The effects of cyclosporine and cyclosporine metabolites in experimental small intestinal transplantation

Cyclosporine metabolites (CM) were compared with cyclosporine for their in vitro and in vivo immunosuppressive, nephrotoxic, and hepatotoxic effects using (A) in vitro mixed lymphocyte induction of monocyte/macrophage procoagulant activity (PCA), an accurate marker of allograft rejection; (B) in vitro toxic effects on renal cells in culture; and (C) a unidirectional rejection model of rat small intestinal transplantation (SIT). CM were composed of OL1, OL17, OL18, and two additional peaks C and H, (peak C: mass = 1235, 15.3% of total CM, peak H: mass = 1205, 6.3% of total CM). In vitro, CM fully suppressed the one-way mixed lymphocyte culture—induced PCA from 52.5±8.2 mU/10⁶ PBM to the basal level 22.3±6.6 mU/10⁶ PBM (p <0.01), which was comparable to CsA (21.3±5.5 mU/10⁶ PBM). Lewis rats that had received Lewis-Brown Norway F₁ hybrid intestinal allografts when treated with CM, demonstrated near-normal histology with minimal signs of rejection as compared with the fulminant clinical and histological rejection observed in the control (untreated and Cremaphor/NaCl treated) animals. PCA was markedly elevated in the control animals, 278±172 (untreated) and 160±98 mU/10⁶ PBM (Cremaphor/normal saline treated), whereas CsA-treated allogeneic transplants expressed only basal levels of PCA (14.0±4 mU/ 10⁶ PBM) (P<0.01), associated with normal histology. CM-treated animals expressed PCA levels of 27.0+10 mU/10⁶ PBM, which was significantly different from both control and CsA treated animals (P<0.01). In contrast to CsA-treated animals, CM-treated allogeneic transplants demonstrated no apparent renal or hepatic toxicity, as measured by blood urea nitrogen (25.3±9.5 vs. 10.0±5.3 mg/dl), alkaline phosphatase (160.7±29.3 vs. 100.3±19.5 U/L), and aspartate transaminase (96.7+23.7 vs. 61.7+11.7 U/L) (P<0.01). Similarly, in contrast to CsA, CM had minimal or no toxicity in renal epithelial and mesangial cells in culture, as measured by minimal or no inhibition of DNA, RNA, and protein synthesis. These results suggest that CM have potent immunosuppressive properties with no apparent nephrotoxicity and hepatotoxicity in vitro and in vivo.