Abstract
In vivo therapeutic potential of classes B and R inhibitory oligonucleotides (INH-ODH) for animal lupus (131.18)
The Journal of immunology (1950), Vol.178(1_Supplement), pp.S241-S241
04/01/2007
DOI: 10.4049/jimmunol.178.Supp.131.18
Abstract
Abstract TLR receptors are implicated in the pathogenesis of systemic lupus erythematosus. Interestingly, MRL mice lacking TLR9 develop more aggressive kidney disease, while those lacking TLR7 show a milder disease. INH-ODNs (linear, Class B) have recently been developed that can block TLR9 activation at low nanomolar concentrations. This holds true particularly for INH-ODNs made with the nuclease-resistant phosphorothioate backbone (PS). Here we show that (PS)-INH-ODNs, in addition to blocking TLR9 stimulation, can also block TLR7 stimulation of mouse macrophages and B cells induced by several (but not all) TLR7 ligands like imiquimod, loxoribine, CL075, CL097 and CL087. Interestingly, certain TLR7/8 ligands escape inhibition by INH-ODNs and may actually enhance B cell G1-M entry, survival and polyclonal IgM secretion. Both inhibition and enhancement are independent of the TLR9 expression. We have recently refined these ODNs to produce INH-ODN sequences capable of forming stable secondary structures. These “innate” INH-ODNs (Class R) showed higher potency for macrophages, dendritic cells and marginal zone B cells over follicular B cells, in vitro. In vivo, both linear and Class R INH-ODNs provided better survival and ameliorated spontaneous lupus disease in MRL-lpr/lpr mice. This work was supported by NIH grant 1 R56 AI064736-01A2 and by a grant from the Carver Trust fund.
Details
- Title: Subtitle
- In vivo therapeutic potential of classes B and R inhibitory oligonucleotides (INH-ODH) for animal lupus (131.18)
- Creators
- Petar LenertElizabeth R. PareigisSarah SeyferMolly LawryRobert F. Ashman
- Resource Type
- Abstract
- Publication Details
- The Journal of immunology (1950), Vol.178(1_Supplement), pp.S241-S241
- DOI
- 10.4049/jimmunol.178.Supp.131.18
- ISSN
- 0022-1767
- eISSN
- 1550-6606
- Language
- English
- Date published
- 04/01/2007
- Academic Unit
- Immunology; Internal Medicine
- Record Identifier
- 9984363155302771
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