MORPHOLOGY OF RAT-KIDNEY AND THYMUS AFTER NATIVE AND ANTIBODY-COUPLEDCYCLOSPORINE-A APPLICATION (REDUCED TOXICITY OF TARGETED DRUG)

This study compares the toxic effects of native cyclosporin A (CyA) wi th those of targeted CyA that is conjugated with the anti-rat-thymocyt e antibody of rabbit origin via the N-(2-hydoxypropyl)methacrylamide ( HPMA) carrier bearing digestible, reactive oligopeptide side chains. T en toxic doses of native CyA (50 mg/kg i.p.) given to young adult rats in the course of 14 d produced a severe renal lesion - diffuse microv acuolization of the proximal tubules in the deep cortex, and hypergran ulation of juxtaglomerular regions. Severe atrophy of the thymic medul la was documented by morphometry. In the cortex the epithelial reticul ar (but not deep interdigitating) cells showed ultrastructural signs o f severe degeneration rind lysis. The immature CD4(+)8(+) double-posit ive cortical lymphocytes were preserved whereas the single-positive me dullary thymocytes were greatly depleted; there was also a restriction of MHC class II antigen expression in the medulla. The number of medu llary B cells was increased. The cytokeratin net was focally shrunken in the cortex and almost negative in the medulla, with loss of Hassall 's corpuscles. After ten corresponding doses of antibody-targeted conj ugated CyA no damage to the renal tubules and arterioles appeared and the antiGBM or immune-complex deposition was absent. The thymus had a normal medulla with numerous mature thymocytes and the cortical epithe lial reticulum remained well preserved. Thus, the main toxic effects o f CyA could be eliminated by targeting. The T-cell-targeted drug was t ested for preserved immunosuppressive properties and nontoxic characte r of HPMA copolymer carrier.