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.