Interleukin-6 receptor blockage ameliorates murine lupus nephritis

Abstract

The therapeutic effects of a neutralizing monoclonal antibody (mAb) to the interleukin-6 receptor (IL-6R) were examined in the MRL-lpr/lpr murine lupus nephritis model. Animals (15 wk old) were treated with ip mAb IL-6R for 5 wk. GFR in these mice at the end of this treatment period were comparable to those of congenic strain disease-resistant MRL-+/+ controls treated with rat immunoglobulin G (IgG) (254 ± 61 versus 285 ± 26 μL/min; P= not significant). GFR was significantly (P < 0.05) lower in Ipr/lpr mice receiving ip rat IgG (disease controls) at the same time (165 ± 76 μL/min). The fractional mesangial volume (Mv) and surface density of open glomerular capillaries (Sv) in mAb II-6R-treated Ipr/lpr and IgG-treated +/+ mice (Mv, 0.21 ± 0.04 and 0.19 ± 0.04 μm3/μm3; Sv, 0.18 ± 0.01 and 0.20 ± 0.01 μm/μm2, respectively) were similar. However, Mv (0.40 ± 0.04) was significantly higher (P < 0.001) and Sv (0.13 ± 0.04) was lower (P < 0.01) in IgG-treated Ipr/lpr animals. Treatment with mAb IL-6R significantly reduced anti-dsDNA antibody levels after Week 2 of treatment, but these values rebounded at Week 4. The late development of neutralizing antibodies and the increased secretion of IL-6 at Week 4 were likely responsible. Despite these events, neutralizing mAb to the IL-6R proved to be effective therapeutically, as demonstrated by preserved glomerular function and structure.