期刊
BIOMATERIALS
卷 283, 期 -, 页码 -出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2022.121441
关键词
Sjogrens syndrome; Dry eye; Lacrimal gland; Interleukin-17; T-cell; Cyclosporine A; Elastin-like polypeptide
资金
- University of Southern Cali-fornia (USC)
- National Institute of Health [R01 EY026635, RO1 GM114839, RO1 EY011386]
- USC Ophthalmology Center Core Grant for Vision Research [P30 EY029220]
- USC Norris Comprehensive Cancer Center [P30 CA014089]
- USC Research Center for Liver Diseases [P30 DK048522]
- L.K. Whittier Foundation
- USC Nano Biophysics Core Facility, and the Translational Research Laboratory at USC School of Pharmacy
This study presents a novel protein-based drug carrier that concentrates medication in the eyes, effectively suppressing the inflammation caused by Sjogren's syndrome and improving ocular surface function.
Sjogren's syndrome (SS) is a multifactorial autoimmune disease with principal symptoms including inflammation and loss of function of lacrimal glands (LG) and salivary glands. While glandular infiltrates includes both B-and T-cells, CD4(+) T cells are strongly implicated. Utilizing the male non-obese diabetic (NOD) mouse model of SS, this work: 1) identifies clinically-relevant elevations in cytokines (IL-17A, IL-2) in LG-derived CD4(+) T cells; and 2) explores tissue-specific immunosuppression of SS using a novel protein-based drug carrier to concentrate cyclosporine A (CsA) directly in the LG. As a potent immunosuppressant, topical ophthalmic CsA is approved for dry eye disorders; however, it cannot effectively resolve inflammation due to limited accumulation in the LG. Systemic CsA has dose-limiting side effects that also limit its ability to block LG inflammation. Using elastin-like polypeptides (ELPs) fused genetically to cyclophilin, the intracellular cognate receptor of CsA, this manuscript reports a sustained-release formulation of CsA that maintains therapeutic drug concentrations in the LG and extends intervals between doses. This formulation blocked both in vitro Th17 cell differentiation and IL-17A secretion. In vivo treatment significantly decreased the abundance of Th17.1 cells, a helper cell population sharing phenotypes of both Th17 and Th1, in the LG of diseased NOD mice. Treatment with even a single dose of the sustained-release formulation was effective enough to improve basal levels of tear production. Thus, this sustained-release formulation suppressed local LG inflammation driven through IL-17 dependent pathways, while improving ocular surface function.
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