The trichothecene mycotoxins are a group of sesquiterpenoid fungal metabolites that include some of the most potent protein synthesis inhibitors known. Since trichothecenes are frequently found in cereal grains and are recalcitrant to inactivation during milling and processing, they enter human foods. Of these, vomitoxin is encountered most often in the U.S. food supply. Ingestion of vomitoxin by mice dramatically elevates serum IgA and induces pathologic effects that are highly analogous to the common human glomerulonephritis IgA nephropathy. It is hypothesized that dietary exposure to trichothecene mycotoxins alters cytokine-mediated T cell regulation of IgA production. The overall goals of this proposal are to understand the cellular and molecular basis by which trichothecenes modulate IgA production within the mucosal and systemic compartments and relate it to potential health hazards associated with ingestion of these naturally-occurring mycotoxins. Using the mouse model , four(4) specific objectives are proposed. The first objective will be to assess the effects of in vitro vomitoxin exposure on cytokine production by isolated T cells and relate secreted cytokines to B cell differentiation. Second, the effects of in vitro vomitoxin exposure on cytokine gene expression will be characterized in cloned T cells. Third, the effects of in vivo vomitoxin-exposure on cytokine secretion and gene expression in mucosal and systemic tissue will be measured and the secreted cytokines related to IgA hyperelevation. Finally, trichothecene structure will be related to modulation of cytokine-mediated T cell regulation of IgA production.
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