Validation of the Candida albicans delayed-type hypersensitivity (DTH) model in the female B6C3F1 mouse for use in immunotoxicological investigations

Abstract

Although numerous models are used to evaluate the immunotoxic effects of xenobiotics on cell-mediated immunity (CMI), no holistic model for evaluating such effects on the delayed-type hypersensitivity (DTH) response has gained widespread acceptance. Due to a lack of interference from antigen-specific antibody production, the Candida albicans DTH model has recently been demonstrated to be a more appropriate model for assessing effects on CMI than other DTH models that utilize different sensitizing antigens, such as sheep erythrocytes (SRBC) or keyhole limpet hemocyanin (KLH). The present studies were conducted to validate the C. albicans DTH model for its ability to detect suppression (or the lack thereof) of CMI following exposure for 28 days to well-characterized immunosuppressive drugs, each having a different mechanism of action. The compounds evaluated included azathioprine (AZA), cyclophosphamide (CPS), cyclosporin A (CSA), dexamethasone (DEX), and the non-immunotoxic compound, benzo[e]pyrene (B[e]P). Exposure to each of the four known immunotoxicants resulted in statistically significant decreases in the DTH response to C. albicans. Footpad swelling was decreased following exposure to AZA at ≥ 20 mg/kg but not at 10 mg/kg, CPS at ≥ 10 mg/kg but not at 5 mg/kg, CSA at ≥ 3 mg/kg but not at 1 mg/kg, or DEX at ≥ 0.3 mg/kg (intermittently at 0.1 mg/kg) but not at 0.03 mg/kg. As expected, exposure to B[e]P for 28 days at doses up to 40 mg/kg had no effect on the DTH response. These results demonstrated that the C. albicans DTH assay in the B6C3F1 mouse was capable of appropriately classifying each test article as to its immunotoxic effects on CMI. Furthermore, comparisons of these results with previous reports of effects on ex vivo CMI end points suggest that this DTH assay may be more sensitive than standard ex vivo assays at detecting immunosuppressive effects.