Hot-topic debate on tolerance: immunosuppression withdrawal.

KEY POINTS: 1. Liver allografts exhibit intrinsic tolerogenic properties that result in their spontaneous acceptance in many experimental animal models. 2. In clinical transplantation, liver allografts require milder immunosuppression regimens than other organs, are relatively resistant to antibody-mediated rejection, and only very rarely are lost because of immunological insults. 3. A fraction of stable liver transplant recipients can withdraw from all immunosuppression therapy and then maintain normal graft function and not experience rejection. This phenomenon is known as spontaneous operational tolerance (SOT). 4. The intentional discontinuation of immunosuppression in stable liver transplant recipients has led to successful weaning in almost 20% of recipients, but the true prevalence of SOT in unselected recipients is still unknown. 5. The prevalence could be higher in pediatric recipients undergoing transplantation before 1 year of age and in adult recipients with more than 10 years of posttransplant follow-up. 6. Rejection occurring during medically supervised immunosuppression weaning trials tends to be mild and, in the overwhelming majority of cases, can be easily resolved without the administration of high-dose immunosuppression. 7. Tolerant liver recipients exhibit specific transcriptional patterns in peripheral blood and liver tissue that may constitute future diagnostic markers of tolerance. 8. There is still no formal proof that the discontinuation of low-dose immunosuppression in long-term survivors of liver transplantation improves the morbidity and mortality rates associated with immunosuppression therapy.