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

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Targeting early changes in the synovial microenvironment : a new class of immunomodulatory therapy? / Aungier, Susan R; Cartwright, Alison J; Schwenzer, Anja; Marshall, Jennifer L; Dyson, Michael R; Slavny, Peter; Parthiban, Kothai; Karatt-Vellatt, Aneesh; Sahbudin, Ilfita; Culbert, Eric; Hextall, Patrick; Clanchy, Felix Il; Williams, Richard; Marsden, Brian D; Raza, Karim; Filer, Andrew; Buckley, Christopher Dominic; McCafferty, John; Midwood, Kim S.

In: Annals of the Rheumatic Diseases, 14.12.2018.

Research output: Contribution to journalArticle

Harvard

Aungier, SR, Cartwright, AJ, Schwenzer, A, Marshall, JL, Dyson, MR, Slavny, P, Parthiban, K, Karatt-Vellatt, A, Sahbudin, I, Culbert, E, Hextall, P, Clanchy, FI, Williams, R, Marsden, BD, Raza, K, Filer, A, Buckley, CD, McCafferty, J & Midwood, KS 2018, 'Targeting early changes in the synovial microenvironment: a new class of immunomodulatory therapy?', Annals of the Rheumatic Diseases. https://doi.org/10.1136/annrheumdis-2018-214294

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Author

Aungier, Susan R ; Cartwright, Alison J ; Schwenzer, Anja ; Marshall, Jennifer L ; Dyson, Michael R ; Slavny, Peter ; Parthiban, Kothai ; Karatt-Vellatt, Aneesh ; Sahbudin, Ilfita ; Culbert, Eric ; Hextall, Patrick ; Clanchy, Felix Il ; Williams, Richard ; Marsden, Brian D ; Raza, Karim ; Filer, Andrew ; Buckley, Christopher Dominic ; McCafferty, John ; Midwood, Kim S. / Targeting early changes in the synovial microenvironment : a new class of immunomodulatory therapy?. In: Annals of the Rheumatic Diseases. 2018.

Bibtex

@article{dbfab7aedc0c4cd6b10019d05b376968,
title = "Targeting early changes in the synovial microenvironment: a new class of immunomodulatory therapy?",
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.",
author = "Aungier, {Susan R} and Cartwright, {Alison J} and Anja Schwenzer and Marshall, {Jennifer L} and Dyson, {Michael R} and Peter Slavny and Kothai Parthiban and Aneesh Karatt-Vellatt and Ilfita Sahbudin and Eric Culbert and Patrick Hextall and Clanchy, {Felix Il} and Richard Williams and Marsden, {Brian D} and Karim Raza and Andrew Filer and Buckley, {Christopher Dominic} and John McCafferty and Midwood, {Kim S}",
note = "{\circledC} Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY. Published by BMJ.",
year = "2018",
month = "12",
day = "14",
doi = "10.1136/annrheumdis-2018-214294",
language = "English",
journal = "Annals of the Rheumatic Diseases",
issn = "0003-4967",
publisher = "BMJ Publishing Group",

}

RIS

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 - Williams, Richard

AU - Marsden, Brian D

AU - Raza, Karim

AU - Filer, Andrew

AU - Buckley, Christopher Dominic

AU - McCafferty, John

AU - Midwood, Kim S

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

JO - Annals of the Rheumatic Diseases

JF - Annals of the Rheumatic Diseases

SN - 0003-4967

ER -