The effect of in vivo administration of exogenous tumor necrosis factor-alpha on the survival of rat islet xenografts in STZ-induced diabetic mice was examined. Daily subcutaneous injections of purified recombinant murine TNF-alpha (3 micrograms/day) for 7 days after transplantation of islets prolonged the survival of the xenografts (26.7 +/- 4.9 days) compared with controls (11.2 +/- 1.1 days). Extension of the treatment from 0 to 59 days after transplantation produced an even greater prolongation of graft survival (53.7 +/- 8.5 days). After cessation of treatment, an accelerated rejection of the grafts occurred. A most interesting finding was that delaying initiation of treatment until 3 days after transplantation and continuing until 60 days produced a remarkable prolongation of xenograft survival (mean survival time > 89.8 +/- 17.5 days) with 2 recipients still normoglycemic at 124 days. Removal of the grafts at this time returned the 2 mice to a diabetic state. A second islet transplant from the same donor rat strain (Wistar-Furth) had an accelerated rejection, indicating that the long-term survival of the xenografts was not because of induction of tolerance. Delaying initiation of TNF treatment until 6 days after transplantation produced only a slight prolongation of survival (17.5 +/- 1.2 days). Prolongation of islet xenograft survival also was obtained by continuous, subcutaneous delivery of TNF-alpha by a 7-day mini-osmotic pump (3 micrograms/day). Lower daily doses of TNF-alpha (0.003, 0.3, and 1.0 micrograms) had no effect on graft survival.(ABSTRACT TRUNCATED AT 250 WORDS)