Abstract
Cathepsin S (CTSS) is highly increased in Sjögren’s syndrome (SS) patients tears and in tears and lacrimal glands (LG) of male non-obese diabetic (NOD) mice, a murine model of SS. To explore CTSS’s utility as a therapeutic target for mitigating ocular manifestations of SS in sites where CTSS is increased in disease, the tears and the LG (systemically), the peptide-based inhibitor, Z-FL-COCHO (Z-FL), was administered to 14–15 week male NOD mice. Systemic intraperitoneal (i.p.) injection for 2 weeks significantly reduced CTSS activity in tears, LG and spleen, significantly reduced total lymphocytic infiltration into LG, reduced CD3+ and CD68+ cell abundance within lymphocytic infiltrates, and significantly increased stimulated tear secretion. Topical administration of Z-FL to a different cohort of 14–15 week male NOD mice for 6 weeks significantly reduced only tear CTSS while not affecting LG and spleen CTSS and attenuated the disease-progression related reduction of basal tear secretion, while not significantly impacting lymphocytic infiltration of the LG. These findings suggest that CTSS inhibitors administered either topically or systemically can mitigate aspects of the ocular manifestations of SS.
Highlights
Www.nature.com/scientificreports further that inhibition of Cathepsin S (CTSS) may be useful for treatment autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus (SLE), and multiple sclerosis[12,13,14]
To estimate the Maximum Tolerated Dose (MTD) for Z-FL administered i.p., a dose-escalation study was conducted with Z-FL dissolved in vehicle (10% DMSO + 40% PEG 300 + 50% sterile PBS) at 0.25, 0.5, 1.0, 2.0 and 4.0 mg/kg body weight (BW)
As no signs of toxicity were observed at any dose, for the purpose of this study, the highest evaluated dose of 4 mg/kg was considered as the MTD, while 1 mg/kg was evaluated as an intermediate dose for a therapeutic i.p. injection protocol
Summary
Www.nature.com/scientificreports further that inhibition of CTSS may be useful for treatment autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus (SLE), and multiple sclerosis[12,13,14]. Our intent was to investigate whether CTSS inhibition could modulate symptoms of SS-like autoimmune dacryoadenitis using systemic or topical Z-FL as proof-of-principal, not to determine which administration modality was preferable, nor to determine the ideal dosage regimen, both of which would require pharmacokinetics evaluation. When given topically as an eyedrop for 6 weeks, twice daily, in 14–15 week male NOD mice, tear CTSS activity and the reduced tear secretion that occurs with disease progression over this treatment regimen were simultaneously attenuated. These findings implicate CTSS as an effector of autoimmune dacryoadenitis, representing a viable therapeutic target for systemic and local administration in treatment of SS-associated dry eye
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