Suppression and resolution of autoimmune arthritis by rhesus θ-defensin-1, an immunomodulatory macrocyclic peptide

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.

Fungicidal Potency and Mechanisms of θ-Defensins against Multidrug-Resistant Candida Species

“…RTD-1, the prototype -defensin, is well tolerated when administered systemically to mice and rats and is nonimmunogenic, highly stable, and effective in the arrest and resolution of autoimmune arthritis when administered as infrequently as once every 5 days (37,55). Further, studies presented here and previously reported (37,52,53,55,71) demonstrated that parenterally administered -defensins are well tolerated in mice and rats. Thus, the drug-like properties of naturally occurring -defensins represent a template for the development of antifungal agents that may prove valuable in the treatment of infections caused by MDR fungal pathogens.…”

“…Antimicrobial Agents and Chemotherapy immunomodulating activities of RTD-1 were not accompanied by immunosuppressive side effects, since peptide treatment of infected/septic animals facilitated recovery (37,53). The immunomodulating properties of RTD-1 were recently extended to a rat model of rheumatoid arthritis, wherein peptide treatment arrested and promoted the resolution of both evolving and severe joint disease (55). While RTD-1 is the first AMP shown to be effective in autoimmune arthritis, several AMPs, including ␣-defensins, ␤-defensins, and cathelicidin LL37, have been shown to have combined antimicrobial/immunomodulatory properties (27,28,(56)(57)(58)(59).…”

“…The potential for therapeutic applications of -defensins for the treatment of systemic infections is supported by preclinical studies demonstrating that RTD-1 is highly effective in mouse models of bacterial and polymicrobial sepsis (37), murine SARS-coronavirus infection (53), and in a mouse model of cystic fibrosis (52). RTD-1, the prototype -defensin, is well tolerated when administered systemically to mice and rats and is nonimmunogenic, highly stable, and effective in the arrest and resolution of autoimmune arthritis when administered as infrequently as once every 5 days (37,55). Further, studies presented here and previously reported (37,52,53,55,71) demonstrated that parenterally administered -defensins are well tolerated in mice and rats.…”

Macrocyclic θ-defensins suppress tumor necrosis factor-α (TNF-α) shedding by inhibition of TNF-α–converting enzyme

“…Also, RTD-1 arrested joint inflammation in a rat model of rheumatoid arthritis (RA), pristaneinduced arthritis, an autoimmune disease characterized by dysregulated proinflammatory cytokines and erosive joint changes similar to those associated with RA (18). Parenteral administration of RTD-1 to rats with established pristane-induced arthritis rapidly induced arrest of disease progression and resolution of arthritis that correlated with significant reductions in proinflammatory cytokines in joint tissues (78).…”

The Role and Potential Application of Antimicrobial Peptides in Autoimmune Diseases

“…Administration of scolopendrasin IX also can reduce the clinical phenotype of RA in a mouse model induced by transgenic K/BxN mice serum (45). Treatment with rhesus θ-defensin 1 (RTD-1), a family of macrocyclic peptides exclusively expressed in monkey, suppressed the joint disease progression and restored limb mobility in a rat model of rheumatoid arthritis (46). Furthermore, the in vivo treatment with the LL-37 peptide in BBdp rats promoted β-cell neogenesis and upregulation of potentially beneficial gut microbes, resulting in a reduction of symptoms of autoimmune diabetes (36).…”