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：（由申请人提供）：尽管有治疗方案， 血吸虫病仍然是几大洲的一个主要公共卫生问题 （一）.使用小鼠作为最终人类宿主模型的实验工作 揭示了疾病的严重程度是由免疫系统的性质调节的， 在感染过程中产生的反应。免疫流行病学研究 血吸虫病流行支持这一观点。通常，小鼠和人类 对感染产生强烈的Th 2反应，这似乎对感染至关重要。 让宿主在感染的时候存活下来 这项建议有两个主要目标。第一，目标1和2所涉及的是 开始了解感染的潜在病理生理学。第二个， 目标3的目标是促进对Th 2应答发展的理解 通过对小鼠品系（CD 154-I-小鼠）的研究， 在感染过程中不能产生Th 2反应。选择的区域 研究反映了上一个供资期的结果，并纳入了相关的 以及该领域令人兴奋的新发展。提案的具体目标 主要有：1）探讨NO和超氧化物在疾病中的相对作用 感染期间的发展，并建立免疫要求 2）确定反应物的来源， NO在感染时血管调节中的作用 CD 154在感染中的作用这些目标将通过各种方法来实现。 免疫学、生物化学和分子生物学技术， 充分利用现有的基因敲除小鼠， 评估p47-phox（NADPH氧化酶）和内皮细胞的作用， 诱导型一氧化氮合酶。另夕h 通过杂交培育携带破坏的新突变小鼠品系 在IL-4/iNOS、IL-4/iNOS和IL-4/p47-phox中， NO和超氧化物在IL-4中发展的严重疾病中的作用 Th 2反应缺陷小鼠。此外， 寄生虫源性NO对宿主反应的调节将得到解决 通过克隆和表达推定的寄生虫NOS， 鉴定能够抑制该NOS的抑制剂，以及 用本发明的组合物治疗感染的eNOS或iNOS或eNOS/iNOS敲除小鼠， 抑制剂. Th 2反应的发展，假设是 在感染过程中对调节NO和O的产生至关重要， 从研究CD 154的作用的新方法来研究， CD 4 O配体。后面的研究有望揭示出 B细胞在感染过程中的作用，这是一个重要的问题， 这次 对这些问题的详细审查应增进对以下问题的了解： 1)寄主对寄生虫寄生的先天生理反应; 2)适应性免疫反应如何与先天免疫反应整合并调节先天免疫反应 3）免疫反应如何调节自身，以及4）寄生虫如何 来影响这些过程。