Suppression of Glomerulonephritis in Lupus‐Prone NZB × NZW Mice by RN486, a Selective Inhibitor of Bruton's Tyrosine Kinase
Open Access
- 10 June 2013
- journal article
- systemic lupus-erythematosus
- Published by Wiley in Arthritis & Rheumatism
- Vol. 65 (9), 2380-2391
- https://doi.org/10.1002/art.38047
Abstract
Objective Bruton's tyrosine kinase (BTK) plays a critical role in B cell development and function. We recently described a selective BTK inhibitor, RN486, that blocks B cell receptor (BCR) and Fcγ receptor signaling and is efficacious in animal models of arthritis. The aim of this study was to examine the potential efficacy of BTK in systemic lupus erythematosus (SLE), using an NZB × NZW mouse model of spontaneous SLE. Methods Mice received RN486 or its vehicle (administered in chow) at a final concentration of 30 mg/kg for 8 weeks, starting at 32 weeks of age. Results The administration of RN486 completely stopped disease progression, as determined by histologic and functional analyses of glomerular nephritis. The efficacy was associated with striking inhibition of B cell activation, as demonstrated by a significant reduction in CD69 expression in response to BCR crosslinking. RN486 markedly reduced the secretion of IgG anti–double‐stranded DNA (anti‐dsDNA) secretion, as determined by enzyme‐linked immunosorbent and enzyme‐linked immunospot assays. Flow cytometric analysis demonstrated depletion of CD138highB220low plasma cells in the spleen. RN486 inhibited secretion of IgG anti‐dsDNA but not IgM anti‐dsDNA, suggesting that pharmacologic blockade of BTK resembles the reported transgenic expression of low levels of endogenous BTK in B cells. In addition, RN486 may also impact the effector function of autoantibodies, as evidenced by a significant reduction in immune complex–mediated activation of human monocytes in vitro and down‐regulation of the expression of macrophage‐related and interferon‐inducible genes in both the kidneys and spleens of treated mice. Conclusion Collectively, our data suggest that BTK inhibitors may simultaneously target autoantibody‐producing and effector cells in SLE, thus constituting a promising therapeutic alternative for this disease.Keywords
This publication has 46 references indexed in Scilit:
- Joint European League Against Rheumatism and European Renal Association–European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritisAnnals Of The Rheumatic Diseases, 2012
- Targeting B-cells in lupus nephritis: should cautious optimism remain?Nephrology Dialysis Transplantation, 2012
- B-cell depletion in the treatment of lupus nephritisNature Reviews Nephrology, 2012
- Beyond the LUNAR trial. Efficacy of rituximab in refractory lupus nephritisNephrology Dialysis Transplantation, 2012
- American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritisArthritis Care & Research, 2012
- The role of B cells in lupus pathogenesisThe International Journal of Biochemistry & Cell Biology, 2010
- Changes in the Incidence of Endstage Renal Disease Due to Lupus Nephritis in the United States, 1996–2004The Journal of Rheumatology, 2009
- Predictors of Survival in Systemic Lupus ErythematosusMedicine, 2006
- Btk dosage determines sensitivity to B cell antigen receptor cross-linkingProceedings of the National Academy of Sciences of the United States of America, 1997
- Defective B cell development and function in Btk-deficient miceImmunity, 1995