TUMOR-NECROSIS-FACTOR-ALPHA PREVENTS REJECTION OF ISLET XENOGRAFTS (RAT TO MOUSE)

The effect of in vivo administration of exogenous tumor necrosis facto r-alpha on the survival of rat islet xenografts in STZ-induced diabeti c mice was examined. Daily subcutaneous injections of purified recombi nant murine TNF-alpha (3 mug/day) for 7 days after transplantation of islets prolonged the survival of the xenografts (26.7 +/- 4.9 days) co mpared with controls (11.2 +/- 1.1 days). Extension of the treatment f rom 0 to 59 days after transplantation produced an even greater prolon gation of graft survival (53.7 +/- 8.5 days). After cessation of treat ment, an accelerated rejection of the grafts occurred. A most interest ing finding was that delaying initiation of treatment until 3 days aft er 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 th e grafts at this time returned the 2 mice to a diabetic state. A secon d islet transplant from the same donor rat strain (Wistar-Furth) had a n accelerated rejection, indicating that the long-term survival of the xenografts was not because of induction of tolerance. Delaying initia tion of TNF treatment until 6 days after transplantation produced only a slight prolongation of survival (17.5 +/- 1.2 days). Prolongation o f islet xenograft survival also was obtained by continuous, subcutaneo us delivery of TNF-alpha by a 7-day miniosmotic pump (3 mug/day). Lowe r daily doses of TNF-alpha (0.003, 0.3, and 1.0 mug) had no effect on graft survival. The findings indicate that daily subcutaneous injectio ns of TNF-alpha will prevent rejection of rat islet xenografts, and if treatment is initiated early in the rejection process (3 days), then marked prolongation of survival continues even after cessation of trea tment with TNF-alpha.