Programmed Death 1 Expression as a Marker for Immune and Physiological Dysfunction in the Critically Ill Surgical Patient

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Invariant natural killer T-cells (iNKT) are a subset of T-cells that play a regulatory role in sepsis. Following cecal ligation and puncture (CLP), iNKT cells emigrate from the liver and into the circulation and peritoneum in a manner dependent upon co-inhibitory molecule Programmed Cell Death Receptor 1 (PD-1). We hypothesized that the effect of PD-1 on iNKT cell emigration was dependent upon the direct PD-1:PD-L1 interaction and that PD-1 and PD-L1 would play a role in chemotaxis and chemokine receptor expression. Adoptive transfer of Vybrant-labelled wild type (WT) cells showed the donor iNKT cells migrated from the liver to the peritoneum following CLP, but PD-L1 deficient donor iNKT cells did not. In a chemotaxis assay, WT iNKT cells chemotaxed to CXCL12, but PD-1 and PD-L1 deficient iNKT cells did not. Using flow cytometry to evaluate chemokine receptor expression, peritoneal iNKT expression of CXCR4 increased following CLP in the WT, PD-1, and PD-L1 deficient animals, and CXCR6 increased in the WT and PD-1 deficient animals. In conclusion here we document that the hepatic emigration of iNKT cells following CLP to the peritoneum appears dependent upon the direct PD-1:PD-L1 interaction, however, while PD-1 and PD-L1 appear to play a role in chemotaxis, this is unlikely a reflection of iNKT cell chemokine receptor expression changes.

Section: Discussionmentioning

confidence: 99%

“…In critically ill septic patients, acute lung injury mortality was associated with increased PD-1 expression on circulating T-cells. An association was also noted between APACHE II scores and expression of PD-1(15). In murine sepsis models, PD-1 affect pulmonary lymphocyte trafficking as well development of acute lung injury(16).…”

Section: Introductionmentioning

confidence: 86%

Effect of PD-1

Young

Heffernan²,

Chung³

et al. 2016

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“…Procalcitonin (PCT) is currently used as a sepsis diagnostic biomarker, but its performance in critically ill patients has been questioned [4]. Consequently, investigators continue to search for additional sepsis biomarkers that can enhance or complement the diagnostic test characteristics of PCT [5][6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Interleukin-27 as a Sepsis Diagnostic Biomarker in Critically Ill Adults

Wong¹,

Lindsell²,

Lahni³

et al. 2013

Purpose-We previously identified interleukin-27 (IL-27) as a sepsis diagnostic biomarker in critically ill children. The current study tested the performance of IL-27 alone and in combination with PCT for diagnosing sepsis in critically ill adults.Methods-Serum samples were made available from a prior prospective study of sepsis biomarkers in critically ill adults. The primary analysis used receiver operating characteristic (ROC) curves to evaluate the performance of IL-27 and PCT. Secondary analysis explored IL-27 performance in subgroups of patients with sepsis secondary to lung and non-lung sources of infection. The net reclassification improvement (NRI) was used to estimate the incremental predictive ability of IL-27 compared to PCT alone. Classification and Regression Tree (CART) analysis was used to generate an IL-27-and PCT-based decision tree. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Results-There AUTHOR CONTRIBUTIONSHRW conceived and developed the study, obtained funding for the study, directly took part in the analyses, and wrote the manuscript. CJL collaborated in the initial design of the study and in obtaining funding, oversaw the statistical analyses, and edited the manuscript. PL conducted all biomarker measurements, managed all biological specimens, and edited the manuscript. KWH assisted with statistical analysis and edited the manuscript. SG was the lead investigator for the original study that generated the prospective database used in the current study, assisted with data analysis, and edited the manuscript. All authors read and approved the final manuscript. AUTHOR COMPETING INTERESTSThe remaining authors have no competing interests to report. adding IL-27 to PCT improved discrimination (NRI = 0.685; p < 0.001). The AUC for the CARTderived decision tree was 0.92 (95% CI: 0.88 -0.96) and was significantly greater than that of PCT alone. NIH Public AccessConclusions-When used in combination with PCT, IL-27 may improve classification of critically ill adults with sepsis secondary to a non-lung source of infection.

“…It has been previously reported that pathogens may utilize PD-1-related molecules to escape from the host's immune defenses. Recently, several studies have reported a relationship between PD-1-related molecules and critically ill patients who either develop septic shock or are significantly injured (13,14,28). If patients with a high 4.…”

Section: Discussionmentioning

confidence: 97%

Perioperative Programmed Death 1 Expression on Cd4+ T Cells Predicts the Incidence of Postoperative Infectious Complications

Kubo

Ono²,

Miyazaki³

et al. 2015

Introduction: Programmed death 1 (PD-1) has been reported to be an immunoinhibitory receptor expressed by chronically stimulated T cells after T-cell activation. The present study was designed to evaluate the relationship between perioperative PD-1 expression on CD4 þ T cells and the incidence of postoperative infectious complications in patients undergoing gastroenterological surgery. Methods: One hundred one patients with gastroenterological disease were enrolled in this study. Blood samples were taken on the preoperative day (Pre) and the first postoperative day (POD1). We calculated the CD4 þ T-cell count and the PD-1 expression on CD4 þ T cells via flow cytometry. Results: Postoperative infectious complications occurred in 30 of the 101 patients. The CD4 þ T-cell count was significantly lower in the patients who developed postoperative infectious complications at POD1 compared with the patients who did not. In addition, the PD-1 expression on CD4 þ T cells was significantly higher at Pre or POD1 in the patients who developed postoperative infectious complications. The preoperative PD-1 expression on CD4 þ Tcells was found to be independently associated with postoperative infectious complications according to multivariate analysis. Conclusions: The perioperative CD4 þ T-cell count or PD-1 expression on CD4 þ T cells may be early predictive markers for the development of postoperative infectious complications.