ISOrTT Registry Mission Statement

Achieving and understanding patients' ability to undergo solid organ transplantation without the need for ongoing immunosuppression is a key goal of transplantation research. The ISOrTT Registry Website exists to fulfill two key missions. The first is to establish a multi-center, international database registering patients who have been successfully maintained off immunosuppression for at least one year after transplantation. Also, ISOrTT will serve to facilitate enrollment of interested patients into appropriate studies of transplant tolerance and serve as a resource on tolerance studies and literature for interested patients, physicians, and families.

Sporadic clinical transplant tolerance has been achieved following solid organ transplantation, most commonly after liver transplantation. Operational tolerance, defined as long term (>12 month) freedom from all immunosuppression in patients with normal graft function was first seen in both non-compliant patients and patients withdrawn for emergent infectious or malignant indications (1, 2). Individual centers have also reported the ability to slowly wean patients from immunosuppression over time or emergently for specific indications after liver (3-7) and kidney (8, 9) transplant.

For reasons that are unclear, patients transplanted as children have been more likely to achieve this operational tolerance than those transplanted as adults (3). Estimates of ability to wean immunosuppression successfully following liver transplant vary from 3-5% of cases (10, 11). In very carefully selected patient populations, up to 20% of patients may be potentially weaned (3). In live donor transplant populations, up to 15% of all patients or 30% of selected patients may be successfully withdrawn from immunosuppressive medications (4,5). Long term follow-up of patients successfully withdrawn, however, is limited to individual center reports. The true incidence and ability to withdraw drugs after liver or other organ transplants is unknown as is the natural history of these patients after drug withdrawal.

A registry of these patients would allow better characterization of the natural history of drug withdrawal and help develop predictive clinical factors that favor drug withdrawal. Furthermore, this would facilitate entry of these patients into ongoing or developing trials of assay development. The development of predictive, reproducible assays (12-15) that can identify patients who may safely be withdrawn from immunosuppression or conversely identify those who require maintenance immunosuppression will be critical to minimizing long term morbidity and mortality in organ transplantation. Assays performed in this unique patient population, such as cytokine gene polymorphisms and dendritic cell subsets, have yielded encouraging but preliminary results (16-18). Other centers have reported the importance of T regulatory cells as a potential mechanism in their tolerant patients and are identifying gene profiles associated with tolerance (15, 19-21).


1. Reyes J, Zeevi A, Ramos H, Tzakis A, Todo S, Demetris AJ et al. Frequent achievement of a drug-free state after orthotopic liver transplantation. Transplantation proceedings 1993;25(6):3315-3319.

2. Tzakis AG, Reyes J, Zeevi A, Ramos H, Nour B, Reinsmoen N et al. Early tolerance in pediatric liver allograft recipients. Journal of pediatric surgery 1994;29(6):754-756.

3. Mazariegos GV, Reyes J, Marino IR, Demetris AJ, Flynn B, Irish W et al. Weaning of immunosuppression in liver transplant recipients. Transplantation 1997;63(2):243-249.

4. 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(3):449-454.

5. Oike F, Yokoi A, Nishimura E, Ogura Y, Fujimoto Y, Kasahara M et al. Complete withdrawal of immunosuppression in living donor liver transplantation. Transplantation proceedings 2002;34(5):1521.

6. Girlanda R, Rela M, Williams R, O'Grady JG, Heaton ND. Long-term outcome of immunosuppression withdrawal after liver transplantation. Transplantation proceedings 2005;37(4):1708-1709.

7. Tisone G, Orlando G, Cardillo A, Palmieri G, Manzia TM, Baiocchi L et al. Complete weaning off immunosuppression in HCV liver transplant recipients is feasible and favourably impacts on the progression of disease recurrence. Journal of hepatology 2006;44(4):702-709.

8. Mazariegos GV, Ramos H, Shapiro R, Zeevi A, Fung JJ, Starzl TE. Weaning of immunosuppression in long-term recipients of living related renal transplants: a preliminary study. Transplantation proceedings 1995;27(1):207-209.

9. Roussey-Kesler G, Giral M, Moreau A, Subra JF, Legendre C, Noel C et al. Clinical operational tolerance after kidney transplantation. Am J Transplant 2006;6(4):736-746.

10. McCaughan GW. Withdrawal of immunosuppression in liver transplant recipients: is this as good as it gets? Liver Transpl 2002;8(4):408-410.

11. Mazariegos GV. Withdrawal of immunosuppression in liver transplantation: lessons learned from PTLD. Pediatric transplantation 2004;8(3):210-213.

12. Devlin J, Doherty D, Thomson L, Wong T, Donaldson P, Portmann B et al. Defining the outcome of immunosuppression withdrawal after liver transplantation. Hepatology (Baltimore, Md 1998;27(4):926-933.

13. Thomson AW, Mazariegos GV, Reyes J, Donnenberg VS, Donnenberg AD, Bentlejewski C et al. Monitoring the patient off immunosuppression. Conceptual framework for a proposed tolerance assay study in liver transplant recipients. Transplantation 2001;72(8 Suppl):S13-22.

14. Reding R, Gras J, Truong DQ, Wieers G, Latinne D. The immunological monitoring of alloreactive responses in liver transplant recipients: a review. Liver Transpl 2006;12(3):373-383.

15. Koshiba T, Li Y, Takemura M, Wu Y, Sakaguchi S, Minato N et al. Clinical, immunological, and pathological aspects of operational tolerance after pediatric living-donor liver transplantation. Transplant immunology 2007;17(2):94-97.

16. Mazariegos GV, Reyes J, Webber SA, Thomson AW, Ostrowski L, Abmed M et al. Cytokine gene polymorphisms in children successfully withdrawn from immunosuppression after liver transplantation. Transplantation 2002;73(8):1342-1345.

17. 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(6):689-696.

18. Mazariegos GV, Zahorchak AF, Reyes J, Chapman H, Zeevi A, Thomson AW. Dendritic cell subset ratio in tolerant, weaning and non-tolerant liver recipients is not affected by extent of immunosuppression. Am J Transplant 2005;5(2):314-322.

19. Li Y, Koshiba T, Yoshizawa A, Yonekawa Y, Masuda K, Ito A et al. Analyses of peripheral blood mononuclear cells in operational tolerance after pediatric living donor liver transplantation. Am J Transplant 2004;4(12):2118-2125.

20. Yoshizawa A, Ito A, Li Y, Koshiba T, Sakaguchi S, Wood KJ et al. The roles of CD25+CD4+ regulatory T cells in operational tolerance after living donor liver transplantation. Transplantation proceedings 2005;37(1):37-39.

21. Martinez-Llordella M, Lozano JJ, Puig-Pey I, Orlando G, Tisone G, Lerut J et al. Using transcriptional profiling to develop a diagnostic test of operational tolerance in liver transplant recipients. The Journal of clinical investigation 2008;118(8):2845-2857.