Rescue therapy for acute rejection using 15-deoxyspergualin (DSG) in combination with superoxide dismutase (SOD) on cardiac allografts in rats.

Abstract

This study was performed to investigate the effect of combination therapy using 15-deoxyspergualin (DSG) plus recombinant human superoxide dismutase (h-SOD) on acute graft rejection in heterotopic rat heart transplantation. DSG was intraperitoneally injected for 10 days at a dose of 5 mg/kg per day, and h-SOD (15,000 or 30,000 microm/kg per day) was continuously administered via external iliac vein for approximately 8 days with a mini-osmotic pump (Alzet model 2001). Administration of the drugs was started on the 4th day after grafting. The grafts treated with h-SOD alone survived slightly longer than the control allografts. The graft survival time was significantly prolonged in the groups treated with DSG alone or DSG plus h-SOD. A higher percentage of induction of immunological unresponsiveness was achieved in the group treated with DSG plus h-SOD at 30,000 microm/kg per day. The ratios of inorganic phosphate (Pi)/phosphocreatine (PCr) and PCr/ATP on the 31P nuclear magnetic resonance spectrogram are useful parameters for assessing the graft injury associated with acute rejection. The ratio of Pi/PCr and that of PCr/ATP were found to increase and decrease, respectively, in proportion to the progress in rejection. In the animals treated with DSG alone, the Pi/PCr ratio was significantly increased from the 4th day, and PCr/ATP ratio decreased from 10th day after grafting. These parameters were not improved during the observation period. However, these parameters were significantly recovered in the animals treated with DSG and h-SOD in combination. Improvement of the parameters seemed to be related to SOD dosage. These results clearly demonstrated that the oxygen free radical plays a toxic role in cardiac allografts with ongoing rejection and, therefore, the administration of h-SOD in combination with DSG can minimize the graft injury.