FK-506 AND ISLET TRANSPLANTATION - A POTENTIAL PROTOCOL FOR INDUCING TOLERANCE

FK-506 (FK) was examined for its potential as an immunosuppressant in mouse skin and islet transplantation, and a protocol for inducing tolerance of islet allografting was conceived. At first FK treatment with various doses (1.0, 3.2, 5.6, 10 mg/kg/day, i.m. 4 wk) was done to observe the effects on skin allograft survival. Animals tolerated doses of less than 5.6 mg/kg/day, and graft survival time was prolonged in proportion to the increase of the FK dose, although all grafts were eventually rejected following termination of the treatment. Animals given FK after islet transplantation showed fluctuating blood glucose levels regardless of the protocol (1.0, 3.2 mg/kg/day, i.m. for 4 wk or 3.2, 10 mg/kg/day on day 0, 1, 2, day 3, 4, 5, or day 7, 8, 9). Nevertheless, some animals given high dose of FK for a short time became normoglycemic (5/24) by 3 mo post transplantation, and showed antigen-specific unresponsiveness. In the second series of experiments, pretransplant donor spleen cell injection (DSI) in combination with FK treatment (10 mg/kg i.m. on day 1, 3, 5, or 7 relative to DSI on day 0; islet grafting on day 10) was examined for the induction of tolerance of the islet allograft. DSI (1x10(7)) alone induced accelerated rejection, but marked prolongation of graft survival occurred following a single injection of FK on day 3 (5/7) or day 5 (4/7). In contrast, other time schedules of DSI and FK injection (on day 1, on day 7) were not effective. These results indicated that although a high dose of FK does have a diabetogenic effect on mouse islet allografts studied here, its potential for inducing tolerance is remarkable, and also that preoperative DSI and a single injection of FK are very effective for inducing tolerance and should be investigated for clinical application.