Evidence that apoptosis of activated T cells occurs in spontaneous tolerance of liver allografts and is blocked by manipulations which break tolerance

Background. Fully allogeneic Liver grafts from piebald virol glare to dark agouti Fats are spontaneously tolerated, whereas kidney transplants between these strains are rejected. Liver tolerance is broken by donor irradiation or peritransplant corticosteroid treatment of recipient rats, both of whic h interfere with the activation of recipient cells. Methods. In this study we used a combination of immunohistochemical stainin g, reverse transcription-polymerase chain reaction, and terminal deoxynucle otide transferase-mediated dUTP nick end labeling and Annexin-V apoptosis a ssays to compare donor cell migration, cytokine profiles, and leukocyte apo ptosis in grafts and lymphoid organs from tolerant liver and rejecting kidn ey recipients. We then examined the effect on apoptosis of treatments which abrogate liver tolerance. Results. Liver transplantation in this tolerant strain combination is accom panied by rapid migration of many passenger leukocytes to the recipient spl een and lymph node, concurrent with a marked but transient increase in the amount of mRNA for the cytokines interleukin-2 and interferon-gamma, Apopto tic cells appear promptly in the spleen, their numbers reaching a peak 2 da ys earlier than has been previously shown for the graft infiltrate. Both CD 4(+) and CD8(+) T cells undergo apoptosis and apoptotic cells are most conc entrated among CD25(+) T cells. In contrast, renal transplant rejection is associated with limited donor cell migration to lymphoid tissues and signif icantly less up-regulation of interleukin-2 and interferon-gamma in the spl een. Few apoptotic cells are detected in spleen or graft infiltrate during rejection, whereas apoptotic renal tubular and glomerular cells are found f rom day 5. Either recipient steroid treatment or donor irradiation signific antly reduced the number of apoptotic cells in liver graft infiltrates and recipient spleen. Conclusions. Taken together, these findings suggest that a mechanism akin t o activation-induced cell death, with apoptosis of alloreactive recipient c ells may be responsible for the induction of spontaneous liver transplant t olerance.