針對白斑症患者中升高的IFN-γ進行人類抗IFN-γ 單株抗體生物製劑治療可抑制對黑色素細胞的直接細胞毒性

摘 要：

白斑症是一種自身免疫性疾病，會逐漸破壞皮膚中的黑色素細胞，導致斑駁的脫色。已有報告指出IFN-γ和CXCL10對白斑症中黑色素細胞的直接病理作用，但關於哪種細胞因子對黑色素細胞具有關鍵的細胞毒性效果，結果存在矛盾。 我們獲取了白斑症患者病變區和非病變區皮膚以及健康對照的間質液分析物，並進行了高靈敏度多重細胞因子檢測。我們還進行了功能研究，以確定高表達細胞因子的直接毒性效果。我們發現白斑症皮膚中IFN-γ、CXCL9、CXCL10和CXCL11顯著升高。離體黑色素細胞研究支持IFN-γ本身對黑色素細胞的直接作用，導致細胞丟失、氧化應激增加和黑素生成中斷。有趣的是，我們發現IFN-γ通過與氧化應激相關的鐵死亡途徑調節細胞死亡，這可能引發白斑症中的自身免疫反應。與選擇性阻斷細胞死亡途徑不同，我們的體外研究支持人類抗IFN-γ單克隆抗體2A6Q通過中斷IFN-γ信號傳導來緩解IFN-γ誘導的黑色素細胞死亡、氧化應激和功能喪失，這可能是白斑症的潛在治療選擇。

Vitiligo is an autoimmune disease that progressively destroys melanocytes in theskin, resulting in patchy disfiguringdepigmentation. The direct pathologicaleffect of IFN-γ,CXCL10 to the melanocytesin vitiligo has been reported, but there arecontradictory results to which cytokineexerts the critical cytotoxic effect onmelanocytes.We obtained the interstitial fluid analytefrom lesion and non-lesion skin of vitiligopatients and healthy control and sent forhigh sensitivity multiplex cytokine panel. Wefurther performed functional study toidentify the direct toxicity effect of the highlyexpressed cytokines.We found a significant elevation of IFN-γ,CXCL9, CXCL10, CXCL11 in the vitiligoskin. Ex vivo melanocyte studies supportthe directrole of IFN-γper se in melanocytecell loss, increased oxidative stress andmelanogenesis disruption. Interestingly, wefound that IFN-γregulated cell deaththrough oxidative stress-related ferroptosiscell death, which may initiate autoimmunityin vitiligo. In contrast to blocking selectedcell death pathway, our in vitro studysupports the rescue effect of human anti-IFN-γmonoclonal antibody 2A6Q to IFN-γinduced cell death, oxidative stress, andloss of function in melanocytes byinterrupting IFN-γsignaling, which may bea potential therapeutic option for vitiligo.