Immune Deregulation in Sepsis and Septic Shock: Reversing Immune Paralysis by Targeting PD-1/PD-L1 Pathway.
Immune Deregulation in Sepsis and Septic Shock: Reversing Immune Paralysis by Targeting PD-1/PD-L1 Pathway.
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DOI：
10.3389/fimmu.2020.624279
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发表时间：
2020
影响因子：
7.3
通讯作者：
Shimaoka M
中科院分区：
文献类型：
--
作者：
Nakamori Y;Park EJ;Shimaoka M
脓毒症仍然是全球人类健康的一个主要问题，因此表现出很高的发病率和死亡率。脓毒症曾经被认为是一种单相性持续的高炎症反应，目前被认为是一种机体对感染的失调反应，从脓毒症的早期阶段起，高炎症和免疫麻痹同时发生，涉及多个器官功能障碍。尽管最近对脓毒症的病理生理机制的了解取得了进展，但尚未有特效的治疗方法在临床试验中得到验证。近年来，针对肿瘤浸润性T淋巴细胞中的程序性细胞死亡蛋白1/程序性死亡配体(PD-1/PD-L)通路等免疫检查点的治疗在肿瘤免疫治疗领域取得了成功。由于脓毒症的免疫麻痹涉及耗尽的T淋巴细胞，未来检查点抑制剂在脓毒症的临床应用是可望的。此外，PD-1/PD-L对先天淋巴样细胞的作用以及胞外型PD-L1的作用还有待进一步研究。回顾免疫调节治疗脓毒症的临床试验多次失败的历史，必须承认脓毒症是一个难以进行临床试验的疾病实体。可能阻碍候选药物进行有效临床试验的一个主要障碍是疾病的复杂性和异质性；临床诊断的脓毒症可能包含多个脓毒症亚组，这些亚组在不同的器官遭受不同程度的超炎症和免疫抑制。因此，选择合适的、更同质的脓毒症亚组是测试针对特定途径的实验性治疗在炎症和/或免疫麻痹中的临床疗效的关键。人工智能(AI)等新兴技术可能有助于识别最适合使用PD-1/PD-L1途径抑制剂治疗的免疫性瘫痪亚群。
Sepsis remains a major problem for human health worldwide, thereby manifesting high rates of morbidity and mortality. Sepsis, once understood as a monophasic sustained hyperinflammation, is currently recognized as a dysregulated host response to infection, with both hyperinflammation and immunoparalysis occurring simultaneously from the earliest stages of sepsis, involving multiple organ dysfunctions. Despite the recent progress in the understanding of the pathophysiology underlying sepsis, no specific treatment to restore immune dysregulation in sepsis has been validated in clinical trials. In recent years, treatment for immune checkpoints such as the programmed cell death protein 1/programmed death ligand (PD-1/PD-L) pathway in tumor-infiltrating T-lymphocytes has been successful in the field of cancer immune therapy. As immune-paralysis in sepsis involves exhausted T-lymphocytes, future clinical applications of checkpoint inhibitors for sepsis are expected. In addition, the functions of PD-1/PD-L on innate lymphoid cells and the role of exosomal forms of PD-L1 warrant further research. Looking back on the history of repeatedly failed clinical trials of immune modulatory therapies for sepsis, sepsis must be recognized as a difficult disease entity for performing clinical trials. A major obstacle that could prevent effective clinical trials of drug candidates is the disease complexity and heterogeneities; clinically diagnosed sepsis could contain multiple sepsis subgroups that suffer different levels of hyper-inflammation and immune-suppression in distinct organs. Thus, the selection of appropriate more homogenous sepsis subgroup is the key for testing the clinical efficacy of experimental therapies targeting specific pathways in either hyperinflammation and/or immunoparalysis. An emerging technology such as artificial intelligence (AI) may help to identify an immune paralysis subgroup who would best be treated by PD-1/PD-L1 pathway inhibitors.