Interleukin 6/gp130信号通路影响白癜风移植疗效的机制

Transplantation therapy is an important means for the treatment of stable vitiligo, the cure rate is about 50%, its efficacy is closely related to skin local immune microenvironment. Vitiligo is an autoimmune disease, with a large number of melanocyte autoantigen specific CD8 + CTL infiltrating the skin around lesions, CD8 + CTL is critical killer cells in vitiligo skin micro-environment, but the destruction mechanism is not clear. Our preliminary study confirmed that IL-6 significantly increased when CD8 + CTL co-cultured with melanocytes, and the IL-6 concentration in the blister fluid of graft failure patients was increased significantly compared with the successful transplantation patients, suggesting that transplantation efficacy is closely related to the local CD8 + CTL and IL-6 may be involved in the killing of melanocytes. The project will further explore the relationship between IL-6 with vitiligo transplant therapy, study the effection of IL-6 on CD8 + CTL and the biological activity of melanocytes. In addition, build a mouse model of human vitiligo to in-depth study the molecular mechanisms of IL-6 involved in melanocytes destruction mediated by CD8 + CTL in the local, seeking to block the IL-6 function to improve the microenvironment of the local skin of transplant patients, in order to further improve transplant efficacy, and earnestly solve the suffering of patients.

移植疗法是治疗稳定期白癜风的重要手段，痊愈率50%左右，其疗效与受皮区免疫微环境密切相关。白癜风作为一种自身免疫性疾病，皮损周围存在大量黑素细胞抗原特异性的CD8+ CTL，是白癜风皮损微环境中关键性的杀伤细胞，但杀伤机制尚不明确。项目组前期研究证实，白癜风皮损周围CD8+ CTL与黑素细胞共培养时，IL-6显著性升高；且移植失败患者疱液中的IL-6浓度较之移植成功患者确有明显差异，提示IL-6与移植疗效密切相关，可能参与局部CD8+ CTL对黑素细胞的杀伤。本项目将进一步探讨IL-6与白癜风移植治疗疗效之间的关系，研究IL-6对白癜风皮损周围CD8+CTL以及黑素细胞生物学活性的影响；并构建人源化的白癜风小鼠模型，深入研究IL-6参与局部CD8+CTL杀伤黑素细胞的具体分子机制；寻找阻断IL-6功能，改善移植患者受皮区微环境的方法，为进一步提高移植疗效，切实解决患者痛苦做出努力。

白癜风作为一种自身免疫性疾病，皮损周围存在大量黑素细胞抗原特异性的CD8+ CTL，是白癜风皮损微环境中关键性的杀伤细胞，但杀伤机制尚不明确。项目组研究证实，IL-6与非节段型白癜风的发病、稳定时间和移植疗效密切相关，在CD8+CTL杀伤黑素细胞中起重要的作用。进一步研究发现，IL-6可直接诱导黑素细胞凋亡，参与IFN-γ诱导的黑素细胞氧化应激以及衰老凋亡。此外，IL-6刺激角质形成细胞表达趋化因子表达，其中CCL23表达显著性升高（P<0.01），Transwell试验证实CCL23在CD8+CTL迁移中发挥重要作用，动物创伤模型证实IL-6敲除小鼠伤口周围淋巴细胞浸润明显减少，提示皮损部位IL-6在局部淋巴细胞皮肤归巢中发挥一定作用。本研究明确了IL-6可直接杀伤黑素细胞，在IFN-γ诱导的黑素细胞衰老中发挥作用，IL-6还可促进局部CD8+CTL的向皮损部位的迁移并参与CD8+CTL对黑素细胞的杀伤，在白癜风的发病中起重要作用。