TNFR2 signalling in inflammatory diseases.

TNF signals via two receptors, TNFR1 and TNFR2, which play contrasting roles in immunity. Most of the pro-inflammatory effects of TNF are mediated by TNFR1, whereas TNFR2 is mainly involved in immune homeostasis and tissue healing, but also contributes to tumour progression. However, all currently available anti-TNF biologics inhibit signalling via both receptors and there is increasing interest in the development of selective inhibitors; TNFR1 inhibitors for autoimmune disease and TNFR2 inhibitors for cancer. It is hypothesised that selective inhibition of TNFR1 in autoimmune disease would alleviate inflammation and promote homeostasis by allowing TNFR2 signalling to proceed unimpeded. Validation of this concept would pave the way for the development and testing of TNF specific antagonists. Another therapeutic approach being explored is the use of TNFR2 specific agonists, which could be administered alone or in combination with a TNFR1 antagonist.

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

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.