Abstract
θ-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 θ-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-1β 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 TNFα, 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 θ-defensins, which are absent in humans, have potential as retroevolutionary biologics for the treatment of RA.
Highlights
Rheumatoid arthritis (RA) is a systemic autoimmune disease that affects 0.5 to 1% the world population [1]
The anti-arthritic effects of RTD-1 were tested in DA/OlaHsd rats with pristane-induced arthritis (PIA), a well-characterized model of chronic RA [16, 22, 25,26,27]
Previous studies disclosed that RTD-1 modulates inflammatory cytokine expression in rodent infectious disease models [9, 14] and in immune-stimulated human leukocytes [9, 15]
Summary
Rheumatoid arthritis (RA) is a systemic autoimmune disease that affects 0.5 to 1% the world population [1]. RA is typically characterized by symmetric polyarthritis involving the extremities with erosive joint changes mediated by hyperplastic synovium (pannus) and chronic. The Southern California Clinical and Translational Science Institute #UL1TR000130 (MES) http:// www.sc-ctsi.org/. Oryn Therapeutics provided support in the form of salary for D.Q.T., but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section
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