Programmed death-1 levels correlate with increased mortality, nosocomial infection and immune dysfunctions in septic shock patients

Abstract

IntroductionSeptic shock remains a major health care problem worldwide. Sepsis-induced immune alterations are thought to play a major role in patients' mortality and susceptibility to nosocomial infections. Programmed death-1 (PD-1) receptor system constitutes a newly described immunoregulatory pathway that negatively controls immune responses. It has recently been shown that PD-1 knock-out mice exhibited a lower mortality in response to experimental sepsis. The objective of the present study was to investigate PD-1-related molecule expressions in septic shock patients.MethodsThis prospective and observational study included 64 septic shock patients, 13 trauma patients and 49 healthy individuals. PD-1-related-molecule expressions were measured by flow cytometry on circulating leukocytes. Plasmatic interleukin (IL)-10 concentration as well as ex vivo mitogen-induced lymphocyte proliferation were assessed.ResultsWe observed that septic shock patients displayed increased PD-1, PD-Ligand1 (PD-L1) and PD-L2 monocyte expressions and enhanced PD-1 and PD-L1 CD4+ T lymphocyte expressions at day 1-2 and 3-5 after the onset of shock in comparison with patients with trauma and healthy volunteers. Importantly, increased expressions were associated with increased occurrence of secondary nosocomial infections and mortality after septic shock as well as with decreased mitogen-induced lymphocyte proliferation and increased circulating IL-10 concentration.ConclusionsThese findings indicate that PD-1-related molecules may constitute a novel immunoregulatory system involved in sepsis-induced immune alterations. Results should be confirmed in a larger cohort of patients. This may offer innovative therapeutic perspectives on the treatment of this hitherto deadly disease.

A Novel Role for Programmed Cell Death Receptor Ligand-1 in Sepsis-Induced Intestinal Dysfunction

“…Furthermore, critically injured or septic patients express significantly increased levels of PD-1 and PD-L1 on their peripheral blood leukocytes (7,12,34,35), which appears to be not only associated with severe injury and/or the development of septic shock, but also correlated with UNCORRECTED PROOF Molecular Medicine www.molmed.org mortality seen in these patients. However, whether this is the cause or effect of the development of the septic state cannot be determined from an observational study.…”

Peroxisome Proliferator-activated Receptor γ Co-activator 1-α as a Critical Co-activator of the Murine Hepatic Oxidative Stress Response and Mitochondrial Biogenesis in Staphylococcus aureus Sepsis

“…More recently, the protein was implicated in the immune response to sepsis because the knock-out mice exhibit decreased lymphocyte apoptosis in sepsis (47) and show improved regional and systemic bacterial clearance after cecal ligation and puncture (48). In human patients, differences in mPD-1 levels in sepsis survivors versus nonsurvivors correlate with rates of secondary nosocomial infections (49). Here in mice, we observed greater mPD-1 induction in PGC-1␣ ϩ/Ϫ mice corresponding to the observed increase in hepatocyte apoptosis, yet it remains unclear whether the mPD-1 up-regulation was the proximate cause or merely associated with the apoptosis, for example through possible modulation of the immune response.…”

Critical Illness–Induced Immune Suppression: Current State of the Science

“…Patients with sepsis whose cells demonstrate increased cell surface inhibitory molecule expression are at increased risk for secondary infections and mortality, providing evidence for another distinguishing marker of immune suppression. 47,48 Last, regulatory T cells are a highly immunosuppressive subset of T cells that are known to produce large quantities of anti-inflammatory cytokines. They appear to be resistant to apoptosis and can predominate in the subacute phase of sepsis in adults 49 although this has not been seen in children.…”