Dupilumab-induced inhibition of myeloid dendritic cell function via TIM-3-TGF-β1 feedback loop in treatment of atopic dermatitis.

Background: Although clinical trials have demonstrated both the efficacy and safety of dupilumab, its impact on dendritic cells (DCs) remains unclear. T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) has emerged as a crucial regulator of immune responses in various inflammatory diseases. Understanding the interplay between TIM-3 and the type 2 inflammatory response in atopic dermatitis (AD) could provide valuable insights into the mechanisms underlying the efficacy of dupilumab.

Objective: We sought to investigate whether TIM-3 induces immune modulation of DCs and determines its role in dupilumab therapy.

Methods: Single-cell technology was used to screen for the expression landscape of immune checkpoints. αIL-4/IL-13 mAb treatment was used in mice to simulate the therapeutic effects of dupilumab treatment. The function of the immune checkpoint TIM-3 was investigated with αTIM-3 mAb. Finally, PBMCs were collected from patients with AD 16 weeks before and after dupilumab treatment (n = 24) to validate the findings observed in the mouse experiments. In addition, AD skin lesions were collected before treatment (n = 8) and after treatment (n = 5) for further validation. To verify the therapeutic effects of TGF-β1 and galectin-9, we also collected PBMCs from untreated patients with AD (n = 21) and conducted in vitro stimulation experiments.

Results: Dupilumab upregulates the immune checkpoint HAVCR2 (encoding TIM-3) by inducing the secretion of TGF-β1 in myeloid DCs. Interestingly, TIM-3 also promotes the secretion of TGF-β1, thus forming a positive feedback loop. This process was found to promote myeloid DC apoptosis, contributing to the observed decrease in the number of myeloid DCs and potentially enhancing the therapeutic effects of dupilumab. The analyses of PBMCs and skin lesions from patients with AD before and after dupilumab treatment showed that dupilumab significantly elevated the levels of TIM-3, which correlated with a reduced proportion of myeloid DCs and suppressed myeloid DC function. In vitro stimulation of PBMCs with TGF-β1 or galectin-9 similarly revealed their ability to inhibit myeloid DC function in AD, suggesting potential therapeutic effects.

Conclusions: Dupilumab improves the symptoms of AD by inducing the expression of TIM-3 to suppress myeloid DC function. Treatment with TGF-β1 or galectin-9 enhanced these effects, demonstrating the therapeutic potential of targeting the TGF-β1/galectin-9-TIM-3 axis in AD.