Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Ave, Los Angeles, CA, 90033, United States.
Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Ave, Los Angeles, CA, 90033, United States; Department of Ophthalmology, Roski Eye Institute, Keck School of Medicine, University of Southern California, 1450 San Pablo St., Room 4900, Mail Code 6103, Los Angeles, CA, 90033, United States.
Biomaterials. 2022 Apr;283:121441. doi: 10.1016/j.biomaterials.2022.121441. Epub 2022 Feb 26.
Sjögren'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.
干燥综合征（SS）是一种多因素自身免疫性疾病，主要症状包括泪腺（LG）和唾液腺的炎症和功能丧失。虽然腺体浸润包括 B 细胞和 T 细胞，但 CD4 T 细胞强烈参与其中。利用男性非肥胖糖尿病（NOD）小鼠 SS 模型，这项工作：1）确定了 LG 衍生的 CD4 T 细胞中细胞因子（IL-17A、IL-2）的临床相关升高；2）利用新型蛋白药物载体将环孢素 A（CsA）直接浓缩在 LG 中，探索 SS 的组织特异性免疫抑制。作为一种有效的免疫抑制剂，局部滴眼用 CsA 被批准用于干眼症；然而，由于在 LG 中的有限积累，它不能有效地解决炎症。全身 CsA 具有剂量限制的副作用，这也限制了其阻断 LG 炎症的能力。本文使用弹性蛋白样多肽（ELPs）与细胞色素 P450 的内源性受体环孢素 A 融合，报告了 CsA 的一种持续释放制剂，该制剂可维持 LG 中的治疗药物浓度并延长剂量间隔。该制剂可阻断体外 Th17 细胞分化和 IL-17A 分泌。体内治疗可显著减少疾病 NOD 小鼠 LG 中 Th17.1 细胞的丰度，Th17.1 细胞是一种具有 Th17 和 Th1 表型的辅助细胞群。即使单次给予持续释放制剂的治疗也足以改善基础泪液产生水平。因此，这种持续释放制剂通过依赖 IL-17 的途径抑制局部 LG 炎症，同时改善眼表面功能。
