24 weeks later. Sustained virological response (SVR) was associated with increased percentage of peripheral blood CD3+ T and CD8+ cytotoxic T lymphocytes and decreased percentage of NKbright cells. After DAA treatment, decreased TIM-3 expression by CD4+ T cells, by NKbright, and by NKT cells was found. Expression of immune checkpoint molecules' ligand PD-L1 by NK cells and by regulatory T cells and galectin-9 by NK cells and monocytes also decreased significantly at SVR. Our data suggest that DAA treatment not only inhibits viral replication but may alter host adaptive and innate immune responses. A decrease in immune checkpoint molecules and their ligands expression both on adaptive and on innate immune cells may contribute to the recovery of exhausted adaptive immune responses and to sustained virological response.
慢性丙型肝炎（CHC）感染与 TIM-3、PD-1 免疫检查点受体表达增加有关，这些受体抑制适应性 T 细胞并增加 NK 细胞对辅助性 T 细胞的细胞毒性，导致 T 细胞耗竭。直接作用抗病毒药物（DAAs）消除病毒可能通过改变这些免疫检查点受体的表达来改变宿主免疫反应。我们进行了一项前瞻性研究，通过多色流式细胞术分析 14 例成功接受 12 周达沙布韦、奥比他韦和帕利昔洛韦/利托那韦联合利巴韦林治疗的 CHC 患者外周血 T 细胞亚群、NK 细胞亚群和单核细胞中 TIM-3、PD-1 及其配体半乳糖凝集素-9、PD-L1 表达的变化。在治疗前、治疗结束时以及 12 和 24 周后采集血液样本。持续病毒学应答（SVR）与外周血 CD3+ T 和 CD8+ 细胞毒性 T 淋巴细胞百分比增加以及 NKbright 细胞百分比降低有关。在 DAA 治疗后，发现 CD4+ T 细胞、NKbright 和 NKT 细胞上的 TIM-3 表达减少。NK 细胞和调节性 T 细胞上的免疫检查点分子配体 PD-L1 以及 NK 细胞和单核细胞上的半乳糖凝集素-9 的表达也在 SVR 时显著降低。我们的数据表明，DAA 治疗不仅抑制病毒复制，还可能改变宿主适应性和先天免疫反应。适应性和先天免疫细胞上免疫检查点分子及其配体表达的减少可能有助于恢复耗竭的适应性免疫反应和持续的病毒学应答。
