T cell help in the B cell response to malaria CS protein

描述（由申请人提供）：虽然疟疾在大多数西方国家已被根除，但由于寄生虫对药物和蚊子对杀虫剂的抵抗力增强，它已成为当今最重要的新发疾病之一。人们为开发一种预防这种疾病的疫苗作出了巨大努力，但由于缺乏对如何引发针对寄生虫的保护性免疫的知识，进展受到严重阻碍。最近的研究表明，对疟疾孢子抗原的体液免疫反应是沿着t依赖性和t非依赖性途径驱动的。然而，T细胞帮助刺激对孢子虫的保护性免疫的作用是有争议的。本提案的目标是首次对疟疾孢子虫感染的体液免疫反应进行全面分析，并确定t依赖性和t非依赖性激活途径在形成反应中使用的抗体库中的作用。这些目标将通过检查正常小鼠和T细胞缺陷小鼠对疟疾孢子虫感染的初级免疫反应来实现。这种反应将首先通过构建一系列的杂交瘤文库来测量，这些文库专门针对被感染的正常小鼠和裸鼠的孢子子的免疫优势抗原。每个文库将分析针对抗原的抗体库，包括复发克隆型、同型使用、精细特异性和亲和力成熟。最后，将比较在t依赖性和t非依赖性条件下获得的文库之间的免疫反应，以确定它们之间的质的差异。该项目将作为一个试点研究，为以后更全面的研究描绘t依赖性和t非依赖性激活途径在激发长期的、针对疟疾感染的保护性免疫中的作用。

DESCRIPTION (provided by the applicant): Although malaria has been eradicated in most of the western world, it has become one of the most important emerging diseases today due to the increased resistance both of the parasite to drugs and the mosquito to insecticides. There has been tremendous effort to develop a vaccine to prevent the disease, but progress has been severely hampered by the lack of knowledge of how protective immunity is elicited against the parasite. Recent work suggests that the humoral immune response to malaria sporozoite antigens is driven along both T-dependent and T-independent pathways. However, the role of T cell help in stimulating protective immunity against sporozoites is controversial. The goal of this proposal is to produce the first comprehensive analysis of the humoral immune response to malaria sporozoite infection, and to determine the role of T-dependent and T-independent activation pathways in shaping the repertoire of antibodies utilized in the response. These goals will be addressed by examining the primary immune response to malaria sporozoite infection in normal and T cell-deficient mice. The response will be measured by first constructing a series of hybridoma libraries specific for the sporozoite's immunodominant antigen from infected normal and nude mice. Each of the libraries will be analyzed for the antibody repertoire utilized against the antigen in regards to recurrent clonotypes, isotype usage, fine specificity, and affinity maturation. Finally, the immune responses between libraries derived under T-dependent and T-independent conditions will be compared to determine what qualitative differences lay between them. This project will act as a pilot study for a later, more comprehensive study to delineate the role of T-dependent and T-independent activation pathways in provoking long-lived, protective immunity against malaria infection.