Induction of Pathogenic Innate and Adaptive Immune Responses by Schistosome Helmi

描述(申请人提供)：血吸虫病是一种严重的、可能致命的寄生虫病，主要在非洲、南美洲和中东和亚洲的一些地区困扰着大约2亿人。血吸虫病的基本病理是CD4T细胞介导的针对寄生虫卵的肉芽肿性炎症反应，在感染曼氏血吸虫的情况下，主要发生在肝脏和肠道。无论是在人类中，还是在小鼠模型中，疾病的严重程度都存在明显的异质性。然而，决定免疫病理程度的确切调控机制却知之甚少。这项建议的主要目的是研究树突状细胞(DC)在决定小鼠血吸虫病病情严重程度中的作用。该项目的具体目标是1)确定从高病理但非低病理小鼠品系分离的DC在暴露于血吸虫活虫和虫卵后是否可以被刺激激活并产生促炎细胞因子；2)确定暴露于血吸虫产品的高病理DC和低病理DC是否优先推动CD4T细胞群体分化为致病Th17细胞或保护性Th2细胞。在几项最先进的标准技术中，该项目将利用一种新颖的、独特的S.Manson/特异性TCR转基因小鼠系统。由于DC是天然免疫和获得性免疫之间的关键纽带，该项目将为免疫病理学如何从寄生虫的最初入侵发展到致病性T细胞介导的肉芽肿性病变的形成提供宝贵的见解。尽管吡喹酮是一种非常有效的药物治疗，但在世界流行地区，再次感染血吸虫是一种常见现象。不幸的是，血吸虫病疫苗还没有开发出来。这项赠款中提出的研究将有助于了解血吸虫病的基本发病机制，并有助于设计特定的免疫疗法。

DESCRIPTION (provided by applicant): Schistosomiasis is a serious, potentially fatal parasitic disease afflicting about 200 million people primarily in Africa, South America and some parts of the Middle East and Asia. The basic pathology in schistosomiasis is a CD4 T cell-mediated granulomatous inflammatory reaction against parasite eggs, which in the case of infection with Schistosoma mansoni, primarily takes place in the liver and intestines. Both in humans, as well as in a murine model, there is marked heterogeneity in the severity of disease. However, the precise regulatory mechanisms that dictate the extent of immunopathology are poorly understood. The main objective of this proposal is to investigate the role of dendritic cells (DC) in determining disease severity in murine schistosomiasis. The specific goals of this project are 1) to determine if DC isolated from high but not low pathology mouse strains can be stimulated to become activated and produce pro- inflammatory cytokines following exposure to live schistosome worms and eggs and 2) to determine if high versus low pathology DC exposed to schistosome products preferentially drive the differentiation of CD4 T cell populations to become pathogenic Th17 or protective Th2 cells, respectively. Among several standard state of the art techniques, this project will take advantage of a novel, unique S. manson/-specific TCR transgenic mouse system. Since DC are a critical link between innate and adaptive immunity, this project will provide invaluable insight into how immunopathology develops from the initial invasion of the parasite to the pathogenic T cell-mediated formation of granulomatous lesions. Despite a highly effective drug treatment with praziquantel, re-infection with schistosomes is a common occurrence in the endemic regions of the world. Unfortunately, a vaccine for schistosomiasis has yet to be developed. The research proposed in this grant will contribute to the understanding of the basic pathogenesis of schistosomiasis and to the design of specific immunotherapies.