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JCI Insight ; 2(7): e90111, 2017 04 06.
Article in English | MEDLINE | ID: mdl-28405610

ABSTRACT

Systemic lupus erythematosus (SLE) is often associated with exaggerated B cell activation promoting plasma cell generation, immune-complex deposition in the kidney, renal infiltration of myeloid cells, and glomerular nephritis. Type-I IFNs amplify these autoimmune processes and promote severe disease. Bruton's tyrosine kinase (Btk) inhibitors are considered novel therapies for SLE. We describe the characterization of a highly selective reversible Btk inhibitor, G-744. G-744 is efficacious, and superior to blocking BAFF and Syk, in ameliorating severe lupus nephritis in both spontaneous and IFNα-accelerated lupus in NZB/W_F1 mice in therapeutic regimens. Selective Btk inhibition ablated plasmablast generation, reduced autoantibodies, and - similar to cyclophosphamide - improved renal pathology in IFNα-accelerated lupus. Employing global transcriptional profiling of spleen and kidney coupled with cross-species human modular repertoire analyses, we identify similarities in the inflammatory process between mice and humans, and we demonstrate that G-744 reduced gene expression signatures essential for splenic B cell terminal differentiation, particularly the secretory pathway, as well as renal transcriptional profiles coupled with myeloid cell-mediated pathology and glomerular plus tubulointerstitial disease in human glomerulonephritis patients. These findings reveal the mechanism through which a selective Btk inhibitor blocks murine autoimmune kidney disease, highlighting pathway activity that may translate to human SLE.


Subject(s)
Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , B-Lymphocytes/immunology , Lupus Nephritis/immunology , Myeloid Cells/metabolism , Plasma Cells/pathology , Agammaglobulinaemia Tyrosine Kinase/metabolism , Animals , Autoantibodies/immunology , B-Lymphocytes/drug effects , Cell Proliferation/drug effects , Disease Models, Animal , Female , Gene Expression/drug effects , Humans , Interferon-alpha/immunology , Kidney/immunology , Kidney/pathology , Lupus Nephritis/metabolism , Lymphocyte Activation/drug effects , Mice , Mice, Inbred NZB , Plasma Cells/drug effects
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