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 r eceived 30 days of treatment with CsA adjusted to 300 mu g/L, rapamyci n (0.05 mg/kg/day), both, or no immunosuppression after intrasplenic a llotransplantation with purified pancreatic islets. Autografts survive d indefinitely. Neither CsA nor rapamycin alone at low doses showed si gnificant 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 graf t function to 23.6+/-13.2 days (P<0.05). These findings support synerg ism between these 2 agents, especially as CsA was not shown to increas e trough rapamycin blood concentration when given together. In the com bined treatment group, a significant (r=0.90, P<0.001) relationship wa s found between rapamycin blood levels and graft survival. Animals hav ing 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 evide nce of adverse effects as measured by hepatic and renal function tests , histology, or electron microscopy.