title: Identification of a novel CpG DNA class and motif that optimally stimulate B cell and plasmacytoid dendritic cell functions.
abstract: Recent reports have identified two major classes of CpG motif-containing oligodeoxynucleotide immunostimulatory sequences (ISS): uniformly modified phosphorothioate (PS) oligodeoxyribonucleotides (ODNs), which initiate B cell functions but poorly activate dendritic cells (DCs) to make interferon (IFN)-alpha, and chimeric PS/phosphodiester (PO) ODNs containing runs of six contiguous guanosines, which induce very high levels of plasmacytoid DC (PDC)-derived IFN-alpha but poorly stimulate B cells. We have generated the first reported ISS, C274, which exhibits very potent effects on all human immune cells known to recognize ISS. C274 is a potent inducer of IFN-gamma/IFN-alpha from peripheral blood mononuclear cells and exhibits accelerated kinetics of activity compared with standard ISS. This ODN also effectively stimulates B cells to proliferate, secrete cytokines, and express costimulatory antigens. In addition, C274 specifically activates PDCs to undergo maturation and secrete cytokines, including very high levels of IFN-alpha. Sequence variation studies based on C274 were used to identify the general motif requirements for this novel and distinct class of ISS. In contrast, chimeric PO/PS CpG-containing ODNs with polyguanosine sequences exert a differential pattern of ISS activity compared with C274, perhaps in part as a result of their greatly different structural nature. This pattern is composed of high IFN-alpha/IFN-gamma induction and low DC maturation in the absence of B cell stimulation. In conclusion, we have generated a novel class of ISS that transcends the limitations ascribed to classes described previously in that it provides excellent stimulation of B cells and simultaneously activates PDCs to differentiate and secrete large amounts of type I IFN.
authors.affiliation: Dynavax Technologies Corporation, Berkeley, California, USA. jmarshall@dvax.com
authors.forename: Jason D
authors.initials: JD
authors.lastname: Marshall
authors.forename: Karen
authors.initials: K
authors.lastname: Fearon
authors.forename: Christi
authors.initials: C
authors.lastname: Abbate
authors.forename: Sandhya
authors.initials: S
authors.lastname: Subramanian
authors.forename: Priscilla
authors.initials: P
authors.lastname: Yee
authors.forename: Josh
authors.initials: J
authors.lastname: Gregorio
authors.forename: Robert L
authors.initials: RL
authors.lastname: Coffman
authors.forename: Gary
authors.initials: G
authors.lastname: Van Nest
mesh_terms: D000276:Adjuvants, Immunologic / Q000737:chemistry / Q000494:pharmacology*; D015703:Antigens, CD / Q000096:biosynthesis; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D001483:Base Sequence; D002478:Cells, Cultured; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D015870:Gene Expression / Q000187:drug effects; D016898:Interferon-alpha / Q000096:biosynthesis / Q000235:genetics; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000145:classification* / Q000494:pharmacology*; D009841:Oligonucleotides / Q000737:chemistry / Q000145:classification / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis
chemical_list: D000276:Adjuvants, Immunologic; D015703:Antigens, CD; C474878:C274 oligonucleotide; C408982:CPG-oligonucleotide; D018925:Chemokines; D016207:Cytokines; D016898:Interferon-alpha; D009838:Oligodeoxyribonucleotides; D009841:Oligonucleotides; D012333:RNA, Messenger; D007371:Interferon-gamma