A Peptide-Based Checkpoint Immunomodulator Alleviates Immune Dysfunction in Murine Polymicrobial Sepsis. Issue 6 (June 2021)

• Record Type: Journal Article
• Authors: Phares, Timothy W.; Kotraiah, Vinayaka; Chung, Chun-Shiang; Unsinger, Jacqueline; Mazer, Monty; Remy, Kenneth E.; Browne, Cecille D.; Buontempo, Peter; Mansour, Marc; Pannucci, James; Ayala, Alfred; Hotchkiss, Richard S.; Gutierrez, Gabriel M.
• Is Part Of: Shock. Volume 55:Issue 6(2021)
• Publication Date: 2021-06
• Subjects: Immune dysfunction -- immunotherapy -- macrophages -- programmed cell-death protein 1 -- T cells -- CD3 -- α-cluster of differentiation -- CFU -- colony-forming units -- CLP -- cecal-ligation and puncture -- IFN -- interferon -- IL -- interleukin -- IP -- intraperitoneally -- irAEs -- immune-related adverse events -- LAG3 -- lymphocyte activation gene 3 -- mAb -- monoclonal antibodies -- MCP-1 -- monocyte chemoattractant protein-1 -- MPO -- myeloperoxidase -- PBS -- phosphate-buffered saline -- PD-1 -- programmed cell-death protein 1 -- PD-L1 -- programmed death-ligand 1 -- RIH -- Rhode Island Hospital -- TNF-α -- tumor necrosis factor-alpha -- WUSTL -- Washington University in St. Louis; Shock -- Periodicals; Shock -- Periodicals; Choc (Pathologie) -- Périodiques; Shock; Periodicals; 616.0475
• DOI: 10.1097/SHK.0000000000001682
• Languages: English
• ISSNs: 1073-2322

Abstract

Abstract : ABSTRACT: Sepsis-induced immunosuppression involves both innate and adaptive immunity and is associated with the increased expression of checkpoint inhibitors, such as programmed cell-death protein 1 (PD-1). The expression of PD-1 is associated with poor outcomes in septic patients, and in models of sepsis, blocking PD-1 or its ligands with antibodies increased survival and alleviated immune suppression. While inhibitory antibodies are effective, they can lead to immune-related adverse events (irAEs), in part due to continual blockade of the PD-1 pathway, resulting in hyperactivation of the immune response. Peptide-based therapeutics are an alternative drug modality that provide a rapid pharmacokinetic profile, reducing the incidence of precipitating irAEs. We recently reported that the potent, peptide-based PD-1 checkpoint antagonist, LD01, improves T-cell responses. The goal of the current study was to determine whether LD01 treatment improved survival, bacterial clearance, and host immunity in the cecal-ligation and puncture (CLP)-induced murine polymicrobial sepsis model. LD01 treatment of CLP-induced sepsis significantly enhanced survival and decreased bacterial burden. Altered survival was associated with improved macrophage phagocytic activity and T-cell production of interferon-γ. Further, myeloperoxidase levels and esterase-positive cells were significantly reduced in LD01-treated mice. Taken together, these data establish that LD01 modulates host immunity and is a viable therapeutic candidate for alleviating immunosuppression that characterizes sepsis and other infectious diseases.