Leflunomide-Mediated Immunomodulation Inhibits Lesion Progression in a Vitiligo Mouse Model

TL;DR

Leflunomide reduces melanocyte destruction in a vitiligo mouse model by modulating T cells and cytokine balance.

Contribution

Leflunomide is shown to inhibit vitiligo progression by targeting CD8+ T cells and the IFN-γ-CXCL9/10 axis.

Findings

Leflunomide (20 mg/kg/day) significantly reduced CD8+ T cell infiltration and CXCL9/10 expression.

Leflunomide restored CD4+/CD8+ T cell homeostasis and shifted cytokine profiles from Th1 to Th2.

Leflunomide disrupted the IFN-γ-driven immune response, offering a repurposing strategy for vitiligo treatment.

Abstract

Autoimmune CD8+ T cell-driven melanocyte destruction constitutes a key pathogenic mechanism in the development of vitiligo. Therefore, the pharmacological inhibition of CD8+ T cell effector functions and skin trafficking is a clinically viable therapeutic strategy. This study investigates leflunomide (LEF), an immunomodulatory drug with established safety in autoimmune diseases, for its therapeutic potential in a tyrosine-related protein (TRP) 2-180-induced vitiligo mouse model. Through flow cytometry, immunofluorescence, ELISA, and histopathological analyses, we systematically evaluated LEF’s effects on T cell regulation, chemokine expression, and cytokine profiles. Key findings demonstrated that LEF (20 mg/kg/day) significantly attenuated depigmentation by reducing CD8+ T cell infiltration and suppressing the IFN-γ-driven expression of CXCL9/10. Furthermore, LEF restored CD4+/CD8+ T cell homeostasis and rebalanced pro-inflammatory (IFN-γ, TNF-α, IL-2) and anti-inflammatory (IL-4, IL-10) cytokines, inducing a shift from Th1 to Th2. These results position LEF as an effective immunomodulator that disrupts the IFN-γ-CXCL9/10 axis and re-establishes immune balance, offering a promising repurposing strategy for halting vitiligo progression.

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