PROLONGATION OF CANINE PANCREATIC-ISLET ALLOGRAFT SURVIVAL WITH COMBINED RAPAMYCIN AND CYCLOSPORINE THERAPY AT LOW-DOSES - RAPAMYCIN EFFICACY IS BLOOD LEVEL RELATED

We studied the survival of 5 groups of apancreatic mongrel dogs that received 30 days of treatment with CsA adjusted to 300 mu g/L, rapamycin (0.05 mg/kg/day), both, or no immunosuppression after intrasplenic allotransplantation with purified pancreatic islets. Autografts survived indefinitely. Neither CsA nor rapamycin alone at low doses showed significant increase in islet allograft survival: 6.2+/-1.7 and 5.0+/-13.2, respectively, versus 3.4+/-1.0 days in controls. Dogs treated with low doses of both CsA and rapamycin demonstrated prolongation of graft function to 23.6+/-13.2 days (P<0.05). These findings support synergism between these 2 agents, especially as CsA was not shown to increase trough rapamycin blood concentration when given together. In the combined treatment group, a significant (r=0.90, P<0.001) relationship was found between rapamycin blood levels and graft survival. Animals having trough rapamycin concentrations > 10 mu g/L had significantly (P<0.05) prolonged graft survival, which suggests that dosing of rapamycin according to blood levels may optimize the effectiveness of the drug. Given at these low doses, combination CsA and rapamycin gave no evidence of adverse effects as measured by hepatic and renal function tests, histology, or electron microscopy.