Validation of a screening battery for immunotoxicity of drugs within a 28 day oral toxicity study, using cyclosporin as a model compound
[Validatie van een test batterij voor immunotoxiciteit van geneesmiddelen in het kader van een 28 daagse orale toxiciteitsstudie met cyclosporine als modelstof.]
van Loveren H, Timmerman HH, Dortant PM, de Waal EJ
RIVM Report 312620001
We have validated a panel of parameters for immunotoxicity that we propose to be incorporated in routine screening for toxicity of pharmaceuticals. This panel comprises serum immunoglobulin concentrations, cellularity of bone marrow, weights and histopathology of thymus, spleen, and lymph nodes, histopathology of Peyers' Patches, and FACScan analysis of lymphocyte subpopulations in the spleen, in addition to parameters of toxicity to other systems. For this purpose we used cyclosporin-A, an immunosuppressive drug, as a model compound with an immunotoxic activity. Rats were exposed by daily gastric intubation of 0, 1.25, 5 or 20 mg cyclosporin A per kg body weight. The histopathology of the thymus, as well as the data provided by FACScan analysis turned out to be valuable parameters, since they detected changes at the lowest dose levels used in this study. Measuring immunoglobulin titers and histological examination the spleen, Peyers' Patches, and lymph nodes were less sensitive in this study, but were valuable in that they supported the other findings, thus providing a more firm base to decide on the relevance of immunotoxicity detected with this battery of tests. Apart from changes in the lymphoid organs, toxicity was evident in the kidneys at 20 mg/kg/day only. These data indicate that the most sensitive target of toxicity of cyclosporin A is the lymphoid system. We conclude that our test battery yielded an immunotoxicity profile of cyclosporin-A in rats that in general was consistent with published findings in the literature, indicating the validity of the test battery that is proposed.