IMMUNOSUPPRESSIVE ACTIVITY AND TOXICITY OF CYCLOSPORINE-A IN RATS PRETREATED WITH HIGH-DOSE CYCLOPHOSPHAMIDE

Cyclophosphamide (Cy; 150 mg/kg) was administered (i.p.) to groups of Sprague-Dawley rats, followed two days later by immunization with ovalbumin (OVA). From that time, cyclosporin A (CsA; 25 mg/kg) or its vehicle was given (p.o.) for a further 13 days. Control animals tested 14 days after immunization, showed strong Arthus-like and modest delayed-type skin reactions to OVA, in contrast to almost total inhibition in animals tested with Cy, CsA or both. Similar effects were observed with respect to serum anti-OVA antibody levels. Despite itself producing lymphopenia, CsA had no additional effect on the lymphocyte depletion caused by Cy. Both drugs, either alone or in combination, caused neutrophilia and monocytosis. An additional eosinophilia due to Cy was prevented by CsA. Cy induced splenomegaly, nodal extramedullary hemopoiesis and increases in both tissue eosinophils and marrow neutrophils. There was also lymphoid depletion in both spleen and lymph nodes which was enhanced by CsA. Thymic lymphoid atrophy was found only when CsA was given. Despite the powerful immunosuppressive properties of both drugs, detailed biochemical and structural analyses showed no other synergistic toxicity, apart from modest hepatic abnormalities. In particular, there was no enhancement of the nephrotoxicity of CsA.