[Evaluation of immunotoxicity testings using azathioprine-treated rats: the International Collaborative...

The immunotoxicological effects of azathioprine (AZP) were examined by enhanced histopathological and function tests in the rat which is routinely used in toxicological tests. Male F344 rats were orally administered AZP in doses of 0, 2.5, 12.5 and 25.0 mg/kg/day for 28 days. Reductions in the organ weights of the thymus, spleen, liver, kidney, and testis in a dose-dependent manner were confirmed. Hematological examination revealed a marked decrease in the number of WBCs, which was associated with a decrease in the number of lymphocytes. In the femoral bone marrow, a significant reduction in the total cell number attributed to the decrease in the number of lymphocytes and granulocytes was observed. Histopathologically, atrophy and obfuscation of the corticomedullary junction in the thymus, the decrease of lymphocytes in the thymus and spleen, and the disappearance of germinal centers in the lymph nodes were observed. As for the functional testings, azathioprine treatment did not affect remarkably the PFC number and the NK cell activity per unit spleen cell number. However, the total spleen cell number per spleen was decreased in a dose-dependent manner. Therefore, the total functional activities (PFC and NK) per spleen were decreased. Thus, in the AZP-treated F344 rats, it was shown that the enhanced histopathological tests were useful to evaluate potential risks to the immune system.