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 the food chain. Of these vomitoxin is encountered most often in the U.S. food supply. Ingestion of vomitoxin by mice results in marked increases in serum IgA. It is hypothesized that dietary exposure to trichothecene mycotoxins impairs normal regulation of IgA production and that this results in accumulation of serum IgA. The overall goals of this proposal are to understand the cellular basis by which trichothecenes modulate IgA production within the mucosal and systemic compartments and relate this effect 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 determine the effects of in vitro exposure to vomitoxin on macrophage and T cell regulation of IgA production in spleen and Peyer's patch (PP) cultures. Second, the effects of in vivo vomitoxin exposure on regulation of IgA production will be assessed by quantitating in vitro IgA secretion in spleen and PP- derived lymphocyte cultures, measuring IgA-secreting B cell and T regulatory cell frequency in spleen and PP, and monitoring mucosal and systemic IgA response to oral antigen challenge. Third, IgA distribution following in vivo vomitoxin exposure will be characterized by monitoring changes in total serum IgA, secretory IgA, and ratio of serum monomeric:polymeric IgA; and by determining potential for IgA deposition in kidney mesangium. Finally trichothecene structure will be related to modulation of IgA production in in vitro cultures.
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