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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Li, Yukui Sullivan, Tim Cong, Yan-ping Tang, Jimmy X. Agrawal, Sudhir Song, Sam S. Kandimalla, Ekambar R. Wang, Daqing Yu, Dong Bhagat, Lakshmi |
| Description | Author Affiliation: Kandimalla ER ( Hybridon, Inc., 345 Vassar Street, Cambridge, MA 02139, USA.); |
| Abstract | Bacterial DNA and synthetic oligomers containing CpG dinucleotides activate the immune system through Toll-like receptor (TLR) 9. Here, we compare the immunostimulatory activity of three immunomers with different nucleotide sequences containing a synthetic cytosine-phosphate-2'-deoxy-7-deazaguanosine dinucleotide (CpR), called immunomodulatory oligonucleotides (IMOs), in mouse, human, and monkey systems. IMOs induced IL-12 and IFN-gamma secretion more than a control non-CpG IMO in mice. All three IMOs activated HEK293 cells expressing TLR9 but not TLR3, -7, or -8. IMOs induced human B-cell proliferation and enhanced expression of CD86 and CD69 surface markers on B cells. The three IMOs induced CD86 expression on human plasmacytoid dendritic cells, but only IMOs that contained a 5'-terminal TCR nucleotide sequence induced IFN-alpha secretion. A sequence that forms a duplex structure also was required for IFN-alpha induction in human peripheral blood mononuclear cell cultures. IMOs induced chemokine and cytokine gene expression in human peripheral blood mononuclear cells. In monkeys, all three IMOs induced transient changes in peripheral blood leukocytes and lymphocytes and activated B and T lymphocytes. All three IMOs induced IFN-alpha in vivo in monkeys; the IMO sequence that forms a stable secondary structure induced the highest levels of IFN-alpha. These studies are, to our knowledge, the first comprehensive studies to compare the activity of IMOs containing synthetic stimulatory CpR dinucleotides in mouse, monkey, and human systems. These results suggest that IMOs induce strong and rapid immunostimulation and that the CpR dinucleotide is recognized by TLR9, leading to immune-cell activation and cytokine secretion in vitro and in vivo. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 19 |
| Volume Number | 102 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2005-05-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Cytokines Chemistry DNA-Binding Proteins Agonists Deoxyguanosine Analogs & Derivatives Oligonucleotides Receptors, Cell Surface Animals Antigens, CD Biosynthesis Antigens, CD86 Antigens, Differentiation, T-Lymphocyte B-Lymphocytes Cytology Metabolism Cell Line Cell Proliferation Chemokines CpG Islands Dendritic Cells Dose-Response Relationship, Drug Enzyme-Linked Immunosorbent Assay Flow Cytometry Gene Expression Regulation Haplorhini Interferon-gamma Interleukin-12 Lectins, C-Type Leukocytes, Mononuclear Lymphocytes Membrane Glycoproteins Mice Mice, Inbred C57BL Molecular Sequence Data Nucleotides Protein Binding RNA, Messenger Time Factors Toll-Like Receptor 3 Toll-Like Receptor 9 Toll-Like Receptors Up-Regulation Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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