INVESTIGATION OF A SCREENING BATTERY FOR IMMUNOTOXICITY OF PHARMACEUTICALS WITHIN A 28-DAY ORAL TOXICITY STUDY USING AZATHIOPRINE AND CYCLOSPORINE-A AS MODEL COMPOUNDS

The authors have investigated a panel of parameters for immunotoxicity that may be incorporated in routine screening for toxicity of pharmac euticals. This panel comprises serum immunoglobulin concentrations, ce llularity of bone marrow, weights and histopathology of thymus, spleen , and lymph nodes, histopathology of Peyers' patches, and FACScan anal ysis of lymphocyte subpopulations in the spleen, in addition to parame ters of toxicity to other systems. To study the value of these assays for pharmaceuticals, the authors used the immunosuppressants azathiopr ine (AZP) and cyclosporin A (CsA) as model compounds with known immuno toxic activity. In two separate experiments, rats were treated by dail y gastric intubation with 0, 5, 12.5, and 25 mg AZP/kg body wt or 0, 1 .25, 5, and 20 mg CsA/ kg body wt. In the AZP study, the histopatholog y of the thymus and the spleen were valuable parameters of immunotoxic ity, since these organs showed microscopic alterations at relatively l ow dose levels. In the CsA experiment, both the histopathology of the thymus and the data provided by FACScan analysis were sensitive indica tors of immunotoxicity detecting effects at the lowest dose level empl oyed, The data indicate that the lymphoid system is the most sensitive target of toxicity after AZP or CsA administration. The authors concl ude that their test battery yielded immunotoxicity profiles of AZP and CsA in rats that were consistent with published findings in the liter ature, indicating the usefulness of the test battery employed. (C) 199 5 Academic Press, Inc.