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Critical Care

, 18:R3

First Online: 04 January 2014Received: 31 August 2013Accepted: 19 December 2013

Abstract

IntroductionA major pathophysiologic mechanism in sepsis is impaired host immunity which results in failure to eradicate invading pathogens and increased susceptibility to secondary infections. Although many immunosuppressive mechanisms exist, increased expression of the inhibitory receptor programmed cell death 1 PD-1 and its ligand PD-L1 are thought to play key roles. The newly recognized phenomenon of T cell exhaustion is mediated in part by PD-1 effects on T cells. This study tested the ability of anti-PD-1 and anti-PD-L1 antibodies to prevent apoptosis and improve lymphocyte function in septic patients.

MethodsBlood was obtained from 43 septic and 15 non-septic critically-ill patients. Effects of anti-PD-1, anti-PD-L1, or isotype-control antibody on lymphocyte apoptosis and interferon gamma IFN-γ and interleukin-2 IL-2 production were quantitated by flow cytometry.

ResultsLymphocytes from septic patients produced decreased IFN-γ and IL-2 and had increased CD8 T cell expression of PD-1 and decreased PD-L1 expression compared to non-septic patients P<0.05. Monocytes from septic patients had increased PD-L1 and decreased HLA-DR expression compared to non-septic patients P<0.01. CD8 T cell expression of PD-1 increased over time in ICU as PD-L1, IFN-γ, and IL2 decreased. In addition, donors with the highest CD8 PD-1 expression together with the lowest CD8 PD-L1 expression also had lower levels of HLA-DR expression in monocytes, and an increased rate of secondary infections, suggestive of a more immune exhausted phenotype. Treatment of cells from septic patients with anti-PD-1 or anti-PD-L1 antibody decreased apoptosis and increased IFN-γ and IL-2 production in septic patients; P<0.01. The percentage of CD4 T cells that were PD-1 positive correlated with the degree of cellular apoptosis P<0.01.

ConclusionsIn vitro blockade of the PD-1:PD-L1 pathway decreases apoptosis and improves immune cell function in septic patients. The current results together with multiple positive studies of anti-PD-1 and anti-PD-L1 in animal models of bacterial and fungal infections and the relative safety profile of anti-PD-1-anti-PD-L1 in human oncology trials to date strongly support the initiation of clinical trials testing these antibodies in sepsis, a disorder with a high mortality.

AbbreviationsALCAbsolute lymphocyte count

CDCluster of differentiation

CINSCritically-ill non-septic

HLA-DRHuman leukocyte antigen-DR

IFN-γInterferon gamma

IL-2Interleukin 2

IQRInterquartile range

NKNatural killer cells

NKTNatural killer T cells

PBMCsPeripheral blood mononuclear cells

PD-1Programmed cell death 1

PD-L1Programmed cell death ligand 1

TCRT cell receptor.

Electronic supplementary materialThe online version of this article doi:10.1186-cc13176 contains supplementary material, which is available to authorized users.

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Author: Katherine Chang - Catherine Svabek - Cristina Vazquez-Guillamet - Bryan Sato - David Rasche - Strother Wilson - Paul Robbin

Source: https://link.springer.com/







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