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A PEPTIDE-BASED CHECKPOINT IMMUNOMODULATOR ALLEVIATES IMMUNE DYSFUNCTION IN MURINE POLYMICROBIAL SEPSIS

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, b...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8284559/
https://www.ncbi.nlm.nih.gov/pubmed/33065715
http://dx.doi.org/10.1097/SHK.0000000000001682
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author 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.
author_facet 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.
author_sort Phares, Timothy W.
collection PubMed
description 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.
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spelling pubmed-82845592021-07-16 A PEPTIDE-BASED CHECKPOINT IMMUNOMODULATOR ALLEVIATES IMMUNE DYSFUNCTION IN MURINE POLYMICROBIAL SEPSIS 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. Shock Article 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. 2021-06-01 /pmc/articles/PMC8284559/ /pubmed/33065715 http://dx.doi.org/10.1097/SHK.0000000000001682 Text en https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
spellingShingle Article
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.
A PEPTIDE-BASED CHECKPOINT IMMUNOMODULATOR ALLEVIATES IMMUNE DYSFUNCTION IN MURINE POLYMICROBIAL SEPSIS
title A PEPTIDE-BASED CHECKPOINT IMMUNOMODULATOR ALLEVIATES IMMUNE DYSFUNCTION IN MURINE POLYMICROBIAL SEPSIS
title_full A PEPTIDE-BASED CHECKPOINT IMMUNOMODULATOR ALLEVIATES IMMUNE DYSFUNCTION IN MURINE POLYMICROBIAL SEPSIS
title_fullStr A PEPTIDE-BASED CHECKPOINT IMMUNOMODULATOR ALLEVIATES IMMUNE DYSFUNCTION IN MURINE POLYMICROBIAL SEPSIS
title_full_unstemmed A PEPTIDE-BASED CHECKPOINT IMMUNOMODULATOR ALLEVIATES IMMUNE DYSFUNCTION IN MURINE POLYMICROBIAL SEPSIS
title_short A PEPTIDE-BASED CHECKPOINT IMMUNOMODULATOR ALLEVIATES IMMUNE DYSFUNCTION IN MURINE POLYMICROBIAL SEPSIS
title_sort peptide-based checkpoint immunomodulator alleviates immune dysfunction in murine polymicrobial sepsis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8284559/
https://www.ncbi.nlm.nih.gov/pubmed/33065715
http://dx.doi.org/10.1097/SHK.0000000000001682
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