Journal
PLOS ONE
Volume 12, Issue 11, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0187868
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Funding
- National Institute of Allergy and Infectious Diseases [AI22931]
- Arthritis Foundation [5997]
- National Institute of Dental and Craniofacial Research [DE021341]
- National Institute of Arthritis and Musculoskeletal and Skin Diseases [AR068833]
- Wright Foundation
- Southern California Clinical and Translational Science Institute [UL1TR000130]
- National Cancer Institute [P30CA014089]
- Seth MacFarlane Foundation
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theta-defensins constitute a family of macrocyclic peptides expressed exclusively in Old World monkeys. The peptides are pleiotropic effectors of innate immunity, possessing broad spectrum antimicrobial activities and immunoregulatory properties. Here we report that rhesus theta-defensin 1 (RTD-1) is highly effective in arresting and reversing joint disease in a rodent model of rheumatoid arthritis (RA). Parenteral RTD-1 treatment of DA/OlaHsd rats with established pristane-induced arthritis (PIA) rapidly suppressed joint disease progression, restored limb mobility, and preserved normal joint architecture. RTD-1 significantly reduced joint IL-1 beta levels compared with controls. RTD-1 dose-dependently inhibited fibroblast-like synoviocyte (FLS) invasiveness and FLS IL-6 production. Consistent with the inhibition of FLS invasiveness, RTD-1 was a potent inhibitor of arthritogenic proteases including ADAMs 17 and 10 which activate TNF alpha, and inhibited matrix metalloproteases, and cathepsin K. RTD-1 was non-toxic, non-immunogenic, and effective when administered as infrequently as once every five days. Thus theta-defensins, which are absent in humans, have potential as retroevolutionary biologics for the treatment of RA.
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