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Laura Contreras-Ruiz, Fayaz A Mir, Bruce Turpie, Sharmila Masli; Thrombospondin-derived peptide attenuates Sjögren’s syndrome-associated ocular surface inflammation. Invest. Ophthalmol. Vis. Sci. 2016;57(12):No Pagination Specified. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Thrombospondin-1 (TSP-1) is an important contributor to regulatory mucosal immunity at the ocular mucosa. Deficiency of TSP-1 in mice results in spontaneous development of Sjögren’s syndrome-associated chronic ocular surface inflammation. Polymorphism in TSP-1-encoding gene in humans is associated with reduced TSP-1 expression in ocular surface cells and the development of chronic ocular surface inflammation. To evaluate whether restoring TSP-1 mediated regulatory mechanism provides a potential new therapeutic approach for chronic ocular surface inflammation, we assessed the efficacy of topically administered TSP-derived peptide in resolving chronic ocular surface inflammation in TSP-1 deficient mice.
Thrombospondin-1 deficient mouse model of chronic ocular surface inflammation was used. Mice (12 wk-old; n=10/group) were treated topically with control or TSP-peptide (10µg/mouse), bilaterally (5µl/eye), once a day for 2 weeks. The disease progression was monitored by corneal fluorescein staining and by determining tear MUC5AC content before and after the treatment. The expression of Foxp3 was assessed by real time PCR in the draining lymph nodes. In addition, the direct effect of TSP-peptide on Foxp3 induction was studied in vitro. After CD4+CD25- T cells were isolated, activated and treated with control or TSP-peptide (10µg/mL) for 48h, Foxp3 expression was evaluated by flow cytometry and TGF-β secretion assessed using ELISA.
Topical TSP-peptide treatment resulted in significantly decreased corneal fluorescein staining and increased tear MUC5AC content as compared to that detected in control peptide-treated mice. The expression of Foxp3 was significantly increased in draining lymph nodes of TSP-peptide-treated mice compared to control peptide-treated mice. In vitro, T cell activation in the presence of TSP-peptide resulted in increased numbers of Foxp3 expressing T cells, and increased levels of TGF-β secretion, as compared to the activation in the presence of control peptide.
Topical administration of TSP-derived peptide in mice with chronic ocular surface inflammation attenuates clinical symptoms while promoting peripheral Treg induction. Thus TSP-derived peptide is a promising therapeutic candidate for the treatment of chronic ocular surface inflammation.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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