title: Targeted delivery of CpG ODN to CD32 on human and monkey plasmacytoid dendritic cells augments IFNα secretion.
abstract: Atopic diseases are characterized by the presence of Th2 cells. Recent studies, in mice and man, demonstrated that allergen-specific Th2 responses can be shifted to Th0/Th1 responses. Plasmacytoid dendritic cells (pDCs) produce large amounts of type I interferons (IFNs) after stimulation of Toll Like Receptor 9 (TLR9) and are likely to play an important role in the reorientation of these Th2 cells. The expression of CD32a on the cell surface of pDCs makes this cell type attractive for targeted delivery of antigen and TLR agonists to revert Th2 responses. Therefore we sought to determine the efficacy of targeted delivery of CpG-C ODN to CD32a on the ability of human and monkey pDCs to secrete inflammatory cytokines. Here we demonstrate that targeted delivery of 3'-biotinylated CpG-C to CD32a on pDC induced phenotypical maturation as determined by CD80, CD83 and CD86 expression. Furthermore, targeting both monkey and human pDCs strongly augmented the secretion of IFNα compared to the delivery of CpG-C in an untargeted fashion (p<0.001). TLR9 induced activation hampers the ability of human pDCs to internalize CD32a. Therefore we opted for targeted delivery of CpG-ODNs to CD32a, which reduces the risk of undesired side effects of systemic TLR treatment and in addition delivers a superior signal for the activation of pDCs. This approach opens new treatment principles for allergic patients.
authors.affiliation: Department of Tumor Immunology, Radboud University Nijmegen Medical Centre and Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands.
authors.forename: Jurjen
authors.initials: J
authors.lastname: Tel
authors.forename: Niels
authors.initials: N
authors.lastname: Beenhakker
authors.forename: Gerrit
authors.initials: G
authors.lastname: Koopman
authors.forename: Bert't
authors.initials: B
authors.lastname: Hart
authors.forename: Geert C
authors.initials: GC
authors.lastname: Mudde
authors.forename: I Jolanda M
authors.initials: IJ
authors.lastname: de Vries
mesh_terms: D000818:Animals; D019921:Biotinylation; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D016898:Interferon-alpha / Q000096:biosynthesis*; D008253:Macaca mulatta; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000378:metabolism*; D011961:Receptors, Fc / Q000235:genetics / Q000378:metabolism; D017452:Receptors, IgG / Q000378:metabolism*; D051217:Toll-Like Receptor 9 / Q000378:metabolism
chemical_list: C408982:CPG-oligonucleotide; D016207:Cytokines; C080568:Fc gamma receptor IIA; D018836:Inflammation Mediators; D016898:Interferon-alpha; D009838:Oligodeoxyribonucleotides; D011961:Receptors, Fc; D017452:Receptors, IgG; D051217:Toll-Like Receptor 9