Apoptosis of parenchymal cells has been described during allograft rejection. Immunologically privileged tissue in the mouse has been found to prevent rejection by initiating apoptosis of infiltrating lymphocytes. The aim of this study was to investigate whether apoptosis may play a role in T-cell regulation during rejection and subsequent tolerance induction after liver transplantation (LTx) and combined liver/small bowel transplantation (LSBTx).LTx and LSBTx (Brown Norway-->Lewis) were performed without immunosuppression. Cell migration, activation, and apoptosis were investigated by means of sequential histology, immunohistochemistry, and the terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end labeling assay. Donor (Brown Norway) and third-party (Dark Agouti) cardiac allografts were transplanted into LSBTx recipients to determine specific tolerance.Transient acute cellular rejection occurred after LTx and LSBTx and was followed by specific tolerance. The kinetics of apoptosis were similar in liver allografts after LTx and LSBTx, but differed from the processes in small bowel allografts after LSBTx. Apoptosis of parenchymal cells in the grafted livers correlated directly with interleukin-2 receptor expression of the infiltrating T cells. During the late phase of rejection, a peak of apoptosis in the lymphocyte infiltrate was demonstrated, characterized as predominantly apoptotic CD8+ T lymphocytes.These results demonstrate that specific tolerance is achieved in both LTx and LSBTx after a transient rejection crisis. Apoptosis is involved in graft rejection and tolerance induction. Activation of T lymphocytes correlates with parenchymal cell apoptosis in the allograft. T-cell inactivation seems to result in apoptosis of cytotoxic T cells and tolerance, which appears to be unique to the liver allograft.