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

摘要: 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 fibrinogen-like globe (FBG) of tenascin-C were generated by phage display. Clones neutralised FBG activation toll-like receptor 4 (TLR4), without impacting pathogenic TLR4 activation, epitope mapped crystallography. Antibodies stained synovial biopsies patients at different stages RA development. Antibody efficacy in preventing cell cytokine release, modulating collagen-induced rats, was assessed. Results Tenascin-C is expressed early development RA, even before disease diagnosis, with higher levels joints people synovitis who eventually developed than whose spontaneously resolved. Anti-FBG inhibited release prevented progression tissue destruction arthritis. Conclusions Early changes microenvironment contribute progression; blocking can ameliorate experimental These data highlight new drug class could offer early, disease-specific modulation engendering global suppression.