The increasing success of clinical small bowel transplantation in recent years has been due largely to improved nonspecific immunosuppression of the recipient, which carries significant morbidity. The induction of donor-specific tolerance would eliminate the risk of long-term immunosuppression while ensuring graft function and survival. We have demonstrated that the intrathymic injection of donor splenocytes with the simultaneous intraperitoneal administration of rabbit anti-rat lymphocyte serum results in indefinite donor-specific cardiac allograft survival in > 85% of recipients. In this study, we further examined the effect of this tolerance induction protocol on the more immunogenic small bowel allograft. Male Buffalo (RT1b) rats were exposed to donor alloantigen by an intrathymic injection of 25 x 10(6) MHC mismatched unfractionated Lewis (RT1(1)) splenocytes. The Buffalo recipients were given 1 ml of rabbit anti-rat lymphocyte serum intra-peritoneally at the time of the donor antigen injection and 21 days later underwent a heterotopic 15-cm Lewis small bowel transplant. Pretransplant intrathymic Lewis alloantigen and anti-rat lymphocyte serum treatment prolonged Lewis small bowel survival by approximately 2.5 times (mean survival time = 18.0 vs 7.0 days for controls, P < 0.05). These small bowel allografts demonstrated pericryptic T cell infiltrates, areas of cryptic necrosis, and a dense submucosal lymphocytic infiltrate, all consistent with acute resection. In contrast to our studies achieving donor-specific cardiac allograft survival, this protocol did not result in indefinite intestinal allograft survival. No Buffalo recipients developed evidence of graft-versus-host disease.(ABSTRACT TRUNCATED AT 250 WORDS)