Results of a cyclosporin A ringstudy.

The aim of the study was to find out whether an extended subacute toxicity study (additional organ weights, histopathology and immune functional tests), routinely employed in testing of chemicals, would shown indications of (adverse) effects on the immune system below general toxicity. Therefore, a five laboratory ring study on the basis of an oral 28-day repeated dose study in rats (OECD guideline 407) was carried out with 1, 5 and 25 mg/kg of cyclosporin A (CsA) per day by gavage. Besides some toxic effects such as reduced body weight gain and increased kidney calcification in the high-dose group, the results of the additional pathologic examinations revealed that CsA caused a pattern of specific morphological alterations of the lymphoid tissues in mid- and high-dose groups. Selected immune parameters such as immunoglobulin determination, plaque-forming assay, flow cytometry, activation status of macrophages and natural killer cells (NK), and proliferative response of spleenocytes and cells from mesenteric lymph nodes (concanvalin A (ConA) and pokeweed mitogen (PWM) stimulation) were also investigated. Some results compared to the controls revealed alterations down to the low-dose group. The extended methodology consistently indicated the potential detection of effects on the immune system below general systemic toxicity. The study will be continued by investigating a second compound with primarily immunostimulating effects. Results from those studies should further contribute to the current discussion of up-dating of repeated dose toxicity guidelines with respect to immunotoxicity.