不同鼠龄BALB/c小鼠肺脏DC的基本属性及其介导RSV感染后免疫应答偏移的作用机制

Early life (neonates infants) is considered to be a “critical window” in which an environmental insult such as virus or allergen could permanently alter health status. To better understand the mechanisms of airway diseases in early life, an age appropriate animal model and a better understanding of lung regional immune system is needed. Respiratory syncytial virus (RSV) is the most common cause of severe lower respiratory tract diseases during infancy and early childhood. The peak for hospitalization with RSV is at 2 months of age.Reinfection is common in infants and is associated with wheezing and asthma after an episode of bronchiolitis. The applicant found previously that the age of initial infection is an important risk factor for disease pathogenesis. The initial neonatal infection induced a T helper 2 (Th2)-biased immune responses, failed to protect the airways on re-infection and resulted in enhanced AHR, increased IL-13 production associated with mucus hyper-production and airway eosinophilia. On the other hand, RSV infection of adult mice induce a Th1-biaed responses. Dendritic cells are the most potent antigen presenting cells. They recognize, capture, process and present antigen to immune effector cells and subsequently direct T cell activation and differentiation.The applicant has found that neonatal mice have very few lung plasmocytoid DC (pDC)and RSV infection did not change much. On the other hand, lung cDC express a higher level of FcRI on baseline level. RSV infection further increased its expression. Based on these observations, the appplicant hypothosized that age-dependent lung DC characteristics, including DC subtypes, numbers, phenotypes and functions,determine the biased immune responses in mice of different age, which in turn determine the airway responses following RSV infection. By using DC depletion mouse model, DC adopted transfer experiments, cytokine and antibody treatment experiments, this project will clarify the age-dependent lung DC characteristics and elucidate the role of lung DC in immune deviation following RSV infection.

新生期/婴儿期是呼吸道病毒感染以及过敏性疾病发病的“窗口期”, 阐明该阶段肺脏免疫学基本属性，建立合适年龄的动物模型，是研究肺部免疫相关疾病的当务之急。RSV是生命早期（2-4个月）最重要的呼吸道病原体。申请人前期研究发现: 初次感染RSV的年龄是决定再次感染后呼吸道反应的关键因素。新生鼠/成年鼠初次感染RSV后分别出现Th2/Th1应答偏移。新生鼠肺脏pDC缺如， cDC高表达FcεRI。据此提出假说：“不同鼠龄小鼠肺脏DC的基本属性差异（包括亚群的组成、数量、表型及功能特点）是决定RSV感染后免疫应答偏移，继而影响呼吸道反应的重要因素”。本项目拟比较不同鼠龄小鼠稳态下肺脏DC的基本属性以及RSV感染后其变化规律。利用基因敲除小鼠、过继转移实验、细胞因子和抗体干预等手段，以再次感染后呼吸道反应作为主要检测指标，阐明不同鼠龄小鼠肺脏DC的基本属性及其参与RSV感染后免疫应答偏移的作用机制。