Dendritic Cell Function in Schistosomiasis

本应用中提出的研究的长期目标是阐明树突状细胞(DC)是如何 解释病原体固有的信号以促进Th1或Th2反应的发展，具有特定的 强调了解血吸虫病如何导致Th2反应的发展。 血吸虫病是一种慢性感染，由血管内感染吸虫寄生虫引起。 血吸虫属，感染超过2亿人，造成约5%的严重疾病 这些人的身份。来自优秀小鼠模型的研究表明，宿主在急性感染期间存活 依赖于强大的Th2反应的发展，尽管它具有保护性，但可以 然而，在感染的慢性阶段，继续引起特定的免疫病理学。 了解宿主如何识别血吸虫并做出安装Th2反应的决定是 因此具有相当重要的意义。树突状细胞负责病原体的识别、处理 病原体衍生的蛋白呈递给Th细胞，并提供额外的信号，其中包括 细胞因子，影响应答的Th细胞向Th1或Th2细胞的发育。在.期间 血吸虫病是寄生虫的卵期诱导Th2反应，现在很清楚 用来自血吸虫卵的分子(“SEA”)冲击的DC也能诱导Th2反应。与此形成对比的是 由细菌或其他病原体冲击的DC诱导的Th1反应 树突状细胞上的受体(TLR)。TLR结扎导致DC激活，而DC暴露于SEA则抑制 激活。在这项应用中，一套补充的细胞、生化和分子技术将是 用于解决以下特定目标：目标1-定义分子从 血吸虫卵抑制TLR启动的DC激活并调节DC以驱动Th2反应；目标2-to 确定树突状细胞中TLR启动的导致抑制Th2细胞发育的途径；目标3-定义 DC内运送血吸虫卵抗原的隔间。拟议的工作包括 独特的医学相关性，有可能促进发现：1)新的血吸虫抗源抗病毒药物 炎症分子；2)调节Th2介导的免疫病理的方法；3)理性的 促进Th1或Th2应答的预防性和治疗性疫苗相关方法。

The long-term goal of the studies proposed in this appilcation 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 folllowing 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 immunpathologies, and 3) rational prophylactic and therapeutic vaccine-relevant methods for promoting Th1 or Th2 responses.