The impact of an anti- PD-1 therapy on hepatitis B specific CD4+ and CD8+ T cells.

抗 PD-1 疗法对乙型肝炎特异性 CD4 和 CD8 T 细胞的影响。

• 批准号: 444927137
• 负责人: Dr. Lea Marie Bartsch
• 金额: --
• 依托单位: Division of Gastroenterology
• 依托单位国家: 德国
• 项目类别: WBP Fellowship
• 财政年份: 2020
• 资助国家: 德国
• 起止时间: 2019-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/444927137?language=en
• 关键词: impact; anti; PD; therapy; hepatitis

Although effective hepatitis B vaccines are available for decades, chronic hepatitis B infection remains a worldwide problem. Currently, the global prevalence is around 240 million chronically infected people. Available antiviral hepatitis B therapies are extremely effective in suppressing viral replication. However, they only cure the infection in a minority of patients, so lifelong therapy is required for the majority of patients.In chronic infection, persistent antigen presentation leads to the development of exhausted T cells. A characteristic of virus-specific exhausted T cells is that they express a variety of inhibitory T cell receptors such as the programmed cell death protein 1 (PD-1). Recent studies in cancer demonstrate that T cell exhaustion can be reversed by modern immunotherapy- for example by anti-PD-1 therapy. Thus, anti-PD-1 therapy could be a central component of the therapeutic arsenal for the treatment of chronic hepatitis B infection.This research project will be part of a clinical trial, investigating the influence of anti-PD-1 therapy on chronic hepatitis B infection. Patients with chronic hepatitis B infection will receive anti-PD1 therapy. Liver and blood samples will be collected and analyzed pre- and post-treatment. In parallel, T cells specific for influenza, CMV and EBV will be analyzed in cancer patients, in order to compare the impact of PD-1 therapy on T cells with distinct exhaustion profiles and to study the impact of higher anti-PD-1 doses given in cancer treatment.The phenotype and function of the virus specific T cells will be analyzed by flow cytometric analysis. In addition, single cell sorting will be performed, and changes in transcriptional circuits between pre- and post-treatment will be analyzed. In collaboration with an expert team of close collaborators, highly innovative methods for single-cell analysis will be employed. Highlights of the proposed research project are the parallel investigation of specific T cells in the blood and the site of infection i.e., the liver, and the highly specific nature of the analysis based on detailed knowledge of target antigen and T cell specificity, which is more challenging in human cancer. This research project will allow comprehensive and detailed insights into T cell regulation and exhaustion and will not only explore a new therapeutic strategy for chronic hepatitis B infection, but also improve our fundamental understanding of T cell immunobiology in humans.

尽管有效的乙型肝炎疫苗已问世数十年，但慢性乙型肝炎感染仍然是一个世界性问题。目前，全球慢性感染者患病率约为2.4亿。现有的抗病毒乙型肝炎疗法在抑制病毒复制方面非常有效。然而，它们只能治愈少数患者的感染，因此大多数患者需要终身治疗。在慢性感染中，持续的抗原呈递会导致 T 细胞衰竭。病毒特异性衰竭 T 细胞的一个特征是它们表达多种抑制性 T 细胞受体，例如程序性细胞死亡蛋白 1 (PD-1)。最近的癌症研究表明，现代免疫疗法（例如抗 PD-1 疗法）可以逆转 T 细胞耗竭。因此，抗 PD-1 疗法可能成为治疗慢性乙型肝炎感染的治疗手段的核心组成部分。该研究项目将是一项临床试验的一部分，旨在调查抗 PD-1 疗法对慢性乙型肝炎感染的影响。 慢性乙型肝炎感染患者将接受抗PD1治疗。将在治疗前和治疗后收集并分析肝脏和血液样本。同时，还将在癌症患者中对流感、CMV 和 EBV 特异性 T 细胞进行分析，以比较 PD-1 治疗对具有不同衰竭特征的 T 细胞的影响，并研究癌症治疗中较高抗 PD-1 剂量的影响。将通过流式细胞术分析病毒特异性 T 细胞的表型和功能。此外，还将进行单细胞分选，并分析治疗前后转录回路的变化。将与密切合作者组成的专家团队合作，采用高度创新的单细胞分析方法。拟议研究项目的亮点是对血液中的特异性 T 细胞和感染部位（肝脏）进行并行研究，以及基于对靶抗原和 T 细胞特异性的详细了解进行分析的高度特异性，这在人类癌症中更具挑战性。该研究项目将全面详细地了解 T 细胞调节和耗竭，不仅探索慢性乙型肝炎感染的新治疗策略，还将提高我们对人类 T 细胞免疫生物学的基本了解。