Therapeutic Effects of a TANK‐Binding Kinase 1 Inhibitor in Germinal Center–Driven Collagen‐Induced Arthritis

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Abstract
Objective The production of class‐switched high‐affinity autoantibodies derived from organised germinal centers (GC) is a hallmark of many autoimmune inflammatory diseases, including rheumatoid arthritis (RA). TANK‐binding kinase 1 (TBK1) is a serine‐threonine kinase involved in the maturation of GC T follicular B helper cells (TFH) downstream of inducible T cell costimulator (ICOS) signalling. We therefore assessed the therapeutic potential of TBK1 inhibition using a small molecule inhibitor – known as WEHI‐112 – in antibody dependent models of inflammatory arthritis. Methods and Results WEHI‐112 ‐ a tool compound, which is semi‐selective for TBK1, but also has activity against IKKε and JAK2 ‐ abolished TBK1‐dependent IRF3 activation and inhibited type I IFN responses in vitro. In vivo, treatment with WEHI‐112 selectively abrogated clinical and histological features of established, antibody‐dependent collagen‐induced arthritis (CIA), but had minimal effects on an antibody‐independent model of antigen‐induced arthritis (AIA) or on K/BxN serum transfer‐induced arthritis (STIA). In keeping with these findings, WEHI‐112 reduced arthritogenic collagen type II (CII)‐specific IgG1 and IgG2b antibody production. Furthermore, WEHI‐112 altered the GC TFH phenotype and GC B cell function in CIA. Conclusion In summary, we report that TBK1 inhibition using WEHI‐112, albeit semi‐selective for TBK1, abrogated antibody‐dependent CIA, most likely explained by targeting TBK1‐mediated mechanisms in the GC reaction as its major effect. This approach may have therapeutic potential in RA and in other GC‐associated autoantibody‐driven inflammatory diseases.
Funding Information
  • John T. Reid Charitable Trusts
  • Australian Cancer Research Foundation
  • National Health and Medical Research Council (1016647, 1023407, 1055374, 9000220)

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