免疫检查点在传染病的封锁

StephenW

Immune checkpoint blockade in infectious diseases

    Michelle N. Wykes & Sharon R. Lewin

    Nature Reviews Immunology
    doi:10.1038/nri.2017.112
    Download Citation
        Applied immunologyInfectious diseasesSignal transductionT cells

Published online:
    09 October 2017

Abstract

The upregulation of immune checkpoint molecules, such as programmed cell death protein 1 (PD1) and cytotoxic T lymphocyte antigen 4 (CTLA4), on immune cells occurs during acute infections, such as malaria, as well as during chronic persistent viral infections, including HIV and hepatitis B virus. These pathways are important for preventing immune-driven pathology but can also limit immune-mediated clearance of the infection. The recent success of immune checkpoint blockade in cancer therapy suggests that targeting these pathways would also be effective for preventing and treating a range of infectious diseases. Here, we review our current understanding of immune checkpoint pathways in the pathogenesis of infectious diseases and discuss the potential for therapeutically targeting these pathways in this setting.
Key points

    Immunosuppressive pathways or immune checkpoints refer to inhibitory receptors expressed on immune cells that are crucial for maintaining self-tolerance and modulating the length and magnitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage.

    Immunosuppressive pathways lead to 'exhausted' T cells, which show inferior effector function and poor recall responses. Many pathogens and malignancies use these pathways to evade immunity.

    Immunotherapy is a type of treatment designed to boost the body's natural immune response to fight disease. It currently uses antibodies made in the laboratory to boost immunity against malignancies but has the potential to treat infectious diseases.

    Malarial pathogenesis was recently shown to be dependent on the programmed cell death protein 1 (PD1) pathway. Targeting this pathway with antibodies or programmed cell death 1 ligand 2 (PDL2) protein has shown protection and thus the potential of immunotherapy as a treatment.

    Immune checkpoint markers may play a role in both HIV and hepatitis B virus (HBV) persistence in individuals on antiviral therapy through increased expression on antigen-specific T cells, limiting immune recognition of infected cells and/or production of antibodies.

    Clinical trials of immune checkpoint blockers in chronic HIV and HBV infection are now starting in individuals with malignancy and will be evaluated in the future as potential strategies to induce remission or allow individuals to safely stop antiviral therapy.

"The effects of PD1 blockade in vivo during HBV infection have been evaluated in mouse and woodchuck models. Blockade of the PD1–PDL1 or PD1–PDL2 pathways with anti-PDL1 and anti-PDL2 antibodies in woodchuck hepatitis virus (WHV)-infected animals partially restored T cell function without hepatotoxicity97. In a separate study of WHV, the combination of antivirals (entecavir), therapeutic vaccination and anti-PDL1 antibody blockade, followed by cessation of entecavir, did not result in rebound of WHV in plasma and instead led to the development of antibodies against WHV surface antigens, with complete viral clearance in some animals98. Interestingly, the addition of anti-PDL1 antibody to the vaccine and entecavir arm compared with the vaccine and entecavir alone arm led to a significantly increased immunological and clinical response and was not associated with hepatotoxicity98. These studies look very promising for similar interventions to achieve sustained remission off NRTIs in human clinical trials."

StephenW

免疫检查点在传染病的封锁

Michelle N. Wykes＆Sharon R. Lewin

Nature Reviews免疫学
doi：10.1038 / nri.2017.112
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应用免疫学感染性疾病信号转导T细胞

在线发布：
2017年10月9日

抽象

免疫细胞死亡蛋白1（PD1）和细胞毒性T淋巴细胞抗原4（CTLA4）等免疫检查点分子对免疫细胞的上调发生在急性感染例如疟疾期间，以及慢性持续性病毒感染，包括HIV这些途径对于预防免疫驱动的病理学是重要的，但是也可以限制免疫介导的感染清除。癌症治疗中免疫检查点阻断的最近成功表明，针对这些途径对于预防和治疗一系列传染病也是有效的。在这里，我们回顾了我们目前对传染病发病机制中免疫检查点途径的理解，并讨论了在这种情况下治疗靶向这些途径的可能性。
关键点

免疫抑制途径或免疫检查点是指免疫细胞上表达的抑制性受体，其对维持自身耐受性和调节外周组织中生理性免疫应答的长度和幅度是重要的，以便使附带组织损伤最小化。

免疫抑制途径导致“耗竭”的T细胞，其表现出较差的效应功能和较差的回忆反应。许多病原体和恶性肿瘤使用这些途径来逃避免疫。

免疫疗法是一种旨在提高机体的天然免疫反应来对抗疾病的治疗方法。目前，它使用实验室制造的抗体来增强对恶性肿瘤的免疫力，但有可能治疗感染性疾病。

最近证实，疟疾发病机制依赖于程序性细胞死亡蛋白1（PD1）途径。用抗体或程序性细胞死亡靶向该途径1配体2（PDL2）蛋白已显示出保护作用，因此具有作为治疗的免疫疗法的潜力。

免疫检查点标志物可能通过在抗原特异性T细胞上的表达增加，限制感染细胞的免疫识别和/或抗体的产生而在抗病毒疗法的个体中在HIV和乙型肝炎病毒（HBV）持久性中起作用。

免疫检查点阻滞剂在慢性HIV和HBV感染中的临床试验现在开始于患有恶性肿瘤的个体，并将在未来作为诱导缓解或允许个体安全停止抗病毒治疗的潜在策略进行评估。

已经在小鼠和土拨鼠模型中评估了在HBV感染期间体内PD1阻断的作用。在土拨鼠肝炎病毒（WHV）感染的动物中部分地用抗PDL1和抗PDL2抗体部分阻断PD1-PDL1或PD1-PDL2途径在单独的WHV研究中，抗病毒药物（恩替卡韦），治疗性疫苗接种和抗-PDL1抗体阻断，继而停用恩替卡韦，不会导致血浆中WHV的反弹，反而导致产生针对WHV表面抗原的抗体，在一些动物中完全病毒清除98。有趣的是，与疫苗和恩替卡韦单独手臂相比，抗-PDL1抗体添加到疫苗和恩替卡韦组导致显着增加的免疫学和临床响应，并且与肝毒性无关98。这些研究看起来非常有希望用于类似的干预，以获得人类临床试验中NRTIs的持续缓解。