Targeting early changes in the synovial microenvironment: a new class of immunomodulatory therapy?

Research output: Contribution to journalArticle

Authors

  • Susan R Aungier
  • Alison J Cartwright
  • Anja Schwenzer
  • Michael R Dyson
  • Peter Slavny
  • Kothai Parthiban
  • Aneesh Karatt-Vellatt
  • Eric Culbert
  • Patrick Hextall
  • Felix Il Clanchy
  • Richard Williams
  • Brian D Marsden
  • John McCafferty
  • Kim S Midwood

Colleges, School and Institutes

Abstract

OBJECTIVES: Controlled immune responses rely on integrated crosstalk between cells and their microenvironment. We investigated whether targeting proinflammatory signals from the extracellular matrix that persist during pathological inflammation provides a viable strategy to treat rheumatoid arthritis (RA).

METHODS: Monoclonal antibodies recognising the fibrinogen-like globe (FBG) of tenascin-C were generated by phage display. Clones that neutralised FBG activation of toll-like receptor 4 (TLR4), without impacting pathogenic TLR4 activation, were epitope mapped by crystallography. Antibodies stained synovial biopsies of patients at different stages of RA development. Antibody efficacy in preventing RA synovial cell cytokine release, and in modulating collagen-induced arthritis in rats, was assessed.

RESULTS: Tenascin-C is expressed early in the development of RA, even before disease diagnosis, with higher levels in the joints of people with synovitis who eventually developed RA than in people whose synovitis spontaneously resolved. Anti-FBG antibodies inhibited cytokine release by RA synovial cells and prevented disease progression and tissue destruction during collagen-induced arthritis.

CONCLUSIONS: Early changes in the synovial microenvironment contribute to RA progression; blocking proinflammatory signals from the matrix can ameliorate experimental arthritis. These data highlight a new drug class that could offer early, disease-specific immune modulation in RA, without engendering global immune suppression.

Details

Original languageEnglish
JournalAnnals of the Rheumatic Diseases
Early online date14 Dec 2018
Publication statusE-pub ahead of print - 14 Dec 2018