Induction of Pathogenic Innate and Adaptive Immune Responses by Schistosome Helmi

血吸虫 Helmi 诱导致病性先天性和适应性免疫反应

• 批准号: 7488609
• 负责人: Mara G Shainheit
• 金额: $ 3.87万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7488609
• 关键词: Africa; Antigens; Arts; CD4 Positive T Lymphocytes; Coculture Techniques; Conditioned Culture Media; Dendritic Cells; Effector Cell; Exposure to; Far East; Goals; Grant; Granuloma; Granulomatous; Helminths; Heterogeneity; Human; Immune response; Immunity; Immunotherapy; Infection; Inflammatory; Intestines; Life; Link; Liver; Mediating; Middle East; Modeling; Monoclonal Antibody HuM291; Mouse Strains; Muromonab-CD3; Mus; Parasites; Parasitic Diseases; Pathogenesis; Pathogenicity; Pathology; Pharmaceutical Preparations; Population; Praziquantel; Production; Reaction; Research; Role; Schistosoma; Schistosoma mansoni; Schistosomiasis; Severity of illness; South America; Standards of Weights and Measures; System; T-Lymphocyte; Techniques; Testing; Th2 Cells; Transgenic Mice; Transgenic Organisms; Vaccines; cytokine; design; egg; immunopathology; insight; novel; parasite invasion; response

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.

描述（由申请人提供）：血吸虫病是一种严重的、可能致命的寄生虫病，主要在非洲、南美洲以及中东和亚洲的部分地区影响约2亿人。血吸虫病的基本病理是CD 4 T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。在人类和鼠模型中，疾病的严重程度存在显著的异质性。然而，决定免疫病理学程度的精确调节机制知之甚少。本研究的主要目的是探讨树突状细胞（DC）在小鼠血吸虫病病情严重程度判断中的作用。该项目的具体目标是1）确定从高病理学而非低病理学小鼠品系分离的DC是否可以在暴露于活的寄生蠕虫和卵后被刺激活化并产生促炎细胞因子，以及2）确定暴露于溶酶体产物的高病理学DC与低病理学DC是否优先驱动CD 4 T细胞群分化为致病性Th 17或保护性Th 2单元格。在几个标准的最先进的技术，该项目将利用一个新颖的，独特的S。曼森/-特异性TCR转基因小鼠系统。由于DC是先天免疫和适应性免疫之间的关键联系，该项目将提供宝贵的见解，了解免疫病理学如何从寄生虫的初始入侵发展到致病性T细胞介导的肉芽肿病变的形成。尽管吡喹酮药物治疗非常有效，但血吸虫再次感染在世界流行地区仍很常见。不幸的是，血吸虫病的疫苗还没有研制出来。这项研究将有助于理解血吸虫病的基本发病机制和设计特异性免疫疗法。