Dataset Information

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

ABSTRACT: ?-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 ?-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? 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?, 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 ?-defensins, which are absent in humans, have potential as retroevolutionary biologics for the treatment of RA.

SUBMITTER: Schaal JB

PROVIDER: S-EPMC5690597 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Publications

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

Schaal Justin B JB Tran Dat Q DQ Subramanian Akshay A Patel Reshma R Laragione Teresina T Roberts Kevin D KD Trinh Katie K Tongaonkar Prasad P Tran Patti A PA Minond Dmitriy D Fields Gregg B GB Beringer Paul P Ouellette André J AJ Gulko Percio S PS Selsted Michael E ME

PloS one 20171116 11

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) rapid ...[more]

PMID: 29145473

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Project description:Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the synovial tissue of the joints. Inadequately controlled disease may cause severe joint damage and deformity. Currently, the anti-arthritic drugs are given systemically, and therefore, they are widely distributed to other organs that are not the intended therapeutic targets. Accordingly, using a particular dose/regimen of a drug to achieve an effective local concentration of the drug in arthritic joints may lead to expected adverse effects involving other organs. Thus, improved methods of drug delivery are needed for arthritis therapy. One attractive approach is the targeting of a systemically administered drug to the inflamed joints. We describe here a prototypic drug delivery system using a novel peptide ligand denoted as ART-1. We previously reported ART-1 (=ADK) as a peptide that preferentially homes to the inflamed joints of arthritic rats and binds to synovial endothelial cells. We tested the ART-1-coated liposomes encapsulating a fluorescent compound for binding to activated endothelial cells in vitro and homing to arthritic joints in vivo, compared to control liposomes lacking the ART-1 coating. Similar liposomes but encapsulating an immunomodulatory cytokine interleukin-27 (ART-1-IL-27 liposomes) were tested for their anti-arthritic activity compared with control liposomes. ART-1-displaying liposomes showed better binding to endothelial cells as well as in vivo homing to arthritic joints compared to control liposomes. Furthermore, ART-1-IL-27 liposomes, when intravenously injected to arthritic rats after the onset of arthritis, were more effective in suppressing disease progression than control-IL-27 liposomes lacking ART-1 or free IL-27 at an equivalent dose of IL-27. In addition, ART-1-directed liposomal IL-27 had a better safety profile than undirected liposomal IL-27 or free IL-27, thereby offering an improved therapeutic index for IL-27 therapy. These results provide a proof-of concept for the use of a novel joint-homing peptide for targeted delivery of drugs including biologics or small molecule compounds to arthritic joints with enhanced efficacy and reduced systemic exposure. This targeted therapy platform may be suitable for use in RA patients.

Dataset Information

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

Publications

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

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