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Immunotoxicological investigation using pharmaceutical drugs: in vivo evaluation of immune effects
1Laboratoire de Toxicologie, INSERM CJF 93.01, Faculté de Pharmacie Paris XI, Chatenay Malabry, France.
Abstract:
Traditional methods for toxicological assessment have indicated that the immune system is a frequent target of toxic insult following subchronic or chronic exposure to xenobiotics. However, most of the xenobiotics evaluated in standardized protocols were environmental chemicals and correlation with available clinical data was not possible. The purpose of this work was to evaluate the potential immunosuppressive effects of pharmaceutical drugs using a standardized protocol developed for immunotoxicological assessment. Two groups of pharmaceutical drugs were utilized: (a) drugs without known immunosuppressive effect linked to their utilization in human therapy (cimetidine, furosemide, indomethacin, amoxicillin, and procainamide) and (b) immunosuppressive drugs (azathioprine, cyclosporine A, and dexamethasone). Ex vivo tests using B6C3F1 mice were performed after a 28-day repeat dose regimen and assessed: (a) immunopathology, (b) cell-mediated immunity, (c) humoral immunity, and (d) nonspecific immunity. Host resistance to Listeria monocytogenes was also assessed following exposure to immunosuppressive drugs. The results showed that (a) immunopathology and immune function assays were necessary to detect all immunotoxicants and (b) the effects observed with nonimmunotoxic drugs were sometimes statistically significant but the biological significance of these effects is unlikely.
Insights
This study assessed pharmaceutical drugs for immunosuppressive effects using a standardized immunotoxicology protocol in mice. While some non-immunosuppressive drugs showed minor effects, only potent immunosuppressants were definitively identified.
Area of Science:
- Immunotoxicology
- Pharmacology
- Drug Safety Assessment
Background:
- The immune system is a common target for xenobiotics, but traditional assessments often use environmental chemicals, limiting clinical correlation.
- Standardized protocols are needed to evaluate the immunotoxic potential of pharmaceutical drugs.
Purpose of the Study:
- To evaluate the immunosuppressive effects of pharmaceutical drugs using a standardized immunotoxicological assessment protocol.
- To differentiate between statistically significant but biologically irrelevant effects and true immunotoxicity.
Main Methods:
- A 28-day repeat dose regimen was administered to B6C3F1 mice using known immunosuppressive drugs and drugs without known immunosuppressive effects.
- Assessed immunopathology, cell-mediated immunity, humoral immunity, nonspecific immunity, and host resistance to Listeria monocytogenes.
Main Results:
- Immunopathology and immune function assays were essential for identifying all immunotoxicants.
- Non-immunosuppressive drugs sometimes produced statistically significant effects, but these were unlikely to be biologically significant.
Conclusions:
- The standardized protocol effectively identified potent immunosuppressive drugs.
- Careful interpretation is needed for statistically significant findings with non-immunosuppressive drugs to avoid misclassifying them as immunotoxic.