Immunosuppression of canine, monkey, and baboon allografts by FK 506: with special reference to synergism with other drugs and to tolerance induction

Abstract

In dogs the most effective oral dose of FK 506 for prevention of renal homograft rejection was 1.5 mg/kg/day. With maximum credit allowed at 90 days, survival was increased to 61.0 +/- 33.6 (SD) days compared with 13.0 +/- 4.1 in untreated control animals. Higher doses were toxic. The smallest dose that was used (0.5 mg/kg/day) prolonged survival after renal transplantation to 33.7 +/- 23.9 (SD) days. When the small dose of FK 506 was combined with 5 mg/kg/day of cyclosporine and 5 mg of prednisone, five of six canine kidney recipients lived for 90 days. These results were degraded by omission of any of the constituent drugs or reduction by half of the triple drug doses. Thirteen of the dogs treated with various drug regimens lived for 90 days, after which time treatment was stopped; 10 of the dogs eventually rejected the grafts, but three had continued graft function for 6 months or longer and may be permanently tolerant. Moreover, in dogs when 1 mg/kg of intramuscular FK was given to 19 kidney and seven liver recipients for 3 days on postoperative days 1 to 3, 4 to 6, or 7 to 9, the animals survived subsequently for 11 to more than 160 days. All but four of the grafts were eventually rejected, but the prolonged effect of a short course of delayed therapy suggests the possibility of tolerance induction. In cynomolgus monkeys and baboons, FK as a single drug was found to be immunosuppressive after kidney transplantation. Correlation in the dogs and primates between immunosuppression, toxicity, and FK blood levels was not possible because of presently imperfect standardization of assay and monitoring techniques. FK had serious side effects in dogs, but not so obviously in monkeys and not at all in baboons.

Fig. 1

Serum creatinine concentration and FK plasma levels in dogs that lived the longest in the dogs of groups 2 through 5 treated with different daily doses of FK 506.

Fig. 2

Survival in dogs receiving multiple drug treatment with FK 506, cyclosporine, and prednisone, along with control experiments. (See text for details.)

Fig. 3

Clinical course of two cynomolgus monkeys that lived for more than 90 days under FK treatment. One monkey (No. 724) is shown by solid lines and open column, and the other (No. 755) is shown by dotted lines and black column. The FK plasma levels were not measured during the first 2 months.

Fig. 4

Clinical course of a baboon that is alive more than 50 days after transplantation under FK treatment.