Schistosome Egg Induced TH2 Responses

血吸虫卵诱导 TH2 反应

• 批准号: 6861044
• 负责人: EDWARD J. PEARCE
• 金额: $ 31.41万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6861044
• 关键词: CD4 molecule; CD40 molecule; Schistosoma; antigen antibody reaction; cellular immunity; cytokine; enzyme linked immunosorbent assay; flow cytometry; gene targeting; genetically modified animals; helminthic antigen; helper T lymphocyte; host organism interaction; immunopathology; laboratory mouse; lymphocyte proliferation; microorganism immunology; nitric oxide synthase; nitrogen oxides; schistosomiasis; superoxides; western blottings

DESCRIPTION: (provided by the applicant): Despite treatment programs, schistosomiasis remains a major public health problem on several continents (1). Experimental work using the mouse as a model for the definitive human host has revealed that disease severity is modulated by the nature of the immune response that develops during infection. Immunoepidemiological studies in areas endemic for schistosomiasis support this view. Typically, mice and humans respond to infection with a strong Th2 response that appears to be crucial for allowing the host to survive while infected. This proposal has two major goals. The first, addressed in Aims 1 and 2, is to begin to understand the underlying pathophysiology of infection. The second, targeted by aim 3, is to advance the understanding of Th2 response development through the study of a mouse strain (the CD 154-I- mouse) that has been found to be incapable of making a Th2 response during infection. The areas chosen for study reflect findings in the previous funding period and incorporate relevant and exciting new developments in the field. The specific aims of the proposal are: 1) To assess the relative roles of NO and superoxide in disease development during infection, and to establish the immunological requirements for the production of these reactive species; 2) To establish the source and function of NO in vascular regulation during infection; 3) To investigate the role of CD 154 during infection. These aims will be addressed using a variety of immunological, biochemical and molecular biological techniques, and will take full advantage of available gene knockout mice for the definitive assessment of the role of p47-phox (of the NADPH oxidase) and endothelial and inducible nitric oxide synthases during infection. Additionally, the development by cross-breeding of new mutant mouse strains carrying disruptions in IL-4IeNOS, IL-4/iNOS, and IL-4/p47-phox is proposed in order to establish the roles of NO and superoxide in the severe disease that develops in IL-4 deficient, Th2-response defective mice. In addition the contribution of parasite derived NO to the regulation of host responses will be addressed through the cloning and expression of the putative parasite NOS, the identification of an inhibitor capable of inhibiting this NOS, and the treatment of infected eNOS or iNOS or eNOS/iNOS knockout mice with the inhibitor. The development of the Th2 response, which is postulated to be crucial for the regulation of the production of NO and 0 during infection, will be examined from the novel approach of investigating the role of CD 154, the ligand for CD4O. The latter studies are expected to shed light on the precise role of B cells during infection, an important question that is unresolved at this time. The examination of these issues in detail should increase the understanding of: 1) the innate physiological response of the host to parasitism by schistosomes; 2) how the adaptive immune response integrates with and regulates the innate response; 3) how the immune response regulates itself, and 4) how the parasite intervenes to influence these processes.

描述：（申请人提供）：尽管治疗计划， 血吸虫病仍然是多个大洲的主要公共卫生问题 （1）。使用小鼠作为确定性人类宿主的模型的实验工作 已经揭示了疾病的严重程度是由免疫的性质调节的 感染期间发展的反应。领域的免疫ePIDEMIologology研究 血吸虫病的特有支持支持这种观点。通常，老鼠和人类 以强烈的Th2反应对感染做出反应，这似乎对 允许宿主在感染时生存。 该提议有两个主要目标。 AIMS 1和2中的第一个是 开始了解感染的潜在病理生理学。第二， AIM 3的目标是提高对TH2响应发展的理解 通过研究已发现的小鼠菌株（CD 154-i-鼠）的研究 在感染期间无法做出Th2反应。选择的区域 研究反映了上一个资金期间的发现，并结合了相关的发现 以及该领域令人兴奋的新事态发展。提案的具体目的 是：1）评估NO和超氧化物在疾病中的相对作用 感染期间的发展，并建立免疫学要求 为了生产这些反应性物种； 2）建立来源和 在感染过程中NO在血管调节中的功能； 3）调查 CD 154在感染过程中的作用。这些目标将使用多种多样来解决 免疫，生化和分子生物学技术的 充分利用可用的基因基因敲除小鼠 评估p47-phox（NADPH氧化酶）和内皮的作用 感染过程中可诱导的一氧化氮合酶。另外， 通过携带中断的新型突变小鼠菌株的杂交开发 在IL-4ienos中，提出了IL-4/Inos和IL-4/P47-Phox，以建立 NO和超氧化物在IL-4中发展的严重疾病中的作用 缺乏Th2反应有缺陷的小鼠。另外 将解决主机响应调节的寄生虫 通过推定的寄生虫NOS的克隆和表达， 鉴定能够抑制该基础的抑制剂，以及 处理感染的eNOS或INOS或ENOS/INOS基因敲除小鼠 抑制剂。 TH2响应的发展，该响应被认为是 对于调节NO的生产至关重要，在感染过程中，将 从研究CD 154的作用的新方法中进行检查， CD4O的配体。后者的研究有望阐明精确的 B细胞在感染过程中的作用，这是一个未解决的重要问题 这次。 对这些问题进行详细检查应增加对： 1）宿主对寄生虫的先天生理反应； 2）适应性免疫反应如何与先天性相结合并调节 回复; 3）免疫反应如何调节自身，4）寄生虫如何 干预以影响这些过程。