Protozoa Immunology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
Front Immunol. 2022 Jun 23;13:866120. doi: 10.3389/fimmu.2022.866120. eCollection 2022.
Chagas disease (CD) is a neglected chronic infection caused by the protozoan parasite (). A significant portion of infected people develops cardiac or digestive alterations over a lifetime. Since several chronic infections associated with antigen persistence and inflammation have been shown to lead to T cell exhaustion, new therapies targeting co-inhibitory receptors to regain T cell activity are under consideration. This study explored immune therapeutic approaches targeting the inhibitory PD-1/PD-L pathway in an experimental model for CD. Infected PD-L1 knockout mice (PD-L1 KO) showed increased systemic parasitemia in blood although no significant differences in parasite load were observed in different organs. Furthermore, we found no significant differences in the frequency of activated T cells or proinflammatory cytokine production when compared to WT counterparts. PD-L1 deficiency led to the production of IL-10 by CD8 T cells and an upregulation of Tim-3 and CD244 (2B4). Unexpectedly, the lack of PD-L1 did not contribute to a significantly improved T cell response to infection. Single blockade and combined blockade of PD-1 and Tim-3 using monoclonal antibodies confirmed the results observed in infected. PD-L1 KO mice. Our results describe for the first time that the interruption of the PD-1/PD-L1 axis during acute infection does not necessarily enhance the immune response against this parasite. Its interruption favors increased levels of parasitemia and sustained upregulation of other co-inhibitory receptors as well as the production of regulatory cytokines. These results suggest that the clinical application of immune therapeutic approaches targeting the axis in CD might be risky and associated with adverse events. It highlights that more research is urgently needed to better understand the immune regulation of T cells in CD before designing immune therapeutic approaches for a clinical context.
恰加斯病（CD）是一种由原生动物寄生虫引起的被忽视的慢性感染。相当一部分感染者在一生中会发展出心脏或消化系统的改变。由于已经证明几种与抗原持续存在和炎症相关的慢性感染会导致 T 细胞衰竭，因此正在考虑针对共抑制受体来恢复 T 细胞活性的新治疗方法。本研究探讨了针对 CD 实验模型中抑制性 PD-1/PD-L 途径的免疫治疗方法。感染 PD-L1 敲除小鼠（PD-L1 KO）尽管在不同器官中未观察到寄生虫负荷的显着差异，但血液中的全身性寄生虫血症增加。此外，与 WT 对应物相比，我们发现活化 T 细胞或促炎细胞因子产生的频率没有显着差异。PD-L1 缺乏导致 CD8 T 细胞产生 IL-10，并上调 Tim-3 和 CD244（2B4）。出乎意料的是，缺乏 PD-L1并没有导致对感染的 T 细胞反应明显改善。使用单克隆抗体对 PD-1 和 Tim-3 进行单独阻断和联合阻断，证实了在感染的 PD-L1 KO 小鼠中观察到的结果。我们的结果首次描述了在急性感染期间中断 PD-1/PD-L1 轴不一定会增强针对这种寄生虫的免疫反应。它有利于寄生虫血症水平升高和其他共抑制受体的持续上调以及调节性细胞因子的产生。这些结果表明，在设计针对 CD 的免疫治疗方法的临床背景之前，针对该轴的免疫治疗方法的临床应用可能存在风险，并与不良事件相关。它强调了在设计针对 CD 的免疫治疗方法的临床背景之前，迫切需要进行更多的研究，以更好地了解 CD 中 T 细胞的免疫调节。
