Abstract
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.
Highlights
Sepsis is one of the most common causes of death among critically ill patients leading to estimated $14 billion in annual health care costs in the United States alone and much more worldwide [1]
A study by Zhu et al showed that Cecal Ligation and Puncture (CLP) induced sepsis caused a significant increase in mRNA and protein levels of programmed death ligand-1 (PD-L1) in the liver, which was associated with visible morphological damage; and treatment with anti-PD-L1 attenuated the sepsis induced liver injury [50]
The advent of programmed death-1 (PD-1)/PD-L1 pathway blocking antibodies has been a boon to the field of cancer therapy and numerous PD-1/PD-L1 blocking antibodies from various pharmaceutical companies have been approved by Food Drug Administration to treat human cancers [62]
Summary
Sepsis is one of the most common causes of death among critically ill patients leading to estimated $14 billion in annual health care costs in the United States alone and much more worldwide [1]. New treatment protocols with aggressive supportive therapy rescue the majority of the septicNepwatiternetastmdeunrtinpgrotthoecoelas rwlyithinaflgagmremssaitvoerysupphpaosret,ivbeutthesruarpvyivroersscuaerethtehemnajporroitnyeotfothdeevseeplotipc patients during the early inflammatory phase, but survivors are prone to develop an immunosuppressive phase [18]. Opportunistic pathogens such as Pseudomonas, Candida, Acinetobacter and Enterococcus are common culprits for secondary infections among septic. Opportunistic pathogens such as Pseudomonas, Candida, Acinetobacter and Enterococcus are common culprits for secondary infections among septic patients [10]. One of the major mechanisms for immunosuppression is hypothesized to be increased expression of immune regulatory checkpoints including PD-1, PD-L1, CTLA4 and BTLA, and targeting these negative regulators of immune responses has shown to improve host resistance to infections [15,17,21,22]. Programmed death ligand, PD-L1 and PD-L2 are the known ligands for PD-1 receptor
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