CD73/A2A轴对炎症性肠病的免疫调节作用及机制研究

One of the key pathogenic mechanisms underlying inflammatory bowel diseases (IBD) is the over-activated immune reactions to the antigens from the intestinal tract. Recent studies using mouse models of graft-versus-host disease and rheumatoid arthritis have demonstrated that CD73/A2A axis is an important component of the immunological network. Similar findings were also identified by our previous work. However, the role of CD73/A2A axis in the development of inflammatory bowel diseases (IBD) remains unknown, and whether CD73/A2A axis manipulation holds therapeutic values for IBD remains unclear. We designed this study to evaluate these scientific questions. Taking advantage of our well-maintained IBD database and the tissue bank, we will first evaluate the associations between the CD73/A2A axis expression in the resected human IBD specimens and the disease activities as well as the immune micro-environment. Then, mouse IBD model will be created to assess the influence of CD73/A2A axis in the clinical progression of IBD using both CD73 knock-out and chemical intervention techniques. The merits of CD73/A2A axis agonists in the treatment of IBD will also be investigated at the same time. Moreover, in vitro cell inflammation model will be developed via stimulating the CD4+T lymphocytes by the anti-CD3 antibody, mimicking the in vivo inflammatory or immunological process in IBD. The impacts of activation and inhibition of CD73/A2A axis on the inflammatory chemokine secretion by CD4+T lymphocytes will be recorded. In summary, our study holds a high potential to unveil a brand-new direction for the IBD pathogenesis, thus providing the possible new key targets and the related chemicals in the treatment of IBD.

炎症性肠病（IBD）的主要致病机制是机体对肠道抗原的过度免疫反应。新近应用移植物抗宿主病及类风湿关节炎动物模型的研究显示CD73/A2A轴占据免疫网络负性调节中的重要一环，我们前期实验也有类似的发现。那么，CD73/A2A轴在IBD的免疫调节中是否也同样扮演着关键角色？干预CD73/A2A轴能否达到治疗IBD的目的？本研究首先应用IBD手术标本，检测CD73/A2A轴表达与IBD疾病活动程度及免疫微环境的关系。其次，建立小鼠IBD模型，利用基因敲除及化学分子干预等技术，探讨CD73/A2A轴在IBD发生发展中的作用，并进一步评价CD73/A2A轴激动剂治疗IBD的潜在价值。最后，应用体外刺激淋巴细胞塑造炎症的细胞模型，通过正向激活及反向抑制调控CD73/A2A轴，观察其对淋巴细胞分泌炎症因子的影响。本项目将揭示IBD免疫调节的新机制，为其药物治疗提供可选择的靶点及化学分子制剂。

炎症性肠病（IBD）的主要致病机制是机体对肠道抗原的过度免疫反应，癌变是其导致病人不良预后的最严重并发症，其具体机制尚未明确。新近应用移植物抗宿主病及类风湿关节炎动物模型的研究显示CD73/A2A轴占据免疫网络负性调节中的重要一环，我们前期实验也有类似的发现。那么，CD73/A2A轴在IBD及IBD癌变的免疫调节中是否也同样扮演着关键角色？干预CD73/A2A轴能否达到防治IBD及IBD癌变的目的？本研究首先应用IBD手术标本，检测CD73/A2A轴表达与IBD疾病活动程度及免疫微环境的关系。其次，建立小鼠IBD模型，利用CD73抑制剂及激动剂，探讨CD73/A2A轴在IBD发生发展中的作用，并进一步评价了CD73/A2A轴激动剂治疗IBD的潜在价值。最后，建立小鼠IBD癌变模型，利用CD73抑制剂及激动剂预测CD73在IBD癌变发生发展中的作用，发现CD73抑制剂可减轻小鼠IBD癌变模型成瘤情况及预后，其具体机制可能是通过ALOX15、Nat8I、Bcl2l15多分子共同作用。本项目揭示了IBD及IBD癌变的免疫调节新机制，为其药物治疗及预防提供可选择的靶点及化学分子制剂。