Laboratory of Cellular Immunotherapy, Institute of Fundamental and Clinical Immunology, 630099, Novosibirsk, Yadrintsevskaya str., 14, Russia.
Department of the Clinic of Immunopathology of Institute of Fundamental and Clinical Immunology, Novosibirsk, Russia.
Immunol Res. 2018 Feb;66(1):31-43. doi: 10.1007/s12026-017-8967-2.
The key role of T cells in hepatitis C virus (HCV) elimination and the ability of dendritic cells (DCs) to induce antiviral T cell responses suggest that DC vaccines could be a promising approach in the treatment of chronic HCV infection. The aim of our study was to evaluate, whether immunotherapy with DCs is safe and elicits anti-HCV T cell responses. Ten patients with HCV (genotype 1) were vaccinated with monocyte-derived DCs, generated in the presence of IFN-α (IFN-DCs) and pulsed with recombinant HCV Core and NS3 proteins. Treatment schedule included four subcutaneous vaccinations with 1 week interval and six vaccinations with month interval. No serious adverse events or an increase in hepatitis C biochemical activity were registered after vaccination. Using ex vivo assays for the detection of proliferative responses, IFN-γ production and CD8 degranulation have shown that immunotherapy elicited antigen-specific responses in all patients although individual heterogeneity existed within their types, magnitude, and timing. Core/NS3-specific proliferative response and CD8 T cell degranulation have already been registered after the first course of vaccination. Of note, Core-specific responses had higher magnitude. The appearance of antigen-specific IFN-γ responses was registered after the second vaccination course. Vaccination did not cause Th2 response and expansion of the CD4CD25CD127 regulatory T cells. Generated immune responses failed to provide virus elimination. Nevertheless, there were inverse correlations between viral load and NS3-specific proliferation (R = 0.62; p = 0.05) and IFN-γ secretion (R = - 0.82; p = 0.001) at 6-month post-treatment period. Immunotherapy with IFN-DCs was safe and elicited HCV-specific T cell responses which were insufficient to eliminate viruses but could be implicated in the restriction of viral replication.
T 细胞在丙型肝炎病毒（HCV）清除中的关键作用和树突状细胞（DC）诱导抗病毒 T 细胞反应的能力表明，DC 疫苗可能是治疗慢性 HCV 感染的一种有前途的方法。我们的研究目的是评估免疫疗法用 DC 是否安全，并引发抗 HCV T 细胞反应。10 例 HCV（基因型 1）患者接受单核细胞来源的 DC 免疫治疗，这些 DC 在 IFN-α（IFN-DC）存在的情况下生成，并与重组 HCV Core 和 NS3 蛋白脉冲。治疗方案包括 4 次皮下接种，间隔 1 周，6 次间隔 1 个月。接种后未出现严重不良事件或丙型肝炎生化活动增加。使用体外检测增殖反应、IFN-γ产生和 CD8 脱颗粒的方法表明，免疫疗法在所有患者中均引起了抗原特异性反应，尽管其类型、幅度和时间存在个体异质性。在第一疗程接种后，已检测到 Core/NS3 特异性增殖反应和 CD8 T 细胞脱颗粒。值得注意的是，Core 特异性反应的幅度更高。在第二次接种疗程后，出现了抗原特异性 IFN-γ 反应。接种未引起 Th2 反应和 CD4CD25CD127 调节性 T 细胞的扩增。产生的免疫反应未能消除病毒。然而，在治疗后 6 个月时，病毒载量与 NS3 特异性增殖（R = 0.62；p = 0.05）和 IFN-γ 分泌（R = -0.82；p = 0.001）之间存在负相关。IFN-DC 免疫疗法是安全的，并引发了 HCV 特异性 T 细胞反应，这些反应不足以消除病毒，但可能参与限制病毒复制。
