Background/Purpose:

Renal disease with loss of organ function results in significant morbidity and mortality in SLE. In the kidneys of affected patients, autoantibody-containing immune complexes (ICs) trigger pathological changes via activation of complement cascades and Fc receptors on resident and infiltrating cells. Bruton’s tyrosine kinase (BTK) is a tyrosine kinase important for B cell development, Fc receptor signaling, and macrophage polarization. In this study, we explore the role of BTK in the pathogenesis of nephritis in an inducible model of lupus nephritis (LN).   

Methods:

We investigated the effects of a novel, highly selective and potent (mouse whole blood CD69 IC₅₀= 13±2 nM) BTK inhibitor, BI-BTK-1 (Boehringer Ingelheim), in female 129 sv/J mice (10 weeks of age) injected with nephrotoxic serum (NTS), an experimental model which closely mimics LN. Mice pre-immunized with rabbit IgG (Day 0) were administered NTS containing rabbit anti-mouse glomerular antibodies (Day 5), inducing a severe IC-mediated crescentic glomerulonephritis. Mice were treated once daily with vehicle alone or BI-BTK-1 (0.3-10 mg/kg, n=16/group), beginning on Day 4. In addition, mice that did not receive the NTS transfer were used as healthy controls. 

Results:

NTS-challenged mice treated with BI-BTK-1 exhibited a statistically significant, dose responsive protection from kidney disease compared to control treated mice, despite equal levels of glomerular IgG deposition and mouse anti-rabbit IgG in all experimental groups. Compared to control treated mice, NTS-challenged mice treated with 10 mg/kg BI-BTK-1 had significantly less proteinuria (1220 mg/dl vs 10 mg/dl, respectively, p<0.0005), serum creatinine (0.74 mg/dl vs 0.48 mg/dl, respectively, p<0.03), and BUN (82 mg/dl vs 25 mg/dl, respectively, p<0.03) (Day 11). Histology assessment confirmed marked renal protection in the BI-BTK-1 treatment groups, as evidenced by significantly less immune deposition (p<0.0001), endocapillary proliferation (p<0.0001), glomerular crescent formation (p<0.0001), interstitial inflammation (p<0.002), and tubular casts/dilatation (p<0.0001). Flow cytometry analysis showed decreased recruitment of inflammatory monocytes from the splenic reservoir in BI-BTK-1 treated mice. Furthermore, serum profiling and kidney gene expression analyses revealed that BTK inhibition was associated with a significant decrease in the levels of key LN-relevant inflammatory cytokines and chemokines (e.g. MIP-1a, MCP-1 and CSF-1). 

Conclusion:

Our results suggest an important role for BTK activation in myeloid cells in the pathogenesis of immune complex-mediated nephritis. Studies to examine the effect of treatment initiation after the development of nephritis are now in progress.  Taken together with previously published studies, these findings further strengthen the rationale for selective BTK inhibition as a promising approach to the treatment of LN.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/blockade-of-immune-complex-mediated-glomerulonephritis-by-highly-selective-inhibition-of-brutons-tyrosine-kinase/