Τ17细胞介导银屑病皮肤炎症性病变形成中CD30L/CD30信号转导的保护性作用机制研究

Psoriasis is one of the most common immune-mediated chronic inflammatory skin disorders characterized by hyperproliferative keratinocytes and massive infiltration of leukocytes. Although the pathogenesis of psoriasis is not fully understood, there is growing evidence that T17 cell (including mainly Th17 and γδ T cell) and the related cytokines, such as IL-17A and IL-22, play critical roles in disease development. In our recent studies, it has been demonstrated that CD30L/CD30 signaling plays critical roles in the differentiation, maintenance and functional regulation of Th17 and IL-17A-producing Vγ6+ γδ T cell in mucosa-associated tissues. But so far, there is few relevant report about CD30L/CD30 signal and skin immune responses. In this study, we have already been found that CD30L gene knockout lead to the susceptibility to psoriasis significantly increased in mice, accompanying massive infiltration of inflammatory cells, such as Vγ4+ γδT cells, and increasing production of inflammatory cytokines. These results suggest that CD30L/CD30 signaling plays a potential protective role in the pathogenesis of psoriasis in mice. Therefore, in this study, we plan to investigate the regulatory role of CD30L/CD30 signaling in skin immune response during the development of psoriasis, elucidate the molecular mechanism of its protective effect, using CD30L-/- mice to induce different types of psoriasis model and the skin samples from psoriasis patients, and then evaluate the therapeutic effect of monoclonal antibody targeting CD30L/CD30 signal on psoriasis. This work will clarify the potential roles of CD30L/CD30 signaling in the pathogenesis of psoriasis and provide an important theoretical basis for psoriasis immune therapy.

银屑病是一种常见的、免疫系统介导的慢性炎症性皮肤病，其发病机制尚不清楚。目前研究发现，T17细胞及其细胞因子在银屑病变形成中起关键作用。以往研究证明，CD30L/CD30信号对肠黏膜Th17和IL-17A+Vγ6+γδT细胞的分化及功能具有重要调节作用。但迄今为止，有关T17细胞介导银屑病皮肤炎症病变形成中CD30L/CD30作用机制的研究鲜有报道。本项目前期研究发现，CD30L基因敲除导致小鼠对银屑病易感性显著升高，并伴随Vγ4+γδT细胞皮损组织浸润及细胞因子分泌增加。结果提示CD30L/CD30信号在银屑病发病机制中具有潜在的保护性作用。因此，本项目将通过对CD30L-/-小鼠银屑病模型及临床患者样本的研究，探讨Τ17细胞介导银屑病皮肤炎症性病变形成中CD30L/CD30信号转导的保护性作用机制，评价以其为靶点的单克隆抗体对银屑病的疗效，为临床银屑病免疫疗法的开发开辟新思路。

银屑病是一种临床常见的，多发性慢性皮肤炎症性疾病，属于自身免疫病的一种。目前银屑病发病机制虽尚不十分清楚，但大量研究表明，皮肤组织内炎症性免疫应答功能紊乱是导致其病变形成的主要诱因之一。以往研究报道，CCR6+Th17细胞在趋化因子CCL20的作用下迁移至皮损部位后，产生IL-17A、IL-22、IL-17F或TNFα等炎性细胞因子，是银屑病免疫免疫学发病机制中的主要效应细胞。然而，近年来越来越多的研究表明，皮肤γδT17细胞，亦是IL-17A和IL-22等细胞因子的重要来源细胞之一，并银屑病的病变形成中发挥重要作用。我们以往的研究发现，TNFSF/TNFRSF家族成员—CD30L/CD30信号转导对小鼠肠黏膜相关淋巴组织内T17细胞（Th17和γδT17）的生存、分化及细胞因子产生起重要的调控作用，但对于炎症性皮损组织内T17细胞介导的免疫应答的调控作用尚不清楚。为深入研究皮肤T17细胞介导的银屑病病变形成中CD30L/CD30信号转导的作用机制，本项目利用CD30L基因敲除小鼠建立咪喹莫特（Imiquimod，IMQ）诱导的寻常型银屑病动物模型，探讨CD30L/CD30信号转导对γδT17细胞介导的皮肤炎症性免疫应答的调控作用，同时评价调节CD30L/CD30信号对小鼠银屑病的治疗效果。本研究结果发现，CD30L/CD30信号转导能够通过下调Vγ4+γδT细胞亚群表面CCR6的表达，进而抑制其向炎症性皮损组织局部迁移，减少炎症性细胞因子IL-17A、IL-17F或IL-22的分泌，在IMQ诱导的小鼠银屑病病变形成中发挥重要的保护性作用。而且，通过刺激性抗CD30抗体调控CD30L/CD30信号对小鼠银屑病的发生发展具有显著疗效。本研究结果揭示CD30L/CD30信号信号靶向性单克隆抗体可能成为银屑病免疫生物学治疗的新方法。