title: Therapeutic Blockade of Immune Complex-Mediated Glomerulonephritis by Highly Selective Inhibition of Bruton's Tyrosine Kinase.
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.
authors.affiliation: Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Samantha A
authors.initials: SA
authors.lastname: Chalmers
authors.affiliation: Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Doerner
authors.affiliation: Small Molecule Discovery Research, Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA.
authors.forename: Todd
authors.initials: T
authors.lastname: Bosanac
authors.affiliation: Immunology and Respiratory Disease Research, Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Khalil
authors.affiliation: Small Molecule Discovery Research, Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA.
authors.forename: Dustin
authors.initials: D
authors.lastname: Smith
authors.affiliation: Immunology and Respiratory Disease Research, Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Harcken
authors.affiliation: Immunology and Respiratory Disease Research, Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA.
authors.forename: Janice
authors.initials: J
authors.lastname: Dimock
authors.affiliation: Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Evan
authors.initials: E
authors.lastname: Der
authors.affiliation: Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Leal
authors.initials: L
authors.lastname: Herlitz
authors.affiliation: Immunology and Respiratory Disease Research, Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Webb
authors.affiliation: Immunology and Respiratory Disease Research, Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA.
authors.forename: Elise
authors.initials: E
authors.lastname: Seccareccia
authors.affiliation: Computational Biology, Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA.
authors.forename: Di
authors.initials: D
authors.lastname: Feng
authors.affiliation: Immunology and Respiratory Disease Research, Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA.
authors.forename: Jay S
authors.initials: JS
authors.lastname: Fine
authors.affiliation: Immunology and Respiratory Disease Research, Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA.
authors.forename: Meera
authors.initials: M
authors.lastname: Ramanujam
authors.affiliation: Immunology and Respiratory Disease Research, Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA.
authors.forename: Elliott
authors.initials: E
authors.lastname: Klein
authors.affiliation: Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Chaim
authors.initials: C
authors.lastname: Putterman
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D000936:Antigen-Antibody Complex / Q000378:metabolism*; D001774:Blood Chemical Analysis; D003176:Complement C3 / Q000032:analysis; D016207:Cytokines / Q000032:analysis; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D020869:Gene Expression Profiling; D007668:Kidney / Q000473:pathology; D008181:Lupus Nephritis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D017423:Sequence Analysis, RNA; D016896:Treatment Outcome
chemical_list: D000936:Antigen-Antibody Complex; D003176:Complement C3; D016207:Cytokines; D004791:Enzyme Inhibitors; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625951:Btk protein, mouse