Background/Purpose: Bruton’s tyrosine kinase (BTK) plays an important role in B cell and FcR mediated myeloid cell activation. We recently described a selective BTK inhibitor, BI-BTK-1, that attenuates nephrotoxic serum nephritis, an induced model of renal disease mediated by passively transferred pathogenic antibodies. In the current study, we examined the efficacy of BI-BTK-1 in SLE and lupus nephritis, using the classical NZB × NZW F1 and MRL/lpr mouse models of spontaneous lupus.

Methods: NZB/W F1 female mice were treated with BI-BTK-1 via medicated chow at doses of 0.3, 1, 3, and 10 mg/kg (from 22-51 weeks of age). MRL/lpr female mice were treated with only the 10 mg/kg dose (weeks 9-27). Mice were monitored for proteinuria and serum autoantibodies. Extensive cytometric characterization of B cell subsets in the spleen and bone marrow, and qPCR of kidney RNA, were performed to understand the effects of BTK inhibition on kidney inflammation and the mechanisms of protection.

Results: Treatment with BI-BTK-1 significantly protected NZB/WF1 and MRL/lpr mice from the development of proteinuria (p<0.05 in NZB/WF1 at all doses and p<0.0001 in MRL/lpr mice at 10mg/kg and above) as well as renal dysfunction (serum BUN) at the time of sacrifice (p<0.05 for all doses of BI-BTK-1 vs control chow fed mice in NZB/WF1, and p<0.0004 in MRL/lpr mice). These beneficial effects of BI-BTK-1 were also reflected in the marked histological protection observed in both NZB/WF1 and MRL/lpr strains in glomerular as well as interstitial pathology scores. Mechanistically, BTK inhibition significantly reduced total B cell numbers and all B cell subsets (immature, transitional, follicular, marginal zone, and class switched) in the spleen (p<0.05 for BI-BTK-1 (3 mg/kg and 10 mg/kg) vs control chow fed mice in NZB/WF1 mice). Anti-dsDNA antibody titers were significantly decreased in the NZB/WF1 mice (p<0.05 for BI-BTK-1 (at doses of > 1 mg/kg) vs control treated mice), but surprisingly not significantly affected in the MRL/lpr strain. qPCR of kidney RNA showed that BI-BTK-1 treated mice displayed a significant decrease in several nephritis associated serum biomarkers, including NGAL and MCP-1. Studies to examine the effects of BI-BTK-1 treatment on survival are currently in progress.

Conclusion: Treatment with BI-BTK-1 was dramatically effective in two different spontaneous lupus strains, supporting the potential use of BTK inhibition as a novel approach for the treatment of lupus nephritis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/btk-inhibition-ameliorates-renal-disease-in-spontaneous-murine-lupus-nephritis/