title: Concomitant detection of IFNα signature and activated monocyte/dendritic cell precursors in the peripheral blood of IFNα-treated subjects at early times after repeated local cytokine treatments.
abstract: BACKGROUND
  Interferons alpha (IFNα) are the cytokines most widely used in clinical medicine for the treatment of cancer and viral infections. Among the immunomodulatory activities possibly involved in their therapeutic efficacy, the importance of IFNα effects on dendritic cells (DC) differentiation and activation has been considered. Despite several studies exploiting microarray technology to characterize IFNα mechanisms of action, there is currently no consensus on the core signature of these cytokines in the peripheral blood of IFNα-treated individuals, as well as on the existence of blood genomic and proteomic markers of low-dose IFNα administered as a vaccine adjuvant.
  
  
  METHODS
  Gene profiling analysis with microarray was performed on PBMC isolated from melanoma patients and healthy individuals 24 hours after each repeated injection of low-dose IFNα, administered as vaccine adjuvant in two separate clinical trials. At the same time points, cytofluorimetric analysis was performed on CD14+ monocytes, to detect the phenotypic modifications exerted by IFNα on antigen presenting cells precursors.
  
  
  RESULTS
  An IFNα signature was consistently observed in both clinical settings 24 hours after each repeated administration of the cytokine. The observed modulation was transient, and did not reach a steady state level refractory to further stimulations. The molecular signature observed ex vivo largely matched the one detected in CD14+ monocytes exposed in vitro to IFNα, including the induction of CXCL10 at the transcriptional and protein level. Interestingly, IFNα ex vivo signature was paralleled by an increase in the percentage and expression of costimulatory molecules by circulating CD14+/CD16+ monocytes, indicated as natural precursors of DC in response to danger signals.
  
  
  CONCLUSIONS
  Our results provide new insights into the identification of a well defined molecular signature as biomarker of IFNα administered as immune adjuvants, and for the characterization of new molecular and cellular players, such as CXCL10 and CD14+/CD16+ cells, mediating and possibly predicting patient response to these cytokines.
authors.affiliation: Department of Cell Biology and Neurosciences Istituto Superiore di Sanità, Rome, Italy. eleonora.arico@iss.it
authors.forename: Eleonora
authors.initials: E
authors.lastname: Aricò
authors.forename: Luciano
authors.initials: L
authors.lastname: Castiello
authors.forename: Francesca
authors.initials: F
authors.lastname: Urbani
authors.forename: Paola
authors.initials: P
authors.lastname: Rizza
authors.forename: Monica C
authors.initials: MC
authors.lastname: Panelli
authors.forename: Ena
authors.initials: E
authors.lastname: Wang
authors.forename: Francesco M
authors.initials: FM
authors.lastname: Marincola
authors.forename: Filippo
authors.initials: F
authors.lastname: Belardelli
mesh_terms: D002469:Cell Separation; D018925:Chemokines / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D020869:Gene Expression Profiling; D006684:HLA-DR Antigens / Q000378:metabolism; D017325:Hepatitis B Vaccines / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D007109:Immunity / Q000187:drug effects / Q000235:genetics; D016130:Immunophenotyping; D016898:Interferon-alpha / Q000008:administration & dosage* / Q000494:pharmacology*; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D017452:Receptors, IgG / Q000378:metabolism; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D018925:Chemokines; D006684:HLA-DR Antigens; D017325:Hepatitis B Vaccines; D016898:Interferon-alpha; D018950:Lipopolysaccharide Receptors; D017452:Receptors, IgG