Rational design of new CpG oligonucleotides that combine B cell activation with high IFN-alpha induction in plasmacytoid dendritic cells.
Two different types of CpG motif-containing oligonucleotides (CpG ODN) have been described: CpG-A with high induction of IFN-alpha in plasmacytoid dendritic cells; and CpG-B with little induction of IFN-alpha, but potent activation of B cells. In this study, we demonstrate that CpG-A fail to activate B cells unless plasmacytoid dendritic cells are present. We identified a new set of CpG ODN sequences which induces high levels of IFN-alpha in plasmacytoid dendritic cells but remains capable of directly activating B cells. These new CpG ODN (termed CpG-C) are more potent stimulants of B cells than CpG-B due to their ability of directly and indirectly (via plasmacytoid dendritic cells) activating B cells. The sequence of CpG-C combines structural elements of both CpG-A and CpG-B. The most potent sequence, M362, contains a 5'-end 'TCGTCG-motif' and a 'GTCGTT-motif', both of which are present in CpG-B (ODN 2006); a palindromic sequence characteristic for CpG-A (ODN 2216); but no poly G motif required for CpG-A. In conclusion, we defined the first CpG-containing sequences that potently activate both TLR9-expressing immune cell subsets in humans, the plasmacytoid dendritic cell and the B cell. CpG-C may allow for improved therapeutic immuno-modulation in vivo.
Hartmann
Gunther
G
Department of Internal Medicine, Division of Clinical Pharmacology, Ludwig-Maximilians-University of Munich, Germany. ghartmann@lrz.uni-muenchen.de
Battiany
Julia
J
Poeck
Hendrik
H
Wagner
Moritz
M
Kerkmann
Miren
M
Lubenow
Norbert
N
Rothenfusser
Simon
S
Endres
Stefan
S
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D051940:B7-2 Antigen; D001483:Base Sequence; D018899:CpG Islands / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000502:physiology; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D004306:Dose-Response Relationship, Immunologic; D015195:Drug Design; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D016898:Interferon-alpha / Q000096:biosynthesis* / Q000235:genetics; D008213:Lymphocyte Activation / Q000187:drug effects*; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D008875:Middle Aged; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000502:physiology; D013329:Structure-Activity Relationship; D051217:Toll-Like Receptor 9
D000276:Adjuvants, Immunologic; D015703:Antigens, CD; D051940:B7-2 Antigen; C497964:CD86 protein, human; C408982:CPG-oligonucleotide; D004268:DNA-Binding Proteins; D016898:Interferon-alpha; D008562:Membrane Glycoproteins; D009838:Oligodeoxyribonucleotides; D011956:Receptors, Cell Surface; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9