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We undertook this study to assess the therapeutic potential of\n TBK<\/jats:styled-content>\n \u20101 inhibition using the small\u2010molecule inhibitor\n WEHI<\/jats:styled-content>\n \u2010112 in antibody\u2010dependent models of inflammatory arthritis.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n Using the models of collagen\u2010induced arthritis (\n CIA<\/jats:styled-content>\n ), antigen\u2010induced arthritis (\n AIA<\/jats:styled-content>\n ), and K\/BxN serum\u2010transfer\u2013induced arthritis (\n STIA<\/jats:styled-content>\n ), we determined the effectiveness of\n WEHI<\/jats:styled-content>\n \u2010112 at inhibiting clinical and histologic features of arthritis in C57\n BL<\/jats:styled-content>\n \/6 and\n DBA<\/jats:styled-content>\n \/1 mice. We used immunohistochemistry to characterize\n GC<\/jats:styled-content>\n populations during\n CIA<\/jats:styled-content>\n development, and we used enzyme\u2010linked immunosorbent assays to determine levels of Ig autoantibodies in\n WEHI<\/jats:styled-content>\n \u2010112\u2013treated mice compared to vehicle\u2010treated mice.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n WEHI<\/jats:styled-content>\n \u2010112, a tool compound that is semiselective for\n TBK<\/jats:styled-content>\n \u20101 but that also has activity against\n IKK<\/jats:styled-content>\n \u03b5 and\n JAK<\/jats:styled-content>\n 2, abolished\n TBK<\/jats:styled-content>\n \u20101\u2013dependent activation of interferon (\n IFN<\/jats:styled-content>\n ) regulatory factor 3 and inhibited type I\n IFN<\/jats:styled-content>\n responses in vitro. In vivo, treatment with\n WEHI<\/jats:styled-content>\n \u2010112 selectively abrogated clinical and histologic features of established, antibody\u2010dependent\n CIA<\/jats:styled-content>\n , but had minimal effects on an antibody\u2010independent model of\n AIA<\/jats:styled-content>\n or on K\/BxN\n STIA<\/jats:styled-content>\n . In keeping with these findings,\n WEHI<\/jats:styled-content>\n \u2010112 reduced arthritogenic type\n II<\/jats:styled-content>\n collagen\u2013specific IgG1 and IgG2b antibody production. Furthermore,\n WEHI<\/jats:styled-content>\n \u2010112 altered the\n GC<\/jats:styled-content>\n Tfh cell phenotype and\n GC<\/jats:styled-content>\n B cell function in\n CIA<\/jats:styled-content>\n .\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n We report that\n TBK<\/jats:styled-content>\n \u20101 inhibition using\n WEHI<\/jats:styled-content>\n \u2010112 abrogated antibody\u2010dependent\n CIA<\/jats:styled-content>\n . As WEHI\u2010112 failed to inhibit non\u2013antibody\u2010driven joint inflammation, we conclude that the major effect of this compound was most likely the targeting of\n TBK<\/jats:styled-content>\n \u20101\u2013mediated mechanisms in the\n GC<\/jats:styled-content>\n reaction. This approach may have therapeutic potential in\n RA<\/jats:styled-content>\n and in other\n GC<\/jats:styled-content>\n \u2010associated autoantibody\u2010driven inflammatory diseases.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/art.40670","type":"journal-article","created":{"date-parts":[[2018,7,16]],"date-time":"2018-07-16T02:14:56Z","timestamp":1531707296000},"page":"50-62","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Therapeutic Effects of a\n TANK<\/scp>\n \u2010Binding Kinase 1 Inhibitor in Germinal Center\u2013Driven Collagen\u2010Induced Arthritis"],"prefix":"10.1002","volume":"71","author":[{"given":"Cynthia","family":"Louis","sequence":"first","affiliation":[{"name":"The Walter and Eliza Hall Institute of Medical Research and the University of Melbourne Parkville Victoria 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