KINETICS OF INTRAGRAFT CYTOKINE EXPRESSION, CELLULAR INFILTRATION, AND CELL-DEATH IN REJECTION OF RENAL-ALLOGRAFTS COMPARED WITH ACCEPTANCEOF LIVER ALLOGRAFTS IN A RAT MODEL - EARLY ACTIVATION AND APOPTOSIS IS ASSOCIATED WITH LIVER GRAFT ACCEPTANCE

Background Liver transplants in the rat strain combination PVG-to-Dark Agouti are spontaneously tolerated, whereas kidney transplants in the same strain combination are rejected in 7-9 days. Methods. To identif y organ-specific differences that might yield further information abou t the mechanism of tolerance induction in this strain combination, liv er or kidney grafts, spleen, and draining lymph nodes were harvested a t days 1, 3, 5, and 7, and examined by immunohistochemistry, terminal deoxynucleotide transferase-mediated dUTP nick end labeling assay, and reverse transcriptase-polymerase chain reaction for interferon-gamma, interleukin (IL)-2, IL-4, and IL-10. Results. Renal allograft rejecti on was associated with the progressive development of an intense monon uclear cell infiltrate, Markers of lymphocyte activation and cytokine up-regulation appeared from day 3, and many apoptotic parenchymal cell s were noted on days 5-7, at the peak of rejection. conversely, liver allograft tolerance was associated with more rapid infiltration by act ivated T cells and earlier increases in cytokine expression, but with a more limited degree of cellular infiltration. Concurrent with the ea rly activation, high levels of apoptosis were found in areas of leukoc yte infiltrate, paralleling the disappearance of activated T cells fro m the graft between days 3 and 5. Conclusions. Apoptosis of infiltrati ng leukocytes in liver allografts may represent an important process i n the induction of spontaneous liver transplant tolerance and may unde rlie the abortive nature of the effector response observed within tole rated livers. In contrast, activated cells in renal allografts in the same strain combination survive and proliferate, express high levels o f cytokines, and are efficient in bringing about graft destruction.