{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T21:20:03Z","timestamp":1791148803599,"version":"4.1.0"},"reference-count":46,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2013,8,26]],"date-time":"2013-08-26T00:00:00Z","timestamp":1377475200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatism"],"published-print":{"date-parts":[[2013,9]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>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 Fc\u03b3 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 \u00d7 NZW mouse model of spontaneous SLE.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>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\u2013double\u2010stranded DNA (anti\u2010dsDNA) secretion, as determined by enzyme\u2010linked immunosorbent and enzyme\u2010linked immunospot assays. Flow cytometric analysis demonstrated depletion of CD138<jats:sup>high<\/jats:sup>B220<jats:sup>low<\/jats:sup> plasma cells in the spleen. RN486 inhibited secretion of IgG anti\u2010dsDNA but not IgM anti\u2010dsDNA, 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\u2013mediated activation of human monocytes in vitro and down\u2010regulation of the expression of macrophage\u2010related and interferon\u2010inducible genes in both the kidneys and spleens of treated mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Collectively, our data suggest that BTK inhibitors may simultaneously target autoantibody\u2010producing and effector cells in SLE, thus constituting a promising therapeutic alternative for this disease.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.38047","type":"journal-article","created":{"date-parts":[[2013,6,10]],"date-time":"2013-06-10T14:41:33Z","timestamp":1370875293000},"page":"2380-2391","source":"Crossref","is-referenced-by-count":73,"title":["Suppression of Glomerulonephritis in Lupus\u2010Prone NZB \u00d7 NZW Mice by RN486, a Selective Inhibitor of Bruton's Tyrosine 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