Abstract
Lupus nephritis (LN) is a potentially dangerous end organ pathology that affects upwards of 60% of lupus patients. Bruton’s tyrosine kinase (BTK) is important for B cell development, Fc receptor signaling, and macrophage polarization. In this study, we investigated the effects of a novel, highly selective and potent BTK inhibitor, BI-BTK-1, in an inducible model of LN in which mice receive nephrotoxic serum (NTS) containing anti-glomerular antibodies. Mice were treated once daily with vehicle alone or BI-BTK-1, either prophylactically or therapeutically. When compared with control treated mice, NTS-challenged mice treated prophylactically with BI-BTK-1 exhibited significantly attenuated kidney disease, which was dose dependent. BI-BTK-1 treatment resulted in decreased infiltrating IBA-1+ cells, as well as C3 deposition within the kidney. RT-PCR on whole kidney RNA and serum profiling indicated that BTK inhibition significantly decreased levels of LN-relevant inflammatory cytokines and chemokines. Renal RNA expression profiling by RNA-seq revealed that BI-BTK-1 dramatically modulated pathways related to inflammation and glomerular injury. Importantly, when administered therapeutically, BI-BTK-1 reversed established proteinuria and improved renal histopathology. Our results highlight the important role for BTK in the pathogenesis of immune complex-mediated nephritis, and BTK inhibition as a promising therapeutic target for LN.
Highlights
Current therapies for lupus nephritis (LN) consist mainly of non-specific immunosuppression which can be associated with dangerous side effects, yet often fail at producing long term remission
In this study we utilized a classic experimental model known as nephrotoxic serum nephritis (NTN), that relies on the passive transfer of pre-formed nephrotoxic antibodies into mice to induce immune complex (IC)-mediated nephritis
BI-Bruton’s tyrosine kinase (BTK)-1 potently inhibited BCR stimulated B cell activation, as measured by CD69 expression in primary human CD19+B cells isolated from PBMCs (Fig. 1b) and human whole blood (Supplemental Fig. 1), as well as the secretion of cytokines from IC stimulated human CD14+monocytes (Fig. 1c)
Summary
Current therapies for lupus nephritis (LN) consist mainly of non-specific immunosuppression which can be associated with dangerous side effects, yet often fail at producing long term remission. Autoantibody complexes deposited in the kidneys can activate complement cascades and Fc receptors on local and infiltrating cells, leading to renal injury[4]. (c) BI-BTK-1 inhibition of anti-human serum albumin immune complex stimulated IL-6 (⦁), TNF (▴) and IL-1b (▪) secretion in human CD14+monocytes. Bruton’s tyrosine kinase (BTK), a member of the Tec family of non-receptor tyrosine kinases, is essential for intracellular signaling in B cells and myeloid lineages. BTK is needed for FcR signaling which mediates immune complex (IC) activation of myeloid cell types such as monocytes and macrophages[10]. Targeting BTK may be a promising therapeutic target in LN, as it affects both B cell and macrophage function. The resulting proliferative glomerulonephritis is characterized by IC deposition, complement activation, and immune cell infiltration. Since NTN is highly similar, histologically and mechanistically, to the glomerulonephritis seen in SLE, it is commonly used as a model for this particular lupus manifestation[12]
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