Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Int J Mol Sci. 2017 Nov 14;18(11):2413. doi: 10.3390/ijms18112413.
Immunosuppression is increasingly being recognized as one of the causes of increased morbidity and mortality during sepsis. Both innate and adaptive immune system dysfunction have been shown to cause an impaired ability to eradicate the primary infection and also lead to frequent occurrence of secondary opportunistic infections. Pre-clinical and clinical studies have shown that inhibitory immune checkpoint molecules, including programmed death-1 (PD-1), programmed death ligand-1 (PD-L1), cytotoxic T lymphocyte antigen-4 (CTLA-4), T cell membrane protein-3 (TIM-3), Lymphocyte activation-gene-3 (LAG-3) and 2B4, are upregulated during the course of sepsis. Engagement of these inhibitory molecules on various immune cells has been consistently shown to inhibit innate immune cell functions (e.g., phagocytosis, cytokine production and pathogen clearance) and also lead to impaired T cell competence. In numerous pre-clinical models of sepsis, therapeutic agents aimed at blocking engagement of inhibitory immune checkpoints on immune cells have been shown to improve innate and adaptive immune cell functions, increase host resistance to infection and significantly improve survival. Therefore, immunotherapy with immune cell checkpoint inhibitors holds significant potential for the future of sepsis therapy and merits further investigation.
免疫抑制被越来越多地认为是脓毒症期间发病率和死亡率增加的原因之一。先天和适应性免疫系统功能障碍已被证明会导致清除原发性感染的能力受损，并且还会导致经常发生继发性机会性感染。临床前和临床研究表明，抑制性免疫检查点分子（包括程序性死亡受体 1（PD-1）、程序性死亡配体 1（PD-L1）、细胞毒性 T 淋巴细胞抗原 4（CTLA-4）、T 细胞膜蛋白 3（TIM-3）、淋巴细胞激活基因 3（LAG-3）和 2B4）在脓毒症过程中上调。在各种免疫细胞上结合这些抑制性分子已被一致证明会抑制先天免疫细胞功能（例如吞噬作用、细胞因子产生和病原体清除），并导致 T 细胞功能受损。在许多脓毒症的临床前模型中，旨在阻断免疫细胞上抑制性免疫检查点结合的治疗剂已被证明可改善先天和适应性免疫细胞功能，增加宿主对感染的抵抗力，并显著提高存活率。因此，免疫细胞检查点抑制剂的免疫疗法为脓毒症治疗的未来提供了巨大的潜力，值得进一步研究。
