慢性纤维化胆道闭锁小鼠模型的建立及其机制研究

Biliary atresia (BA) is a fatal liver fibrosis disease in children, the cause is unknown and lack of effective diagnosis and treatment. The current used animal model can only represent the acute inflammatory response caused bile duct damage, but lack of chronic liver fibrosis process as showed in clinical BA patients. Our previous study showed the depletion of myeloid-derived suppressor cells (MDSC) using antibody could successfully establish a chronic liver fibrosis BA model, the pathological and clinical laboratory examinations features were similar to that of BA patients. Why can MDSC inhibitor induce liver fibrosis in BA mice? Our preliminary data indicated that the number of dendritic cells (DCs) and T cells was significantly reduced in the spleen and liver of the mice when compare to the acute model, suggested the reduced MDSCs might affect its downstream DCs differentiation, further inhibit the proliferation and activation of the T cells and cause immunocompromisation, therefore, the T Cell-mediated acute bile duct injury was reduced, and the persistence of virus infection in the liver will promote the chronic liver fibrosis. To further improve the success rate of the animal model and to clarify its immunological mechanism, we will 1) adjust the time, dose and frequency of the antibody; 2) investigate the relationship of the MDSC, DC on T cells and the effect of cytokine changes in this model; 3) observe the effect of Diphtheria Toxin which inhibit DC cell on BA Mice. The establishment of this animal model will provide a new platform for BA pathogenesis research and drug development.

胆道闭锁(BA)是引起小儿肝纤维化的致死性疾病，病因未明，缺乏有效的诊疗方式，亟需合适的动物模型以供研究，但现有动物模型存在诸多缺陷，主要表现为只能模拟BA急性炎症反应，而缺乏慢性纤维化的病理过程。在前期研究中我们发现使用髓源性抑制细胞（MDSC）特异性抗体可建立慢性纤维化BA小鼠模型，且与BA患者病理特征吻合。抑制MDSC为什么可诱导BA小鼠发生慢性纤维化？预实验显示：该模型小鼠树突状细胞（DC）及T细胞数量显著性下降，提示MDSC分化成DC数量减少，从而降低了对新生小鼠初始T细胞的激活及增殖，因而减低了T细胞主导的急性胆管损伤。为提高该动物模型的成功率，并明确其免疫学机制，我们将1）调控抗体使用的时间、剂量和次数；2）论证该小鼠MDSC、DC及T细胞三者的关系；3）观察DC细胞抑制药物白喉毒素对BA小鼠的影响。本动物模型的建立将为BA发病机制研究及药物开发提供新平台。

胆道闭锁(BA)是引起小儿肝纤维化的致死性疾病，病因未明，缺乏有效的诊疗方式，亟需合适的动物模型以供研究，但现有动物模型存在诸多缺陷，主要表现为只能模拟BA急性炎症反应，而缺乏慢性纤维化的病理过程。在前期研究中我们发现使用髓源性抑制细胞（MDSC）特异性抗体可建立慢性纤维化BA小鼠模型，且与BA患者病理特征吻合。本项目为提高该动物模型构建的成功率，并明确其免疫学机制，通过1）调整实验条件，提高造模成功率；2）探究该小鼠模型，明确该模型是否适用于研究；3）探究MDSC在BA形成中的作用。本项目发现MDSC可能对胆管上皮细胞有损伤作用，而小剂量应用MDSC抑制剂可有诱导慢性纤维化BA小鼠模型，本模型弥补了急性BA模型的不足，能更好地模拟BA的临床变化，有助于BA发病机制及治疗预后的研究。