Abstract 1318: Peptide mimotope of DNA blocks toll like receptor (TLR) 9 activation.
Authors:
H Ben-Zvi, C Aranow, M Mackay, B Diamond.
Background:
Plaquenil works through blocking activation of toll-like receptors on plasmacytoid dendritic cells (PDCs). PDCs, when activated, produce interferon, which then leads to the maturation of myeloid dendritic cells which present antigen to T cells. This study addresses a new technique to block TLR 9, which recognizes DNA-containing immune complexes.
Methods:
A 5 amino acid peptide DWEYS binds anti-DNA antibodies. The D form of DWEYS was studied to see if it could intercalate into DNA-containing immune complexes and block TLR 9 activation.
Results:
3 lupus plasma added to normal PBMCs led to high expression of 3 interferon inducible genes. Pre-treatment with DWEYS blocked this.
Conclusion:
DWEYS can block TLR9 in a dose-dependent manner, abrogating the interferon response.
Editorial Comments:
Currently, Plaquenil remains the major medication for SLE. Our respect for it continues to grow. It is amazing that it was used for 50 years before we really understood what it did – blocking activation of PDCs through toll-like receptors. In addition to a 50% reduction in flares, it reduces progression to SLE, reduces lupus nephritis, and reduces thrombosis. It is able to do all this with great safety – to the point that we call it an immunomodulator, not an immunosuppressive.
Is DWEYS the next Plaquenil? RNA-containing immune complexes activate PDCs through TLR7. Will blocking TLR9 be enough? How much blockade is needed for efficacy, and would this have any safety concerns? This elegant in vitro study can hopefully lead to human trials.
