Journal article
Sequence requirements for oligodeoxyribonucleotide inhibitory activity
International immunology, Vol.17(4), pp.411-420
04/2005
DOI: 10.1093/intimm/dxh222
PMID: 15746247
Abstract
Inhibitory oligonucleotides (IN-ODN) differing from stimulatory CpG ODN (ST-ODN) by as few as two bases can block ST-ODN-induced proliferation, apoptosis protection and IL-6 secretion in B lymphocytes and the production of IL-12p40 by non-B cells. The main objective of this study was to determine the ODN sequence requirements for inhibition in mice. Starting with a strongly inhibitory 15-mer prototype phosphorothioate sequence, we tested the 60 sequences that differed from the prototype by one base, revealing the three areas that are critical for activity. Between these areas were the spacer sequences where base composition mattered little, but the number of bases was important. Truncation of three bases at the 3′ end of the 15-mer and one at the 5′ end was tolerated with minimal loss of activity. This approach yielded an ‘optimal’ sequence of 5′ CC x notC notC xxGGGx or CC x notC notC xGGGxx 3′, where x is any base. The sequence requirements for optimal inhibition of B cell responses to Type B (K) ODN and mixed splenocyte IL-12p40 responses to Type A (D) ODN were strikingly similar. Inhibition of ST-ODN by IN-ODN was competitive. A hypothetical model of the ODN-binding site is proposed. Synthetic IN-ODN with the sequence characteristics defined here should provide antidotes for excessive innate reactions to DNA.
Details
- Title: Subtitle
- Sequence requirements for oligodeoxyribonucleotide inhibitory activity
- Creators
- Robert F Ashman - Department of Internal Medicine, Division of Rheumatology, University of Iowa, 200 Hawkins Drive C31 GH, Iowa City, IA 52242, USAJ. Adam Goeken - Department of Internal Medicine, Division of Rheumatology, University of Iowa, 200 Hawkins Drive C31 GH, Iowa City, IA 52242, USAJennifer Drahos - Department of Internal Medicine, Division of Rheumatology, University of Iowa, 200 Hawkins Drive C31 GH, Iowa City, IA 52242, USAPetar Lenert - Department of Internal Medicine, Division of Rheumatology, University of Iowa, 200 Hawkins Drive C31 GH, Iowa City, IA 52242, USA
- Resource Type
- Journal article
- Publication Details
- International immunology, Vol.17(4), pp.411-420
- Publisher
- Oxford University Press
- DOI
- 10.1093/intimm/dxh222
- PMID
- 15746247
- ISSN
- 0953-8178
- eISSN
- 1460-2377
- Language
- English
- Date published
- 04/2005
- Academic Unit
- Pathology; Immunology; Internal Medicine
- Record Identifier
- 9984094628902771
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