Dendritic Cell Function in Schistosomiasis

描述（由申请人提供）：本申请中提出的研究的长期目标是阐明树突状细胞（DC）如何解释病原体固有信号以促进Th 1或Th 2应答的发展，特别强调了解血吸虫病如何导致Th 2应答的发展。血吸虫病是由血吸虫属的吸虫蠕虫寄生虫的血管内感染引起的慢性感染，其感染超过2亿人，在这些个体中的约5%中引起严重疾病。来自优秀小鼠模型的研究表明，急性感染期间宿主的存活取决于强Th 2应答的发展，尽管其具有保护性质，但在感染的慢性阶段仍然可以继续引起特定的免疫病理学。因此，了解宿主如何识别干扰体并决定启动Th 2应答具有相当重要的意义。树突状细胞负责病原体识别，加工病原体衍生的蛋白质以呈递给Th细胞，并提供额外的信号，其中包括细胞因子，其影响应答Th细胞向Th 1或Th 2细胞的发育。在血吸虫病期间，是寄生虫的卵阶段诱导Th 2应答，并且现在清楚的是，用来自寄生虫卵的分子（“SEA”）脉冲的DC也诱导Th 2应答。这与用细菌或其它病原体脉冲的DC诱导的Th 1应答形成对比，所述细菌或其它病原体连接DC上的Toll样受体（TLR）。TLR连接导致DC活化，而DC暴露于SEA抑制活化。在本申请中，将使用一组互补的细胞、生物化学和分子技术来解决以下具体目的：目的1 -确定来自卵裂球的分子通过其抑制TLR-启动的DC活化和调节DC以驱动Th 2应答的途径;目的2-鉴定DC中导致抑制Th 2细胞发育的TLR-启动的途径;目的3 -确定树突状细胞内卵抗原被递送的区室。所提出的工作具有明显的医学相关性，具有促进以下发现的潜力：1）新的溶酶体衍生的抗炎分子; 2）调节Th 2介导的免疫病理学的方法，以及3）用于促进Th 1或Th 2应答的合理的预防性和治疗性疫苗相关方法。

DESCRIPTION (provided by applicant): The long-term goal of the studies proposed in this application is to elucidate how dendritic cells (DCs) interpret pathogen-inherent signals to promote Th1 or Th2 response development, with a particular emphasis on understanding how schistosomiasis leads to the development of a Th2 response. Schistosomiasis is a chronic infection caused by intravascular infection with trematode helminth parasites of the genus Schistosoma, which infect over 200 million people, causing serious disease in approximately 5% of these individuals. Studies from excellent mouse models indicate that host survival during acute infection is dependent on the development of a strong Th2 response, which despite its protective nature can nevertheless proceed to cause specific immunopathologies during the chronic stages of infection. Understanding how hosts recognize schistosomes and make the decision to mount Th2 responses is therefore of considerable importance. Dendritic cells are responsible for pathogen-recognition, processing pathogen-derived proteins for presentation to Th cells, and providing additional signals, amongst which are cytokines, that influence the development of responding Th cells into Th1 or Th2 cells. During schistosomiasis it is the egg stage of the parasite that induces the Th2 response, and it is now clear that DCs pulsed with molecules ("SEA") from schistosome eggs also induce Th2 responses. This contrasts with the Th1 responses that are induced by DCs pulsed with bacteria or other pathogens that ligate Toll like receptors (TLRs) on DCs. TLR ligation leads to DC activation, whereas exposure of DCs to SEA inhibits activation. In this application a complementary set of cellular, biochemical and molecular techniques will be used to address the following specific aims: Aim 1 - To define the pathway through which molecules from schistosome eggs inhibit TLR-initiated DC activation and condition DCs to drive Th2 responses; Aim 2- To identify TLR-initiated pathways in DCs that lead to suppression of Th2 cell development; Aim 3 - To define the compartment into which schistosome egg antigens are delivered within DCs. The proposed work has distinct medical relevance, with the potential to facilitate the discovery of: 1) new schistosome-derived anti- inflammatory molecules; 2) methods to regulate Th2-mediated immunopathologies, and 3) rational prophylactic and therapeutic vaccine-relevant methods for promoting Th1 or Th2 responses.