Btk-specific inhibition blocks pathogenic plasma cell signatures and myeloid cell–associated damage in IFNα-driven lupus nephritis
Arna Katewa, … , Michael J. Townsend, Karin Reif
Arna Katewa, … , Michael J. Townsend, Karin Reif
Published April 6, 2017
Citation Information: JCI Insight. 2017;2(7):e90111. https://doi.org/10.1172/jci.insight.90111.
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Research Article Immunology

Btk-specific inhibition blocks pathogenic plasma cell signatures and myeloid cell–associated damage in IFNα-driven lupus nephritis

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.

Authors

Arna Katewa, Yugang Wang, Jason A. Hackney, Tao Huang, Eric Suto, Nandhini Ramamoorthi, Cary D. Austin, Meire Bremer, Jacob Zhi Chen, James J. Crawford, Kevin S. Currie, Peter Blomgren, Jason DeVoss, Julie A. DiPaolo, Jonathan Hau, Adam Johnson, Justin Lesch, Laura E. DeForge, Zhonghua Lin, Marya Liimatta, Joseph W. Lubach, Sami McVay, Zora Modrusan, Allen Nguyen, Chungkee Poon, Jianyong Wang, Lichuan Liu, Wyne P. Lee, Harvey Wong, Wendy B. Young, Michael J. Townsend, Karin Reif

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Figure 3

Effect of G-744 on splenic B, T, and plasma cells in IFNα-accelerated NZB/W_F1 lupus model.

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Effect of G-744 on splenic B, T, and plasma cells in IFNα-accelerated NZ...
Fourteen-week-old preautoimmune NZB/W_F1 female mice (n = 10/group) were administered with adenovirus containing murine IFNα. Drug treatment was started 3 weeks after AdIFNα injection with 100 mg/kg G-744, vehicle HPMC, 5 mg/kg BR3-Fc, 5 mg/kg Ig control Abs, or Cyclophosphamide (CTX) as described in Methods and continued for 4 weeks. Graphs show the number and phenotype of splenic lymphocyte population from individual surviving mice as determined by flow cytometry and expressed as mean ± SEM, symbols represent individual mice: (A) number of proliferating B cells (CD5–B220+Ki67+); (B) number of B2 cells (B220+CD38+); (C) CD86 levels on B cells (CD5–B220+); (D) ICOS levels on CD4 T cells (CD5+CD4+); (E) number of GC B cells (B220+CD38lo); number of (F) total, (G) IgM+, (H) IgG1+, (I) IgG2a+, and (J) IgG2b+ splenic CD138+B220–/lo PCs. Significance indicate *P < 0.05, G-744 or CTX versus vehicle, BR3-Fc versus Ig control (one-way ANOVA with Dunnett’s multiple comparison test); §P < 0.05, compare G-744 with BR3-Fc (2-tailed Student’s t test with Welch’s correction).