A Peptide-Based Checkpoint Immunomodulator Alleviates Immune Dysfunction in Murine Polymicrobial Sepsis.

Autor:	Phares TW; Explorations in Global Health (ExGloH), Leidos Inc, Frederick, Maryland., Kotraiah V; Explorations in Global Health (ExGloH), Leidos Inc, Frederick, Maryland., Chung CS; Lifespan-Rhode Island Hospital, Providence, Rhode Island., Unsinger J; Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri., Mazer M; Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri., Remy KE; Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri.; Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri.; Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri., Browne CD; Leidos Life Sciences, Leidos Inc, Frederick, Maryland., Buontempo P; Explorations in Global Health (ExGloH), Leidos Inc, Frederick, Maryland., Mansour M; MM Scientific Consultants, Inc, Halifax, Nova Scotia, Canada., Pannucci J; Explorations in Global Health (ExGloH), Leidos Inc, Frederick, Maryland., Ayala A; Lifespan-Rhode Island Hospital, Providence, Rhode Island., Hotchkiss RS; Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri.; Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.; Department of Surgery, Washington University School of Medicine, St. Louis, Missouri., Gutierrez GM; Explorations in Global Health (ExGloH), Leidos Inc, Frederick, Maryland.
Jazyk:	angličtina
Zdroj:	Shock (Augusta, Ga.) [Shock] 2021 Jun 01; Vol. 55 (6), pp. 806-815.
DOI:	10.1097/SHK.0000000000001682
Abstrakt:	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. Competing Interests: TWP, VK, CDB, JP, and GMG are employed by the company Leidos, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors report no conflicts of interest. (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Shock Society.)
Databáze:	MEDLINE
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