mRNA-based approach to monitor recombinant gamma-interferon restoration of LPS-induced endotoxin tolerance

Turrel-Davin, Fanny; Venet, Fabienne; Monnin, Cécile; Barbalat, Véronique; Cerrato, Elisabeth; Pachot, Alexandre; Lepape, Alain; Alberti-Segui, Christine; Monneret, Guillaume

doi:10.1186/cc10513

Cited by 32 publications

(50 citation statements)

References 35 publications

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“…The fact that pro- and anti-inflammatory mediators are released simultaneously during the early phase of peritoneal sepsis confirms what was recently noted in animal models of sepsis [20] and septic patients [4,21,22]. The only data available regarding IFNγ and outcome during abdominal infection come from experimental studies and the results are conflicting.…”

Section: Discussionsupporting

confidence: 74%

Local and systemic innate immune response to secondary human peritonitis

et al. 2013

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IntroductionOur aim was to describe inflammatory cytokines response in the peritoneum and plasma of patients with peritonitis. We also tested the hypothesis that scenarios associated with worse outcome would result in different cytokine release patterns. Therefore, we compared cytokine responses according to the occurrence of septic shock, mortality, type of peritonitis and peritoneal microbiology.MethodsPeritoneal and plasma cytokines (interleukin (IL) 1, tumor necrosis factor α (TNFα), IL-6, IL-10, and interferon γ (IFNγ)) were measured in 66 patients with secondary peritonitis.ResultsThe concentration ratio between peritoneal fluid and plasma cytokines varied from 5 (2 to 21) (IFNγ) to 1310 (145 to 3888) (IL-1). There was no correlation between plasma and peritoneal fluid concentration of any cytokine. In the plasma, TNFα, IL-6, IFNγ and IL-10 were higher in patients with shock versus no shock and in nonsurvivors versus survivors (P ≤0.03). There was no differential plasma release for any cytokine between community-acquired and postoperative peritonitis. The presence of anaerobes or Enterococcus species in peritoneal fluid was associated with higher plasma TNFα: 50 (37 to 106) versus 38 (29 to 66) and 45 (36 to 87) versus 39 (27 to 67) pg/ml, respectively (P = 0.02). In the peritoneal compartment, occurrence of shock did not result in any difference in peritoneal cytokines. Peritoneal IL-10 was higher in patients who survived (1505 (450 to 3130) versus 102 (9 to 710) pg/ml; P = 0.04). The presence of anaerobes and Enterococcus species was associated with higher peritoneal IFNγ: 2 (1 to 6) versus 10 (5 to 28) and 7 (2 to 39) versus 2 (1 to 6), P = 0.01 and 0.05, respectively).ConclusionsPeritonitis triggers an acute systemic and peritoneal innate immune response with a simultaneous release of pro and anti-inflammatory cytokines. Higher levels of all cytokines were observed in the plasma of patients with the most severe conditions (shock, non-survivors), but this difference was not reflected in their peritoneal fluid. There was always a large gradient in cytokine concentration between peritoneal and plasma compartments highlighting the importance of compartmentalization of innate immune response in peritonitis.

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Section: Discussionsupporting

confidence: 74%

Local and systemic innate immune response to secondary human peritonitis

et al. 2013

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“…Lipopolysaccharide, LPS) and that become transiently unresponsive to further challenge with endotoxin. Functionally, endotoxin-tolerant monocytes exhibit an increased phagocytic activity, impaired antigen presentation, decrease in secretion of pro-inflammatory cytokines and increase in secretion of anti-inflammatory cytokine [14]–[19].…”

Section: Introductionmentioning

confidence: 99%

Identification of Biomarkers of Response to IFNg during Endotoxin Tolerance: Application to Septic Shock

et al. 2013

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The rapid development in septic patients of features of marked immunosuppression associated with increased risk of nosocomial infections and mortality represents the rational for the initiation of immune targeted treatments in sepsis. However, as there is no clinical sign of immune dysfunctions, the current challenge is to develop biomarkers that will help clinicians identify the patients that would benefit from immunotherapy and monitor its efficacy. Using an in vitro model of endotoxin tolerance (ET), a pivotal feature of sepsis-induced immunosuppression in monocytes, we identified using gene expression profiling by microarray a panel of transcripts associated with the development of ET which expression was restored after immunostimulation with interferon-gamma (IFN-γ). These results were confirmed by qRT-PCR. Importantly, this short-list of markers was further evaluated in patients. Of these transcripts, six (TNFAIP6, FCN1, CXCL10, GBP1, CXCL5 and PID1) were differentially expressed in septic patients’ blood compared to healthy blood upon ex vivo LPS stimulation and were restored by IFN-γ. In this study, by combining a microarray approach in an in vitro model and a validation in clinical samples, we identified a panel of six new transcripts that could be used for the identification of septic patients eligible for IFNg therapy. Along with the previously identified markers TNFa, IL10 and HLA-DRA, the potential value of these markers should now be evaluated in a larger cohort of patients. Upon favorable results, they could serve as stratification tools prior to immunostimulatory treatment and to monitor drug efficacy.

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“…Similarly, recent work highlights a prominent role for epigenetic regulation at different levels such as histone modification and chromatin remodelling 75,76 . In vitro , these epigenetic modifications are restored following IFNγ stimulation and associated with recovery of monocyte cytokine release 76,77 . Thus, IFNγ may abrogate endotoxin tolerance by facilitating TLR-induced chromatin remodelling 78 .…”

Section: Impact Of Sepsis On Immune Cellsmentioning

confidence: 99%

Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy

2013

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Sepsis — severe life-threatening infection with organ dysfunction — initiates a complex interplay of host pro- and anti-inflammatory processes. In a real sense, sepsis can be considered a race to the death between the pathogens and the host immune system. It is the proper balance between the often competing pro- and anti-inflammatory pathways that determines the fate of the individual. Although the field of sepsis research has witnessed the failure of many highly-touted clinical trials, a better understanding of the pathophysiological basis of the disorder and the mechanisms responsible for the associated pro- and anti-inflammatory responses is leading to a novel approach to treat this highly lethal condition. Biomarker-guided immunotherapy administered to patients at the proper immune phase of sepsis represents a potential major advance in the treatment of sepsis and more broadly in the field of infectious disease.

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mRNA-based approach to monitor recombinant gamma-interferon restoration of LPS-induced endotoxin tolerance

Cited by 32 publications

References 35 publications

Local and systemic innate immune response to secondary human peritonitis

Local and systemic innate immune response to secondary human peritonitis

Identification of Biomarkers of Response to IFNg during Endotoxin Tolerance: Application to Septic Shock

Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy

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