Btk inhibition treats TLR7/IFN driven murine lupus

Clin Immunol. 2016 Mar:164:65-77. doi: 10.1016/j.clim.2016.01.012. Epub 2016 Jan 25.

Abstract

Bruton's tyrosine kinase (Btk) is expressed in a variety of immune cells and previous work has demonstrated that blocking Btk is a promising strategy for treating autoimmune diseases. Herein, we utilized a tool Btk inhibitor, M7583, to determine the therapeutic efficacy of Btk inhibition in two mouse lupus models driven by TLR7 activation and type I interferon. In BXSB-Yaa lupus mice, Btk inhibition reduced autoantibodies, nephritis, and mortality. In the pristane-induced DBA/1 lupus model, Btk inhibition suppressed arthritis, but autoantibodies and the IFN gene signature were not significantly affected; suggesting efficacy was mediated through inhibition of Fc receptors. In vitro studies using primary human macrophages revealed that Btk inhibition can block activation by immune complexes and TLR7 which contributes to tissue damage in SLE. Overall, our results provide translational insight into how Btk inhibition may provide benefit to a variety of SLE patients by affecting both BCR and FcR signaling.

Keywords: Bruton's tyrosine kinase; Interferon; Lupus; TLR7.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Agammaglobulinaemia Tyrosine Kinase
  • Animals
  • Arthritis / drug therapy
  • Arthritis / pathology
  • Autoantibodies / blood
  • Disease Models, Animal
  • Female
  • Foot Joints / drug effects
  • Foot Joints / pathology
  • Humans
  • Immunosuppressive Agents
  • Interferon Type I / immunology
  • Kidney / drug effects
  • Kidney / pathology
  • Lupus Erythematosus, Systemic / chemically induced
  • Lupus Erythematosus, Systemic / drug therapy*
  • Lupus Erythematosus, Systemic / immunology
  • Lupus Erythematosus, Systemic / pathology
  • Macrophages / drug effects
  • Macrophages / immunology
  • Male
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Nephritis / drug therapy
  • Nephritis / pathology
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Proteinuria / drug therapy
  • Proteinuria / pathology
  • Terpenes
  • Toll-Like Receptor 7 / immunology

Substances

  • Autoantibodies
  • Immunosuppressive Agents
  • Interferon Type I
  • Protein Kinase Inhibitors
  • TLR7 protein, human
  • Terpenes
  • Toll-Like Receptor 7
  • pristane
  • Protein-Tyrosine Kinases
  • Agammaglobulinaemia Tyrosine Kinase
  • BTK protein, human
  • Btk protein, mouse