Mechanism underlying the effect of combined therapy using glucosamine and low-dose cyclosporine A on the development of atopic dermatitis-like skin lesions in NC/Nga mice

摘要

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 (500 mg/kg) alone, low-dose CsA (2, 5, and 10 mg/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.