Immune parameters are affected differently after cyclosporine A exposure in Fischer 344 rats and B6C3F1 mice: implications for immunotoxicology

Abstract Knowledge of interspecies differences, commonly evaluated in other disciplines such as carcinogenesis, is a prerequisite for an appropriate assessment of immunotoxicological risks. The purpose of this study was to assess interspecies differences following exposure of Fischer 344 rats and B6C3F1 mice to cyclosporine A. These animals were exposed daily to cyclosporine A by oral gavage at 0, 5, 10, 25 mg/kg/day for 14 consecutive days. The results showed that splenocytes lymphoproliferation in response to concanavalin A or phytohemagglutinin, and IgM antibody-forming cells to sheep red blood cells, were affected in both species. Cytotoxic T-lymphocyte activity and mixed lymphocyte response were significantly inhibited in the rat following cyclosporine A exposure while they remained unaffected in the mouse. In contrast, natural killer cell activity was significantly depressed in the B6C3F1 mouse but not in the Fischer 344 rat. The discrepancies between the two species in cytotoxic T-lymphocyte activity and mixed lymphocyte response assays could partially be explained by the constantly higher blood level of cyclosporine A in the rat than in the mouse. When these tests were performed using rat and mouse splenocytes exposed to cyclosporin A in vitro (10 −9 to 10 −5 M) it was possible to correlate in vivo and in vitro data for concanavalin A- and phytohemagglutinin- induced lymphoproliferation and for cytotoxic T-lymphocyte activity but not for mixed lymphocyte response. Natural killer activity was 10-fold more sensitive in mice than in rats in vitro but these results did not clarify the in vivo difference. In conclusion, these results emphasize that the utilization of more than one species should be considered when assessing immunotoxicity.