title: IFN-α cannot substitute lack of IFN-γ responsiveness in cells of an IFN-γR1 deficient patient.
abstract: Patients with complete IFN-γR deficiency are unable to respond to IFN-γ and have impaired Th1-immunity and recurrent, severe infections with weakly virulent Mycobacteria. Since IFN-α and IFN-γ share signalling pathways, treatment with IFN-α has been proposed in complete IFN-γR deficiency. We stimulated cells from healthy controls and from a patient lacking IFN-γR1 with IFN-α and IFN-γ, to establish whether IFN-α would substitute for IFN-γ effects. IFN-α induced STAT1 phosphorylation in monocytes of the IFN-γR1(-/-) patient, but did not prime for LPS-induced IL-12p70, IL-12p40, IL-23 or TNF production. In control cells, IFN-α inhibited the priming effect of IFN-γ on LPS-induced pro-inflammatory cytokine release. Finally, IFN-γ but not IFN-α induced killing of M. smegmatis in cultured macrophages. In conclusion, no evidence was found to support the use of IFN-α in IFN-γR-deficient patients as intervention against mycobacterial infection; on the contrary, treatment of individuals with IFN-α may even adversely affect host defence against Mycobacteria.
authors.affiliation: Department of Infectious Diseases, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
authors.forename: Diederik
authors.initials: D
authors.lastname: van de Wetering
authors.forename: Annelies
authors.initials: A
authors.lastname: van Wengen
authors.forename: Nigel D L
authors.initials: ND
authors.lastname: Savage
authors.forename: Esther
authors.initials: E
authors.lastname: van de Vosse
authors.forename: Jaap T
authors.initials: JT
authors.lastname: van Dissel
mesh_terms: D002478:Cells, Cultured; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000627:therapeutic use*; D007378:Interleukins / Q000096:biosynthesis / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000382:microbiology; D018950:Lipopolysaccharide Receptors / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000382:microbiology; D009164:Mycobacterium Infections / Q000188:drug therapy* / Q000276:immunology*; D020102:Mycobacterium smegmatis / Q000276:immunology; D017471:Receptors, Interferon / Q000235:genetics*; D050794:STAT1 Transcription Factor / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology; D000096743:Interferon gamma Receptor
chemical_list: D016898:Interferon-alpha; D007371:Interferon-gamma; D007378:Interleukins; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D000096743:Interferon gamma Receptor; C494079:STAT1 protein, human