Journal article
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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
Actions
Access Document
- Files:
-
-
(Preview, Version of record, pdf, 1.4MB, Terms of use)
-
- Publisher copy:
- 10.1136/annrheumdis-2018-214294
Authors
- Publisher:
- BMJ Publishing Group
- Journal:
- Annals of the Rheumatic Diseases More from this journal
- Publication date:
- 2018-12-14
- Acceptance date:
- 2018-11-20
- DOI:
- EISSN:
-
1468-2060
- ISSN:
-
0003-4967
- Keywords:
- Pubs id:
-
pubs:944818
- UUID:
-
uuid:a6232d90-2339-42c4-91f3-06b05bce710b
- Local pid:
-
pubs:944818
- Deposit date:
-
2018-11-21
Terms of use
- Copyright holder:
- Aungier et al
- Copyright date:
- 2018
- Notes:
- This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made.
- Licence:
- CC Attribution (CC BY)
If you are the owner of this record, you can report an update to it here: Report update to this record