Schistosomiasis continues to be a major helminthic disease suffered by millions of people throughout the world. This proposal describes the continuation of studies to investigate basic immunologic and immunopathologic mechanisms in the experimental murine model of schistosomiasis. The analysis and understanding of the specific T cell response and of non-specific immunoregulatory mechanisms will facilitate the design of strategies to down-regulate the T cell-mediated granulomatous hypersensitivity responsible for the schistosomal disease. Known and newly identified parasite egg antigens will be investigated with the use of specific T cell clones/hybridomas and their epitopes will be mapped. The recognition of specifiC antigens/epitopes, as well as of the corresponding T cell receptor repertoire, will be compared in large and small granuloma-forming strains of mice possibly representing polar forms of human disease. The hypothesis that the down-modulation of schistosomal disease is due to the induction of specific T cell anergy by granuloma macrophages will be further tested. Specific experiments will investigate the role of IL-10 in the inhibition of macrophage-derived """"""""costimulatory"""""""" signals necessary for the stimulation of T cells. IL-10 and costimulation-blocking reagents will be directly tested for their ability to down-regulate the magnitude of granulomatous inflammation in vivo. The long-term goals of this project are the design and administration of appropriate egg antigens/peptides, in possible conjunction with anti- costimulation agents, for induction of lasting specific T cell anergy and amelioration of granulomatous disease.
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