Dose–Response Relationships of Weight, Cellularity, Plaque-Forming Cell Response, and Histology in the Spleen of Rats Treated with Antimetabolites

Abstract

Our previous reports revealed the usefulness of investigating the changes in the weight, cellularity, and histology in the spleen caused by alkylating agents to evaluate immunotoxicity, compared with the plaque-forming cell (PFC) assay using appropriate conditions. In this study, dose–response relationships of weight, cellularity, PFC response, and histology in the spleen in rats treated with antimetabolites were studied. A single administration of azathioprine or 6-mercaptopurine (6-MP) caused decreases in spleen weights and cellularity and the PFC response at nearly the same dose level. In the rats treated with these agents for 7 days, spleen weights and cellularity tended to be decreased at doses lower than those suppressing the PFC response. In the rats singly treated with 5-fluorouracil (5-FU), spleen weights and cellularity were decreased at a dose lower than that suppressing the PFC response. At low and middle doses, the PFC response was inversely enhanced by this agent. A 7-day administration of 5-FU caused reductions in spleen weights and cellularity and PFC response at the same dose level. In addition, the spleen in the rats dosed with azathioprine, 6-MP, or 5-FU was histopathologically examined and indicated a dose-related decrease in the size of the spleen without changes in the tissue architecture at doses suppressing the PFC response. On the other hand, in the red pulp, the extramedullary hematopoiesis disappeared by these antimetabolites at the doses. These results indicate that decreases in the weight and cellularity and histological changes in the spleen caused by antimetabolites are detectable at doses suppressing the PFC response.