AIRE调控胸腺树突状细胞分化成熟在移植物抗宿主病中的作用及机制研究

Allogeneic hematopoietic stem cell transplantation（allo-HSCT）is one of the most effective methods to treat malignant diseases of hematopoietic system. Nevertheless, graft-versus-host disease (GVHD) is the major complication post allo-HSCT causing significant morbidity and mortality. Dendritic cells (DCs) have a dual immunological function that can either activate or suppress immune responses depending on their maturational state and the degree of their activation. Mature DCs（mDCs）can induce different functional T cell responses. therefore，it play a central role in the pathophysiology of GVHD. However, immature DCs (imDCs) is associated with a significant reduction in acute GVHD by activation of naive T cells and in maintaining T cell tolerance. Autoimmune regulator (AIRE) plays an important role in the establishment and maintenance of central and peripheral immunological tolerance. Our previous study revealed that the expression of AIRE was progressively down-regulated in thymic tissue in murine GVHD model. Therefore, we hypothesize that the effect and mechanism of AIRE on modulating dendritic cell differentiation and maturation is associated with the occurrence and progression of a mouse model GVHD. In this project, we will investigate the effect and mechanism of AIRE on modulating dendritic cell differentiation and maturation and its role in graft-versus-host disease at different levels by using murine GVHD model and construction of AIRE gene transfected DCs. This project will Further enhance the cognition of the occurrence and development mechanism of GVHD.

异基因造血干细胞移植(allo-HSCT)是治疗造血系统恶性疾病最有效手段之一。而移植物抗宿主病(GVHD)的发生影响了患者的生存率和生活质量。树突状细胞(DCs)有促进GVHD和诱导免疫耐受双重潜能，其功能取决于DCs成熟状态。成熟DCs诱导免疫应答，促使GVHD发生；未成熟DCs可克隆清除自身反应性T细胞介导免疫耐受。自身免疫调节因子(AIRE)在免疫耐受中起着重要作用。我们前期实验证实，GVHD小鼠胸腺组织AIRE表达下调。AIRE可能通过调控胸腺组织中DCs的分化成熟参与allo-HSCT后GVHD的发生。本项目拟采用基因转染技术，建立AIRE过表达和稳定下调的DCs模型，研究AIRE对DCs分化成熟和功能的影响。然后将AIRE过表达和稳定下调的DCs作用于小鼠GVHD模型，探讨AIRE过表达和稳定下调的DCs对小鼠GVHD和造血重建的影响，进一步增强对GVHD发生发展机制的认识。

异基因造血干细胞移植(allo-HSCT)是治疗造血系统恶性疾病最有效手段之一。而移植后急性移植物抗宿主病和慢性移植物抗宿主病严重影响患者的生存率、存活时间和生活质量。树突状细胞(DCs)是体内功能最为强大的专职抗原递呈细胞，能高效地摄取、加工、处理并递呈抗原。它不仅能诱导T细胞增殖和抗原特异性免疫反应，也能诱导免疫耐受。因而它在移植物抗宿主病（GVHD）的发生中发挥着重要的作用。靶向激活的DCs可针对供体移植物建立特异性免疫耐受，而又无T细胞免疫抑制相关并发症的发生。自身免疫调节因子(AIRE)是一种具有转录活化潜能的DNA结合蛋白，在免疫耐受中起着重要作用。我们前期实验证实，GVHD小鼠胸腺组织AIRE表达下调。AIRE可能通过调控胸腺组织中DCs的分化成熟参与allo-HSCT后GVHD的发生。本项目采用基因转染技术，建立AIRE过表达和稳定下调的DCs模型，研究AIRE对DCs分化成熟和功能的影响。然后将AIRE过表达和稳定下调的DCs作用于小鼠GVHD模型，探讨AIRE过表达和稳定下调的DCs对小鼠GVHD和造血重建的影响，在防治GVHD发生发展方面具有很好的前景。