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

Henry M. Jackson Fdn For The Adv Mil/Med, Rockville MD

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Abstract

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.