Department of Dermatology, Dongguk University Ilsan Hospital, Dongguk University Graduate School of Medicine, Goyang 410-773, South Korea.
Int Immunopharmacol. 2013 Feb;15(2):424-32. doi: 10.1016/j.intimp.2013.01.005. Epub 2013 Jan 22.
Combination therapy is often used in the treatment of atopic dermatitis (AD) to improve clinical efficacy or to spare the dose of each drug. Cyclosporine A (CsA) is a calcineurin inhibitor that was developed for the treatment of AD. Glucosamine (Glu) is a potent immunosuppressant that inhibits Th2-mediated immunity. We previously reported that Glu has an ameliorative effect on the development of the pathology in NC/Nga mice. The aims of our study were to investigate the therapeutic efficacy of combination of Glu and low-dose CsA in dermatophagoides farina (Df)-induced AD-like skin lesions in NC/Nga mice and to determine the underlying therapeutic mechanisms. The Df-induced NC/Nga mice with a clinical score of 7 were used for treatment with Glu (500mg/kg) alone, low-dose CsA (2, 5, and 10mg/kg) or in combination. The clinical scores were reduced significantly by the combination treatment with Glu and low-dose CsA. The suppression of dermatitis by combined therapy was accompanied by decrease in the plasma level of IgE and in the splenic level of IL-4, IL-5, IL-13, TARC and eotaxin. Histological analysis of the skin also revealed that combination treatment significantly reduced the inflammatory cellular infiltrate, including mast cells and eosinophils. Particularly, immunological evaluation reveals an increase of CD4(+)CD25(+) Treg cells in the combined treatment. The induction of TSLP, which leads to systemic Th2 response, was reduced in the skin on combination treatment. The protein expression of filaggrin and involucrin was recovered by combination treatment in the skin lesions, whereas the protein expression of keratin-10 and keratin-14 decreased in the combination treatment. Collectively, our findings suggest that combination treatment of Glu and low-dose CsA leads to the therapeutic effects in Df-induced AD-like skin lesion in NC/Nga mice through inhibition of IgE, inflammatory cellular infiltrate, and recovery of skin barrier function via a mechanism that may inhibition of Th2-mediated immune responses, in part, increment of CD4(+)CD25(+) Treg cells. These results suggest that this combined immunosuppressive treatment may provide important implications for the design of therapeutic strategies aimed at AD treatment.
联合治疗常用于治疗特应性皮炎（AD），以提高临床疗效或减少每种药物的剂量。环孢素 A（CsA）是一种钙调神经磷酸酶抑制剂，最初是为治疗 AD 而开发的。氨基葡萄糖（Glu）是一种有效的免疫抑制剂，可抑制 Th2 介导的免疫。我们之前报道过，Glu 对 NC/Nga 小鼠病理发展具有改善作用。本研究的目的是研究 Glu 与低剂量 CsA 联合治疗尘螨（Df）诱导的 NC/Nga 小鼠 AD 样皮肤病变的治疗效果，并确定其潜在的治疗机制。我们使用临床评分 7 的 Df 诱导的 NC/Nga 小鼠，单独使用 Glu（500mg/kg）、低剂量 CsA（2、5 和 10mg/kg）或联合治疗。联合治疗可显著降低临床评分。联合治疗抑制皮炎的同时，还降低了血浆 IgE 水平和脾 IL-4、IL-5、IL-13、TARC 和嗜酸性粒细胞趋化因子水平。皮肤组织学分析也显示，联合治疗可显著减少炎症细胞浸润，包括肥大细胞和嗜酸性粒细胞。特别是，免疫评估显示联合治疗可增加 CD4+CD25+Treg 细胞。联合治疗可降低皮肤中 TSLP 的诱导，而 TSLP 可导致全身性 Th2 反应。联合治疗可恢复皮肤病变中 filaggrin 和 involucrin 的蛋白表达，而联合治疗可降低角质蛋白-10 和角质蛋白-14 的蛋白表达。综上所述，我们的研究结果表明，Glu 与低剂量 CsA 联合治疗可通过抑制 IgE、炎症细胞浸润和恢复皮肤屏障功能，对 Df 诱导的 NC/Nga 小鼠 AD 样皮肤病变产生治疗效果，其机制可能部分通过抑制 Th2 介导的免疫反应，增加 CD4+CD25+Treg 细胞。这些结果表明，这种联合免疫抑制治疗可能为 AD 治疗的治疗策略设计提供重要意义。
