Effects of MSC-derived extracellular vesicles and dupilumab on the spleen and skin in a house dust mite-induced atopic dermatitis model.

Abstract

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized as a biphasic T-lymphocyte-mediated disease involving T-helper cells. Dupilumab is a human monoclonal antibody that inhibits Th2-related cytokines and has recently been approved for patients with AD. However, the effects of dupilumab are relatively narrow in scope, primarily targeting cytokine-driven inflammatory pathways, with few reported systemic effects. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) could serve as an alternative therapeutic strategy for AD. This study aims to compare the effects of a single subcutaneous injection of EVs and biweekly subcutaneous injection of dupilumab on the skin and spleen in a house dust mite-induced model of AD. Clinical and histological analyses, including H&E and toluidine blue staining, showed that both EVs and dupilumab ameliorated AD in an animal model. Biodistribution analysis through live animal imaging revealed that subcutaneously injected EVs can migrate to the spleen, and flow cytometry analysis showed that EVs restored the splenic ratio of CD4+/CD8 + and spleen enlargement. Cytokine analysis of the skin and spleen showed that EVs effectively regulated both Th2 and Th1 responses, while dupilumab had limited effects on Th1 response. Further, mechanistic analyses revealed that both EVs and dupilumab ameliorated AD via the JAK/STAT signaling pathway. Thus, a single subcutaneous injection of EVs was equally effective as a biweekly subcutaneous injection of dupilumab in ameliorating AD. While dupilumab specifically targets and inhibits the Th2 immune response, clinical-scale EV therapeutics can regulate a broad spectrum of immune responses.