Vitiligo is a common autoimmune disease affecting about 0.5%-2% of the global population. It is characterized by white patches on the skin caused by the attack of melanocytes by autoreactive CD8+ T cells. In vitiligo, interferon-gamma (IFN-γ) produced by CD8+ T cells induces local keratinocytes and fibroblasts to secrete CXCL9 and CXCL10 through the IFN-γ receptor-JAK pathway, leading to the recruitment of more CXCR3+ CD8+ T cells.
Ruxolitinib cream (Ruxolitinib, a selective JAK1/2 inhibitor), which disrupts the pathological IFN-γ-chemokine signaling axis to block CD8+ T cell recruitment, has recently become the first approved drug for treating non-segmental vitiligo (the most common type of vitiligo) patients (not yet approved in China). However, its clinical response rate is about 30%, with adverse events such as acne, nasopharyngitis, and itching. Therefore, treating vitiligo remains challenging, and new therapies are needed.
Given the central role of autoreactive CD8+ T cells in vitiligo immunopathology, elucidating upstream regulators of these CD8+ T cell responses may provide new therapeutic options.
On June 16, 2025, the team led by Wang Honglin from the First People's Hospital affiliated with Shanghai Jiao Tong University School of Medicine, along with Professor Xu Aie from Hangzhou Third People's Hospital (with doctoral students Yang Xiuli and Ding Wenxiang from Shanghai Jiao Tong University School of Medicine as co-first authors), published a research paper titled "Nociceptor-derived CGRP enhances dermal type I conventional dendritic cell function to drive autoreactive CD8+ T cell responses in vitiligo" in Immunity, a Cell journal sub-journal.
This study, combining single-cell sequencing, spatial transcriptomics, whole-skin clearing imaging, nearly 10 types of genetically engineered mice, and an investigator-initiated clinical trial (IIT), originally revealed a novel pathogenic mechanism in vitiligo involving the "nociceptor-CGRP-cDC1-CD8+ T cell" axis. Blocking this neuro-immune interaction axis with the CGRP receptor antagonist Rimegepant significantly inhibited disease progression in vitiligo mouse models and showed promising therapeutic effects in a clinical trial of 57 vitiligo patients, providing a new treatment strategy for vitiligo.
Vitiligo is an autoimmune disease characterized by depigmented white patches on the skin. Autoreactive CD8+ T cells kill melanocytes in vitiligo, but the precise immune pathogenesis and ideal drug targets remain unclear.
In this latest study, the research team performed single-cell and spatial transcriptomic analysis of vitiligo lesional skin and found that type I conventional dendritic cells (cDC1) activated CD8+ T cells and that dermal cDC1 specifically highly expressed the CGRP receptor CALCRL-RAMP1, suggesting that dermal cDC1 in vitiligo might be regulated by CGRP signaling.
In vitiligo mouse models, knocking out Nav1.8+ nociceptors, cDC1-specific deletion of the CGRP receptor, or treatment with the CGRP receptor antagonist Rimegepant (approved in China for migraine treatment) all eliminated CD8+ T cell autoreactivity and prevented skin depigmentation. Conversely, injecting CGRP into mice lacking nociceptors restored vitiligo symptoms. Based on these results, the team innovatively proposed a new pathogenic mechanism for vitiligo—the nociceptor-CGRP-cDC1-CD8+ T cell axis.
Next, the team reformulated Rimegepant from an oral drug to a topical ointment and conducted an investigator-initiated clinical trial (IIT) with 57 vitiligo patients divided into three groups, treated for 6-12 weeks. Group A received placebo or 0.1% Rimegepant ointment alone; Group B received placebo or 0.1% Rimegepant ointment combined with weekly NB-UVB phototherapy; Group C involved the same patient with two adjacent vitiligo patches, each treated with placebo or 0.1% Rimegepant ointment plus phototherapy. Results from all groups showed that Rimegepant ointment helped skin repigmentation and significantly improved the repigmentation rate of vitiligo lesions.
Overall, these results indicate that nociceptor-derived CGRP promotes cDC1-CD8+ T cell interactions and highlight CGRP receptor antagonists as a potential therapeutic strategy for vitiligo, effectively improving vitiligo in both mice and humans.
The research team has completed Phase 2 clinical trials and is currently cleaning and analyzing data. After the formal unblinding of Phase 2 trial data, they plan to apply to the National Medical Products Administration's Center for Drug Evaluation for breakthrough therapy designation.
https://www.cell.com/immunity/abstract/S1074-7613(25)00239-0
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