Monocyte deactivation in septic patients: Restoration by IFN-γ treatment

Abstract

Neutralization of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha) or interleukin-1 (IL-1), decreases mortality in several animal models of sepsis. However, recent clinical trials did not show an unequivocal improvement in survival. In contrast to animals, which succumb to shock during the first 72 hours, we found that many patients die much later with signs of opportunistic infections accompanied by downregulation of their monocytic HLA-DR expression and reduced ability to produce lipopolysaccharide (LPS)-induced TNF-alpha in vitro. This phenomenon of monocyte deactivation in septic patients with fatal outcome shows similarities to experimental monocytic refractoriness induced by LPS desensitization or by pretreatment with its endogenous mediators IL-10 and transforming growth factor-beta (TGF-beta). In order to strengthen their antimicrobial defense, here we tested whether interferon-gamma (IFN-gamma) can improve monocytic functions in these patients and in experimental monocytic deactivation. The considerably lowered in vitro levels of LPS-induced TNF-alpha in these situations were significantly enhanced by IFN-gamma, but did not reach the extremely high levels of IFN-gamma primed naive cells from healthy donors. Moreover, IFN-gamma applied to septic patients with low monocytic HLA-DR expression restored the deficient HLA-DR expression and in vitro LPS-induced TNF-alpha secretion. Recovery of monocyte function resulted in clearance of sepsis in eight of nine patients. These data suggest that IFN-gamma treatment in carefully selected septic patients is a novel therapeutic strategy worth pursuing.

Interleukin-1β inducesin vivotolerance to lipopolysaccharide in mice

“…It has recently been suggested that patients which succumb to septic shock after 72 h have similar clinical signs of endotoxin tolerance, and it has also been determined that the treatment of septic patients with IFN-g restored both deficient HLA-DR expression and LPS-induced TNF-a secretion in vitro [14]. All these data strongly suggest that more detailed studies on the mechanisms involved in tolerance to LPS would be beneficial for the management of sepsis or septic shock.…”

“…Despite the fact that host mechanisms responsible for LPS tolerance are not well understood, they seem to be crucial for patients with sepsis [3]. In fact, deactivation of monocytes in these late-stage sepsis patients, who die much later with signs of opportunistic infections, is accompanied by down-regulation of HLA-DR expression, loss of antigen-presenting capacity, and a profound reduction in their ability to produce LPS-induced TNF-a in vitro [3,14].…”

Immunoparalysis and Adverse Outcomes from Critical Illness

“…While a normal monocyte will produce copious amounts of TNFα when exposed to LPS, an immunoparalyzed monocyte will not [28][29][30][31][32][33]. This approach suffers from a lack of standardization across investigators.…”

Measurement of monocytic HLA-DR (mHLA-DR) expression in patients with severe sepsis and septic shock: assessment of immune organ failure

“…This state of sepsis-induced immunosuppression is triggered and supported by elevated levels of endotoxin and anti-inflammatory cytokines, characterised by a functional failure of innate and adaptive immunity [4], and is associated with increased mortality from sepsis [7,8]. Data from recent immunomodulatory trials show that this condition can be reversed by both immunostimulation [9][10][11] or reduction of inhibitory factors [12].…”