Schistosome Egg Induced TH2 Responses

描述：(申请人提供)：尽管有治疗计划， 血吸虫病仍然是几个大洲的主要公共卫生问题 (1)。用小鼠作为确定的人类宿主的模型的实验工作 揭示了疾病的严重程度是由免疫的性质调节的 在感染过程中产生的反应。地区的免疫流行病学研究 血吸虫病的流行支持这一观点。通常，老鼠和人类 以强烈的Th2反应应对感染，这似乎对 让宿主在被感染的情况下存活。 这项提议有两个主要目标。目标1和目标2中提到的第一个问题是 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Th2反应发展的理解 通过对已发现的一种小鼠品系(CD154-I-小鼠)的研究 在感染期间不能做出Th2反应。所选择的区域 研究反映了上一个资助期的结果，并纳入了相关的 以及该领域令人兴奋的新发展。该提案的具体目的 1)评估一氧化氮和超氧化物在疾病中的相对作用 在感染过程中的发育，并建立免疫学要求 用于生产这些活性物种；2)确定来源和 3)探讨NO在感染时血管调节中的作用。 CD154在感染中的作用这些目标将通过各种方式来实现 免疫学、生化和分子生物学技术，并将 充分利用现有的基因敲除小鼠，以获得最终的 评估P47-Phox(NADPH氧化酶)和内皮细胞的作用 感染过程中的诱导型一氧化氮合酶。此外， 通过杂交培育携带干扰的新突变小鼠品系 在IL-4IeNOS中，提出了IL-4/iNOS和IL-4/P47-Phox，以建立 一氧化氮和超氧化物歧化酶在IL-4所致重症疾病中的作用 Th2反应缺陷的小鼠。此外，还包括 寄生虫衍生的NO对宿主反应的调节将被解决 通过克隆和表达推测的寄生虫一氧化氮合酶， 鉴定一种能够抑制这种一氧化氮合酶的抑制剂，以及 对感染eNOS或iNOS或eNOS/iNOS基因敲除小鼠的治疗作用 抑制剂。Th2反应的发展，被认为是 对于调节感染过程中NO和0的产生至关重要，Will 从研究CD154的作用的新方法来看， CD4O的配体。后一项研究预计将有助于揭示 B细胞在感染中的作用，这是一个尚未解决的重要问题 这一次。 对这些问题的详细审查应能增进对以下问题的理解： 1)宿主对血吸虫寄生的先天生理反应； 2)获得性免疫反应如何与先天免疫结合和调节 反应；3)免疫反应如何自我调节，以及4)寄生虫如何 干预以影响这些过程。

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.