Introduction
Trauma and sepsis remain a major cause of mortality [1]. Early recognition and prompt intervention with supportive measures and improvements in critical care environments have led to some improvement in mortality rates [2]. However, many patients now survive the initial acute phase of treatment, but are left with a prolonged hospital stay, riddled with infective complications [3]. Such a major physiological insult may be the cause of immune dysfunction, which leaves patients susceptible to secondary infections [4-6]. There is now evidence demonstrating that even up to 3 years following the initial insult, patients have persisting immune defects and chronic illness associated with their critical care [7].
This form of immune dysfunction, or tolerance, to microbial danger and pathogen-associated molecular patterns (DAMPs and PAMPs) is characterized by impaired monocyte function [8]. Evidence shows that in response to infection, surgical patients have a downregulation of the toll-like receptor pathway as well as the Inhibitor of Kappa B and Nuclear Factor Kappa B pathways, resulting in impaired immune responses. Decreased monocyte HLA-DR expression and decreased TNF-α production in response to ex-vivo LPS stimulation are both associated with increased nosocomial infections and death in many patients following trauma or sepsis [5, 8].
Various prospective studies have trialed interferon-gamma (IFN-γ) with a goal of restoring monocyte function and improve morbidity or mortality. Such evidence has shown recovery of monocyte function as well as a reduction in re-operations for infection, decreased infection-related deaths and ventilation-associated pneumonia [9-12] However, consistent improvements in mortality in such patients have not been demonstrated and thus IFN-γ, like many other immunoadjuvants, have not succeeded in altering clinical practice [13].
The reasons for a failure to demonstrate benefit may be related to trial design and suboptimal timing and dosing of IFN-γ, or may be related to patient selection (i.e. patients included regardless of monocyte function) [14]. On closer inspection of the clinical trials, it is apparent that the benefit of IFN-γ treatment to monocyte function was present for the duration of treatment. However, on cessation of IFN-γ treatment, a rebound impairment of monocyte function was observed.
An important factor influencing the success of these trials may be the incomplete understanding of mechanisms of pleiotropic agents such as IFN-γ may have on other aspects of our redundant, evolved immune system. Trauma and sepsis affect not only the innate immune cells but also the adaptive immune system [15-17]. In response to such a stimulus, increased PD-1 expression occurs on T-cells, NK cells and B cells [18, 19]. Its ligand, PD-L1, is increased on monocytes, macrophages, dendritic cells and neutrophils [20, 21]. Increases in monocyte PD-L1 expression correlates with impaired monocyte function, increased sequential organ failure assessment scores and are predictive of death during septic shock [22-25].
Such changes in this acute setting are thought to be analogous to changes in the microenvironment in cancer [7, 26]. The activation of the PD-1/PD-L1 pathway causes lymphocyte exhaustion and apoptosis, which may impair cellular function and bacterial clearance. The consequent T-cell dysfunction associated with PD-1/PD-L1 upregulation is associated with septic shock and increased mortality [27, 28]. Animal models of sepsis have shown that ligation of this pathway improves survival, suggesting that the modulation of the PD-1/PD-L1 pathway may be important in governing T-cell function [29-32].
Current thinking for immunotherapy for the critically ill patient is to individualize adjunctive therapy depending on the specific biomarker-driven immunopathologic phenotype of the patient [33], as exemplified by IFN-γ for the patient with monocyte impairment and/or an anti-PD-L1 or IL-7 agent for the patient with T-cell anergy and apoptosis [34]. However, these are overlapping phenomena and understanding how immunotherapy agents influence the multiple facets of the immune response is critical in developing effective trials in the critically ill.
The purpose of this study was to examine IFN-γ in an ex-vivo model of infection to determine the effect of IFN-γ on monocyte PD-L1 expression and determine its influence on T-cell function.