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

尽管有效的B型肝炎疫苗已经问世几十年，但慢性B型肝炎感染仍然是一个世界性的问题。目前，全球流行率约为2.4亿慢性感染者。现有的抗病毒B型肝炎治疗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，持续的抗原呈递导致T细胞耗竭。病毒特异性耗竭T细胞的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，T细胞耗竭可以通过现代免疫疗法逆转-例如通过抗PD-1疗法。因此，抗PD-1治疗可能是治疗慢性B型肝炎感染的治疗武器库的核心组成部分。本研究项目将是临床试验的一部分，研究抗PD-1治疗对慢性B型肝炎感染的影响。 慢性B型肝炎感染患者将接受抗PD 1治疗。将在治疗前后采集肝脏和血液样本并进行分析。同时，将在癌症患者中分析流感、CMV和EBV特异性T细胞，以比较PD-1治疗对具有不同耗竭特征的T细胞的影响，并研究在癌症治疗中给予更高抗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，将进行单细胞分选，并分析处理前和处理后之间转录回路的变化。在与密切合作者组成的专家团队的合作下，将采用高度创新的单细胞分析方法。拟议研究项目的重点是对血液中的特定T细胞和感染部位进行平行研究，即，肝脏，以及基于靶抗原和T细胞特异性的详细知识的分析的高度特异性，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细胞的调节和耗竭，不仅将探索慢性B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理解。

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.