title: Long-term in vitro and in vivo effects of γ-irradiated BCG on innate and adaptive immunity.
abstract: BCG vaccination is associated with a reduced mortality from nonmycobacterial infections. This is likely to be mediated by a combination of innate-immune memory ("trained immunity") and heterologous effects on adaptive immunity. As such, BCG could be used to boost host immunity but not in immunocompromised hosts, as it is a live, attenuated vaccine. Therefore, we assessed whether killed γBCG has similar potentiating effects. In an in vitro model of trained immunity, human monocytes were incubated with γBCG for 24 h and restimulated after 6 d. Cytokine production and the role of pattern recognition receptors and histone methylation markers were assessed. The in vivo effects of γBCG vaccination were studied in a proof-of-principle trial in 15 healthy volunteers. γBCG induced trained immunity in vitro via the NOD2 receptor pathway and up-regulation of H3K4me3 histone methylation. However, these effects were less strong than those induced by live BCG. γBCG vaccination in volunteers had only minimal effects on innate immunity, whereas a significant increase in heterologous Th1/Th17 immunity was observed. Our results indicate that γBCG induces long-term training of innate immunity in vitro. In vivo, γBCG induces mainly heterologous effects on the adaptive-immune system, whereas effects on innate cytokine production are limited.
authors.affiliation: Departments of *Internal Medicine and Gastroenterology, Radboud University Medical Center, Nijmegen, The Netherlands; Research Center for Vitamins and Vaccines, Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark; and Odense Patient Data Explorative Network, University of Southern Denmark/Odense University Hospital, Copenhagen, Denmark.
authors.forename: Rob J W
authors.initials: RJ
authors.lastname: Arts
authors.affiliation: Departments of *Internal Medicine and Gastroenterology, Radboud University Medical Center, Nijmegen, The Netherlands; Research Center for Vitamins and Vaccines, Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark; and Odense Patient Data Explorative Network, University of Southern Denmark/Odense University Hospital, Copenhagen, Denmark.
authors.forename: Bastiaan A
authors.initials: BA
authors.lastname: Blok
authors.affiliation: Departments of *Internal Medicine and Gastroenterology, Radboud University Medical Center, Nijmegen, The Netherlands; Research Center for Vitamins and Vaccines, Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark; and Odense Patient Data Explorative Network, University of Southern Denmark/Odense University Hospital, Copenhagen, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Aaby
authors.affiliation: Departments of *Internal Medicine and Gastroenterology, Radboud University Medical Center, Nijmegen, The Netherlands; Research Center for Vitamins and Vaccines, Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark; and Odense Patient Data Explorative Network, University of Southern Denmark/Odense University Hospital, Copenhagen, Denmark.
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
authors.affiliation: Departments of *Internal Medicine and Gastroenterology, Radboud University Medical Center, Nijmegen, The Netherlands; Research Center for Vitamins and Vaccines, Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark; and Odense Patient Data Explorative Network, University of Southern Denmark/Odense University Hospital, Copenhagen, Denmark.
authors.forename: Dirk
authors.initials: D
authors.lastname: de Jong
authors.affiliation: Departments of *Internal Medicine and Gastroenterology, Radboud University Medical Center, Nijmegen, The Netherlands; Research Center for Vitamins and Vaccines, Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark; and Odense Patient Data Explorative Network, University of Southern Denmark/Odense University Hospital, Copenhagen, Denmark.
authors.forename: Jos W M
authors.initials: JW
authors.lastname: van der Meer
authors.affiliation: Departments of *Internal Medicine and Gastroenterology, Radboud University Medical Center, Nijmegen, The Netherlands; Research Center for Vitamins and Vaccines, Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark; and Odense Patient Data Explorative Network, University of Southern Denmark/Odense University Hospital, Copenhagen, Denmark.
authors.forename: Christine Stabell
authors.initials: CS
authors.lastname: Benn
authors.affiliation: Departments of *Internal Medicine and Gastroenterology, Radboud University Medical Center, Nijmegen, The Netherlands; Research Center for Vitamins and Vaccines, Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark; and Odense Patient Data Explorative Network, University of Southern Denmark/Odense University Hospital, Copenhagen, Denmark.
authors.forename: Reinout
authors.initials: R
authors.lastname: van Crevel
authors.affiliation: Departments of *Internal Medicine and Gastroenterology, Radboud University Medical Center, Nijmegen, The Netherlands; Research Center for Vitamins and Vaccines, Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark; and Odense Patient Data Explorative Network, University of Southern Denmark/Odense University Hospital, Copenhagen, Denmark mihai.netea@radboudumc.nl.
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects*; D000328:Adult; D016207:Cytokines / Q000276:immunology; D005260:Female; D005720:Gamma Rays; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D008297:Male; D009163:Mycobacterium bovis / Q000276:immunology*; D053473:Nod2 Signaling Adaptor Protein / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D016207:Cytokines; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein
keywords: heterologous immunity; nonspecific vaccination effects; trained immunity