Therapeutic Blockade of Immune Complex-Mediated Glomerulonephritis by Highly Selective Inhibition of Bruton's Tyrosine Kinase

被引：33

作者：

Chalmers, Samantha A. ^{[1
]}

Doerner, Jessica ^{[1
]}

Bosanac, Todd ^{[2
]}

Khalil, Sara ^{[3
]}

Smith, Dustin ^{[2
]}

Harcken, Christian ^{[3
]}

Dimock, Janice ^{[3
]}

Der, Evan ^{[1
]}

Herlitz, Leal ^{[4
]}

Webb, Deborah ^{[3
]}

Seccareccia, Elise ^{[3
]}

Feng, Di ^{[5
]}

Fine, Jay S. ^{[3
]}

Ramanujam, Meera ^{[3
]}

Klein, Elliott ^{[3
]}

Putterman, Chaim ^{[1
]}

机构：

[1] Albert Einstein Coll Med, Bronx, NY 10467 USA

[2] Boehringer Ingelheim Pharmaceut Inc, Small Mol Discovery Res, 90 E Ridge POB 368, Ridgefield, CT 06877 USA

[3] Boehringer Ingelheim Pharmaceut Inc, Immunol & Resp Dis Res, 90 E Ridge POB 368, Ridgefield, CT 06877 USA

[4] Cleveland Clin, Cleveland, OH 44106 USA

[5] Boehringer Ingelheim Pharmaceut Inc, Computat Biol, 90 E Ridge POB 368, Ridgefield, CT 06877 USA

来源：

SCIENTIFIC REPORTS | 2016年 / 6卷

关键词：

GELATINASE-ASSOCIATED LIPOCALIN; TARGETING BTK; MURINE LUPUS; DISEASE; PATHOGENESIS; MACROPHAGES; ACTIVATION;

D O I：

10.1038/srep26164

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：13

共 25 条

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