Background and aims Systemic Lupus Erythematosus (SLE) is associated with an increased IFN gene signature detectable in the peripheral blood. Plasmacytoid dendritic cells (pDC) are potent producers of IFNα in response to TLR9 and TLR7-agonists. pDCs which express high levels of CD123 (IL-3Rα) can be depleted by JNJ-56022473 (JNJ-473), a novel Fc-engineered neutralising and depleting therapeutic antibody targeting CD123.
Methods We investigated the effects of pDC depletion with JNJ-473 on IFNα production and gene expression within SLE patient PBMC (n=8) stimulated with TLR-agonists, SLE-immune complexes (IC, SLE IgG with necrotic cell lysates (NCL)) and sera from SLE patients with NCL.
Results Stimulation with CpGc, SLE-IC or SLE sera was able to induce high levels of IFNα, which was greatly decreased by pDC depletion with JNJ-473. SLE-IC and SLE sera stimulation also induced the differential expression of hundreds of genes and could induce similar genes to TLR9-agonism. pDC depletion with JNJ-473 prevented the upregulation of TLR9-induced genes. JNJ-473 conferred minimal effects on the induction of genes in response to the TLR4-agonist LPS. Furthermore, a distinct 11-gene IFN signature was induced by CpGc and SLE-IC that was significantly reduced by treatment with JNJ-473, suggesting that the depletion of pDCs with JNJ-473 could have distinct and specific effects on the detectable IFN signature in many SLE patients.
Conclusions Depletion of pDCs with JNJ-473 is able to dramatically decrease IFNα production and IFN gene signature induced by TLR9-agonists and SLE-IC.
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