Immunosuppressive Effects of the Cyclosporin Derivative SDZ IMM 125 on Kidney Allograft in the Dog and Small Bowel and Pancreas Allografts in the Rat

Abstract

The efficacy of SDZ IMM 125 in preventing allograft rejection was evaluated in kidney transplantation in the dog and orthotopic small bowel and heterotopic pancreas transplantation in the rat. Seven groups (n= 6) were involved in dog kidney transplantation. Untreated recipients rejected kidney allografts with a mean survival time (MST) of 8.0 ± 1.8 days. There was a graded dose response in SDZ IMM 125-treated groups: 10 mg/kg/day, MST 11.3 ± 3.5 days,P= 0.065; 15 mg/kg/day, MST 44.8 ± 10.8 days,P= 0.0001; and 20 mg/kg/day, MST 47.3 ± 5.6 days,P= 0.0001, same as in cyclosporin A (CsA)-treated groups: 10 mg/kg/day, MST 25.8 ± 13.7 days,P= 0.001; 15 mg/kg/day, MST 38.3 ± 18.1 days,P= 0.002; and 20 mg/kg/day, MST 38.7 ± 17.7 days,P= 0.002. Low dose of SDZ IMM 125 (10 mg/kg/day) was less effective in prolonging the graft survival than low dose of CsA. High dose (20 mg/kg/day) treatment of both SDZ IMM 125 and CsA led to abnormal recipient liver enzymes alanine aminotransferase and aspartate aminotransferase postoperatively. A histopathological study demonstrated fatty degeneration of hepatic cells in both 20 mg/kg/day SDZ IMM 125- and CsA-treated groups. We also tested the effect of SDZ IMM 125 in orthotopic small bowel transplantation with three combinations, namely host-versus-graft (HVG), graft-versus-host (GVH), and combined HVG and GVH immune responses and pancreas transplantation in the rat with different doses. The results indicate that SDZ IMM 125 is a potent immunosuppressant to prolong the kidney allograft survival in the dog, to alleviate HVG and GVH responses in small bowel transplantation, and to delay pancreas allograft rejection in the rat. Low dose of SDZ IMM 125 is less effective than a similar dose of CsA to prevent kidney allograft rejection in the dog.