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II-15 Inhibition of TLR recognition of self nucleic acids by plasmacytoid dendritic cells using oligonucleotide-based inhibitors in lupus
  1. Franck J Barrat
  1. The Hospital for Special Surgery, Auto immunity and Inflammation Program, 535 E.70th St., New York

Abstract

Background SLE is an autoimmune disease where the immune tolerance to self-nucleic acids is broken with devastating consequences. The hallmark of the disease is an increased IFN-α signature in the blood which is accompanied with high levels of autoantibodies and disease activity. Self-nucleic acid recognition by Toll-like receptors (TLR)7 and TLR9 on B cells and plasmacytoid dendritic cells (PDC) is believed to be key in the pathogenesis of SLE promoting immune complexes (IC) and the production of type I IFN, both of which are associated with the severity of the disease.

Results We have generated and described oligonucleotide-based bi-functional inhibitors of TLR7&9 (called ImmunoRegulatory Sequences, IRS) and have shown that these can block IFN production by PDC as well as B cell activation. In addition, IRS are active in vivo and treatment of lupus-prone mice lead to reduced disease symptoms and end-organ damage. SLE patient are often treated with glucocorticoids (GC) but under maintenance levels often suffer from disease flares that necessitate high dose pulse therapy. We have shown that PDC were significantly more resistant to GC induced death in lupus-prone mice, a phenomenon that was completely reversed by pre-treatment with TLR7&9 inhibitor. These data provide a new understanding of the role of self-recognition of DNA and RNA by TLR as an important parameter during inflammatory response. These data also stress the potential utilisation of TLR7&9 specific inhibitors as cortico-sparing drugs which would be open new possibilities with respect to therapeutic applications. Finally, we have shown that IRS can prevent skin lesions following mechanical injury by blocking PDC activation in the skin environment. The lead IRS inhibitor, called DV1179, has entered a human clinical trial and its safety was assessed in multiple ascending doses in healthy volunteers and lupus patients, however no effect on IFN response was observed in lupus patients.

Conclusions These data provide a new understanding of the role of self-recognition of DNA and RNA by TLR as an important parameter during inflammatory response. These data also stress the potential of blocking PDC activation to increase patient’s response to corticosteroid treatment although the use of oligo-nucleotide based inhibitors did not reduce the IFN signature in lupus patients. Other approaches could be tested as well.

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