Novel chimeric immunomodulatory compounds containing short CpG oligodeoxyribonucleotides have differential activities in human cells
| Autor: | Karen L. Fearon, Jason Marshall, Josh Gregorio, Gary Van Nest, Edith M. Hessel, Christina Abbate, Mabel Chu, Robert L. Coffman, Priscilla Yee |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Oligonucleotides
Alpha interferon Biology Peripheral blood mononuclear cell chemistry.chemical_compound Interferon-gamma Mice Adjuvants Immunologic Interferon Genetics medicine Animals Humans Nucleotide RNA Messenger Lung Cells Cultured chemistry.chemical_classification Regulation of gene expression Mice Inbred BALB C Base Sequence Molecular Structure Oligonucleotide Interferon-alpha Articles Thionucleotides Molecular biology Cell biology chemistry CpG site Gene Expression Regulation Leukocytes Mononuclear CpG Islands Interferons DNA medicine.drug |
| Zdroj: | Nucleic acids research. 31(17) |
| ISSN: | 1362-4962 |
| Popis: | Immunostimulatory DNA sequences (ISS) containing CpG motifs induce interferon-alpha (IFN-alpha) and interferon-gamma (IFN-gamma) from human peripheral blood mononuclear cells and stimulate human B cells to proliferate and produce IL-6. We studied the motif and structural requirements for both types of activity using novel chimeric immunomodulatory compounds (CICs), which contain multiple heptameric ISS connected by non-nucleoside spacers in both linear and branched configurations. We found that the optimal motifs and structure for IFN-alpha production versus B cell activation differed. IFN-alpha production was optimal for CICs containing the sequences 5'-TCGXCGX and 5'-TCGXTCG, where X is any nucleotide. The presentation of multiple copies of these heptameric ISS with free 5'-ends via long, hydrophilic spacers, such as hexaethylene glycol, significantly enhanced the induction of IFN-alpha. Conversely, human B cell activity was predominantly dependent on ISS motif, with 5'-TCGTXXX and 5'-AACGTTC being the most active sequences. Thus, we found CICs could be 'programmed' for IFN-alpha production or B cell activation as independent variables. Additionally, CICs with separate human- and mouse-specific motifs were synthesized and these were used to confirm in vivo activity in mice. CICs may offer unique advantages over conventional ISS because identification of the optimal motifs, spacers and structures for different biological properties allows for the assembly of CICs exhibiting a defined set of activities tailored for specific clinical applications. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|