TY - JOUR
T1 - Targeting early changes in the synovial microenvironment
T2 - a new class of immunomodulatory therapy?
AU - Aungier, Susan R
AU - Cartwright, Alison J
AU - Schwenzer, Anja
AU - Marshall, Jennifer L
AU - Dyson, Michael R
AU - Slavny, Peter
AU - Parthiban, Kothai
AU - Karatt-Vellatt, Aneesh
AU - Sahbudin, Ilfita
AU - Culbert, Eric
AU - Hextall, Patrick
AU - Clanchy, Felix Il
AU - Marsden, Brian D
AU - Raza, Karim
AU - Filer, Andrew
AU - Buckley, Christopher Dominic
AU - McCafferty, John
AU - Midwood, Kim S
AU - Williams, Richard O
N1 - © Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY. Published by BMJ.
PY - 2018/12/14
Y1 - 2018/12/14
N2 - 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.
AB - 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.
U2 - 10.1136/annrheumdis-2018-214294
DO - 10.1136/annrheumdis-2018-214294
M3 - Article
C2 - 30552174
SN - 0003-4967
JO - Annals of the Rheumatic Diseases
JF - Annals of the Rheumatic Diseases
ER -