The program is a five year continuation of a comprehensive study of the immunobiology of experimental lymphatic filariasis in the congenitally athymic nude' and euthymic normal' mouse. This novel murine model of brugian filariasis, represents a fundamental departure from conventional animal models such as the cat and the gerbil. Unlike conventional hosts, the immunologic makeup of the inbred mouse is well defined allowing manipulation of protective as well as pathologic immune responses to infective third stage larvae and adult worms. Further, the lymphatics of nude mice parasitized by adult Brugia malayi become massively dilated allowing cannulation for direct intralymphatic adoptive immunologic reconstitution, and for sampling lymph for antigen and mediator analyses. We know of no other animal model in which dilated lymphatics can be used as biological chambers in which to study mechanisms of protective versus pathologic immunity to filarial parasites and their products. Components of humoral and cellular immune responses to filarial antigens identified in normal mice, will be adoptively transferred to nude mice. Ultimately protective (larvicidal) or pathologic reactions to larval or adult worm antigens in the lymphatic tissues of parasitized mice, will be defined by flourescence microscopy employing monoclonal antibodies to discrete antigens and cell surface markers, and by ultrastructural analysis using transmission electron microscopy. Viability of larvae recovered from lymphatics after immunologic manipulation will be assessed by infectivity for clean nude mice. Filarial antigens, with emphasis upon excretory-secretory (E-S) products of B. malayi, will be purified by affinity chromatography on monoclonal antibody-bound columns from the lymph of parasitized mice, characterized by polyacrylamide gel electrophoresis and electro-immunoblotting then protective function in vivo. Similar methodology will be used for antigens of other filarial species as the host range of the nude mouse is explored. We expect this research to have important applications in the specific immunodiagnosis of human filariasis and in futher immunologic intervention in the disease process.
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