title: Identification of biomarkers of response to IFNg during endotoxin tolerance: application to septic shock.
abstract: 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.
authors.affiliation: Joint Unit Hospices Civils de Lyon-Biomérieux « sepsis », Hôpital Edouard Herriot, Lyon, France. florence.frager@biomerieux.com
authors.forename: Florence
authors.initials: F
authors.lastname: Allantaz-Frager
authors.forename: Fanny
authors.initials: F
authors.lastname: Turrel-Davin
authors.forename: Fabienne
authors.initials: F
authors.lastname: Venet
authors.forename: Cécile
authors.initials: C
authors.lastname: Monnin
authors.forename: Amélie
authors.initials: A
authors.lastname: De Saint Jean
authors.forename: Véronique
authors.initials: V
authors.lastname: Barbalat
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Cerrato
authors.forename: Alexandre
authors.initials: A
authors.lastname: Pachot
authors.forename: Alain
authors.initials: A
authors.lastname: Lepape
authors.forename: Guillaume
authors.initials: G
authors.lastname: Monneret
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000097:blood; D003428:Cross Infection / Q000097:blood / Q000235:genetics / Q000276:immunology; D004361:Drug Tolerance; D004731:Endotoxins / Q000276:immunology*; D005260:Female; D059805:HLA-DR alpha-Chains / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology*; D007165:Immunosuppression Therapy / Q000379:methods; D007167:Immunotherapy / Q000379:methods; D007371:Interferon-gamma / Q000276:immunology*; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology; D018805:Sepsis / Q000097:blood / Q000235:genetics / Q000276:immunology*; D012772:Shock, Septic / Q000097:blood / Q000235:genetics / Q000276:immunology*; D059467:Transcriptome; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
chemical_list: D015415:Biomarkers; D004731:Endotoxins; D059805:HLA-DR alpha-Chains; C508609:IL10 protein, human; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma