Withdrawal of Immunosuppression in Liver Transplantation maintains stable function without the need for chronic immunosuppression;4 it occurs more frequently in liver allografts than with other solid organ transplantation. Some reports support elective immunosuppressive drug weaning for selected liver transplant recipients.1 It is thought that donor cell chimerism is associated with donor specific tolerance and allograft acceptance. Studies report- ing on the possibility of these hypotheses have not revealed the exact mechanism underlying tolerance.5-7 Thomson, et al.4 attempted to evaluate the validity of immunologic and biologic tests that correlated with and were predictive of a state of tolerance. They analyzed dendritic cell types, cytokine secretion, donor specific antibody prevalence, and cytokine genotypes, however, failed to identify any clini- cally useful markers. Mazariego, et al.8 suggested that an increased ratio of plasmacytoid dendritic cell to myeloid dendritic cell was a significant factor for achieving opera- tional tolerance. Therefore, the mechanism underlying tolerance is not known, and there have been no large-scale studies of elective weaning off of immunosuppressant treatment. There are only a limited number of studies on accidentally weaned noncompliant patients and withdra- wal of immunosuppressant due to severe infection or PTLD, or small groups of selectively chosen patients for elective weaning at certain centers.1-3,9-14 Mazariego, et al.12 reported that azathioprine/prednisone- and tacrolimus-based treatment of patients were more likely to be off drugs at one year after transplantation com- pared to cyclosporine treated patients, and Takatsuki, et al.3 suggested that the graft survival was better in patients who received a living-related donor transplantation. Lerut, et al.1 reviewed reports on the withdrawal of immunosuppression and found that immunosuppression withdrawal is possible in 19.4% of transplant recipients, and that the common favorable clinical markers were: 1) an age > two years post liver transplantation, 2) a low incidence of rejection, 3) non- immune mediated liver disease, and 4) minimal immu- nosuppression. Most of the prospective elective withdra- wal studies included patients followed for longer than two years. However, Eason, et al.10 enrolled patients with less than six months of follow-up, and only one of their eighteen patients was weaned off the immunosuppression success- fully. Therefore, it remains unclear when immunosup- pression can safely be withdrawn. Some reports have raised concerns about chronic rejection after withdrawal of immunosuppression.1,15 Koshiba, et al.16 reported that liver biopsy after complete withdrawal of the immunosuppressant revealed changes of the bile duct and fibrosis. However, there were no such findings in our study. The five patients included in this study had long-term (> 3 years) stable graft function, no rejection for more than 1 year after withdrawal of immunosuppression, non-immune mediated liver diseases, and were all pediatric cases; all of these factors are favorable markers, according to previous reports. Although a small number of patients were studied, this is the first report on tolerance in pediatric liver trans- plant recipients in Korea after withdrawal of immunosup- pression. To improve the quality of life for liver transplant recipients, confirmation of our findings with a multicenter trial is now needed to determine patient factors, clinical timing and biological markers associated with successful immunosuppressant withdrawal. REFERENCES 1. Lerut J, Sanchez-Fueyo A. An appraisal of tolerance in liver transplantation. Am J Transplant 2006;6:1774-80. 2. Devlin J, Doherty D, Thomson L, Wong T, Donaldson P, Portmann B, et al. Defining the outcome of immunosuppression withdrawal after liver transplantation. Hepatology 1998;27:926-33. 3. Takatsuki M, Uemoto S, Inomata Y, Egawa H, Kiuchi T, Fujita S, et al. Weaning of immunosuppression in living donor liver transplant recipients. Transplantation 2001;72:449-54. 4. Thomson AW, Mazariegos GV, Reyes J, Donnenberg VS, Donnenberg AD, Bentlejewski C, et al. Monitoring the patient off immunosuppression. Conceptual framework for a proposed tole- rance assay study in liver transplant recipients. Transplantation 2001;72 (8 Suppl):S13-22. 5. Starzl TE, Demetris AJ, Murase N, Ildstad S, Ricordi C, Trucco M. Cell migration, chimerism, and graft acceptance. Lancet 1992; 339:1579-82. 6. Pons JA, Yélamos J, Ramírez P, Oliver-Bonet M, Sánchez A, Rodríquez-Gago M, et al. Endothelial cell chimerism does not influence allograft tolerance in liver transplant patients after with- drawal of immunosuppression. Transplantation 2003;75:1045-7. 7. Tryphonopoulos P, Tzakis AG, Weppler D, Garcia-Morales R, Kato T, Madariaga JR, et al. The role of donor bone marrow infu- sions in withdrawal of immunosuppression in adult liver allo- transplantation. Am J Transplant 2005;5:608-13. 8. Mazariegos GV, Zahorchak AF, Reyes J, Ostrowski L, Flynn B, Zeevi A, et al. Dendritic cell subset ratio in peripheral blood correlates with successful withdrawal of immunosuppression in liver transplant patients. Am J Transplant 2003;3:689-96. 9. Hurwitz M, Desai DM, Cox KL, Berquist WE, Esquivel CO, Millan MT. Complete immunosuppressive withdrawal as a uni- form approach to post-transplant lymphoproliferative disease in pediatric liver transplantation. Pediatr Transplant 2004;8:267-72. 10. Eason JD, Cohen AJ, Nair S, Alcantera T, Loss GE. Tolerance: is it worth the risk? Transplantation 2005;79:1157-9. 11. Massarollo PC, Mies S, Abdala E, Leit̃ao RM, Raia S. Immu- nosuppression withdrawal for treatment of severe infections in liver transplantation. Transplant Proc 1998;30:1472-4. 12. Mazariegos GV, Reyes J, Marino I, Flynn B, Fung JJ, Starzl TE. Risks and benefits of weaning immunosuppression in liver trans- plant recipients: long-term follow-up. Transplant Proc 1997;29: 1174-7. 13. Mazariegos GV, Reyes J, Marino IR, Demetris AJ, Flynn B, Irish W, et al. Weaning of immunosuppression in liver transplant recipients. Transplantation 1997;63:243-9. Yonsei Med J http://www.eymj.org Volume 50 Number 6 December 2009 787