Antagonizing HMGB1 inhibits proteinuria in a murine model of lupus-like disease (131.24)

Abstract

Abstract High mobility group box 1 (HMGB1) is an abundant chromatin protein that acts like an inflammatory cytokine when it is released by dying or stimulated cells. Elevated levels are detected at sites of inflammation in a number of autoimmune disorders including SLE. In addition, HMGB1 has been shown to contribute to the activation of plasmacytoid dendritic cells as well as B cells, cell types that are implicated in the pathogenesis of SLE. To address the role of HMGB1 in experimental lupus, we investigated the protective efficacy of a fully humanized mAb (IA-4, which recognizes both mouse and human HMGB1) in an IFNα-accelerated lupus model. In this model, adenovirus IFNα-treated NZB/W F1 mice exhibit 90–100% proteinuria incidence at 4–6 weeks post-treatment. The functionality of IA-4 has been demonstrated in vitro by its ability to inhibit rHMGB1-induced IL-6 secretion in human PBMC (IC50 = 0.9 nM). Prophylactic administration of the anti-HMGB1 mAb IA-4 at 10 mg/kg significantly inhibited the proteinuria severity score at seven weeks (65% inhibition; p<0.05 compared to an isotype control). Consistent with the proteinuria data, histopathological assessment of the kidney also revealed protection with IA-4 treatment. Despite its protection in nephritis, IA-4 treatment showed no detectable effect on serum levels of IFN-α and autoantibodies against dsDNA or SSA/Ro. Taken together, these data suggest that HMGB1 is a critical effector molecule in lupus nephritis and that anti-HMGB1 treatment may provide a potential therapeutic benefit for the treatment of SLE.