Researchers recently discovered that spontaneous operational tolerance in liver transplants in the pediatric population with conditions like Alagille syndrome (ALGS) is not a permanent state, as published in Liver Transplantation.

Therefore, it is essential for patients who are clinically stable off immunosuppression to undergo regular follow-up and laboratory monitoring and surveillance biopsies to rule out subclinical rejection. Wozniak et al assessed the long-term outcomes in a cohort of 18 pediatric liver transplant recipients with spontaneous operational tolerance, defined as a normal biochemical liver function off immunosuppression for >1 year. Of all individuals included, 2 had ALGS.

“Over a 10-year prospective study period, with a median patient follow-up time of almost 9 years, 11 of 18 patients (61%) maintained tolerance. Conversely, 7 of 18 patients (39%) lost tolerance due to T-cell mediated rejection, chronic rejection, initiation of [immunosuppression] for a new diagnosis of lupus, and unknown,” the authors wrote.

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Aside from assessing the sustainability of tolerance over time, this study also characterized liver histopathology findings in surveillance liver biopsies, where 11 patients had liver biopsies performed during their time off immunosuppression (5 maintained tolerance and 6 lost tolerance). Of those 6 patients who lost tolerance, 5 demonstrated histologic evidence of allograft rejection on surveillance liver biopsies performed after a median duration of 2.2 years of operational tolerance while off immunosuppression. Finally, 5 had fibrosis, including 2 patients who maintained tolerance.

Regarding immunologic markers in patients with tolerance, donor-specific antibodies (DSA) testing and peripheral blood T cell immunophenotyping were performed on 12 of the 18 patients. Of these, 6 participants were negative for DSA, 4 maintained tolerance, while 2 subsequently lost tolerance. Moreover, 5 patients tested positive for both human leukocyte antigen antibodies and DSA.

In brief, advances in surgical techniques and immunosuppressive protocols have led to dramatic improvements in the success of liver transplants. However, the need for long-term immunosuppression contributes to significant morbidity and mortality in transplant recipients. This is especially problematic in the pediatric population as children who receive transplantation require chronic, life-long immunosuppression associated with complications such as infection, nephrotoxicity, cardiovascular disease, post-transplant lymphoproliferative disease, and other malignancies.

As such, there is a need to individualize, minimize, and possibly even discontinue immunosuppression in certain pediatric transplant recipients, the authors said. Withdrawal can be safely performed in selected liver transplant recipients, but the long-term outcomes and sustainability of tolerance have not been well-studied.


Wozniak L, Venick R, Naini B, et al. Operational tolerance is not always permanent: a 10‐year prospective study in pediatric liver transplant recipients. Liver Transpl. Published online April 8, 2022. doi:10.1002/lt.26474