Targeting the elevated IFN-gamma in vitiligo patients by human anti- IFN-gamma monoclonal antibody hampers direct cytotoxicity in melanocyte

Background: Vitiligo is an autoimmune disease that progressively destroys melanocytes in the skin, resulting in patchy disfiguring depigmentation. The direct pathological effect of IFN-gamma, CXCL10 to the melanocytes in vitiligo has been reported, but there are contradictory results to which cytokine exerts the critical cytotoxic effect on melanocytes. Objective: The overarching goal was to study the direct toxicity of highly expressed cytokine in vitiligo skin lesions to melanocytes. Methods: We obtained the interstitial fluid analyte from lesion and non-lesion skin of vitiligo patients and healthy control and sent for high sensitivity multiplex cytokine panel. We further performed functional study to identify the direct toxicity effect of the highly expressed cytokines. Results: We found a significant elevation of IFN-gamma, CXCL9, CXCL10, CXCL11 in the vitiligo skin. Ex vivo melanocyte studies support the direct role of IFN-gamma per se in melanocyte cell loss, increased oxidative stress and melanogenesis disruption. Interestingly, we found that IFN-gamma regulated cell death through oxidative stress-related ferroptosis cell death, which may initiate autoimmunity in vitiligo. In contrast to blocking selected cell death pathway, our in vitro study supports the rescue effect of human anti-IFN-gamma monoclonal antibody 2A6Q to IFN-gamma induced cell death, oxidative stress, and loss of function in melanocytes by interrupting IFN-gamma signaling, which may be a potential therapeutic option for vitiligo. Conclusion: This study further confirms the direct of toxicity effect of IFN-gamma per se towards melanocyte in vitiligo skin and the potential utility of human anti-IFN-gamma monoclonal antibody in treating vitiligo. (c) 2023 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.

Automated summary

This study aimed to investigate the direct toxicity of highly expressed cytokines in vitiligo skin lesions to melanocytes. The results showed that IFN-gamma can cause loss of melanocytes, increased oxidative stress, and disruption of melanogenesis. The use of anti-IFN-gamma monoclonal antibody may be a potential therapeutic option for vitiligo. In conclusion, this study confirms the direct toxicity effect of IFN-gamma on melanocytes in vitiligo skin and the potential utility of anti-IFN-gamma monoclonal antibody in treating vitiligo.