Of all solid organs that are transplanted, the liver has historically been regarded as being immunologically privileged – the most resistant to immunologic attack and damage. Presentation of antigens via the portal venous system is more likely to result in a tolerizing response than presentation via the systemic venous system. In several allogeneic models ranging from rodent to canine to swine, minimal or even no exposure to immunosuppression has resulted in successful and durable graft function after transplantation (28
). In the human arena, the liver is unique among transplanted solid organs in several ways. First, while episodes of acute rejection commonly connote deleterious outcomes for nearly all other transplanted organs, acute rejection after liver transplantation does not share in such long-term connotations (32
). Second, it is well-known that some episodes of acute rejection may resolve spontaneously without treatment (34
). Third, although chronic rejection threatens the longevity of other transplanted organs, its incidence and importance is less in the post-liver transplant setting, particularly in the age of modern immunosuppression (36
). Furthermore, it has been suggested that tacrolimus has nearly eliminated the threat of chronic rejection for pediatric liver transplant recipients in general (37
) and that living donor liver transplants may be particularly immune to chronic rejection (39
). And finally, while humoral mechanisms of acute and chronic allograft rejection are operational for all other solid organs, they exert little impact on liver allografts. All of these favorable immunologic factors, in conjunction with specter of lifelong immunosuppression with its attendant toxicities has stimulated tremendous interest in complete immunosuppression withdrawal for pediatric liver transplant recipients.
As for clinical data, there exist single center experiences that demonstrate successful, prospective immunosuppression withdrawal from liver transplant recipients (24
). The collective experience has also been recently reviewed (50
). Two, in particular, are informative regarding children. The University Pittsburgh have reported on 95 prospectively withdrawn recipients; at study entry, 31 were ≤ 20 years old and the remaining were 21 – 68 years old (40
). At last publication, 19% were completely off immunosuppression, 39% were still weaning, 29% have experienced rejection and 13% have withdrawn from the study. Of the 28 patients with rejection, 18 had biopsy-proven episodes, seven had clinically suspected episodes and three had biopsy findings suggestive of “incipient” chronic rejection but not diagnostic of chronic rejection. All 28 recipients were treated with resumption or escalation of baseline immunosuppression, with or without bolus corticosteroids. Although it appears as if the pediatric cohort had better outcomes with higher weaning success rate and lower rejection rate, these conclusions are substantially tempered by the fact that large proportions of both cohorts were still weaning (55% of pediatric and 30% of adult). More recently, outcomes regarding the pediatric cohort have been updated (51*
). Of 64 pediatric liver transplant recipients that have attempted immunosuppression withdrawal, 22 (34%) were successful, nine (14%) experienced acute rejection, while the remaining 33 (52%) have reached neither endpoint and are still weaning.
Kyoto University has also reported their experience with immunosuppression withdrawal in pediatric liver transplant recipients. Overall, they observed a success rate for complete immunosuppression withdrawal of 42% (48 of 115 recipients) (43
). Twenty patients (17%) experienced rejection; all rejection episodes were easily reversed except one that required OKT3 therapy. One recipient developed chronic rejection that was successfully treated with triple immunosuppression - corticosteroid, tacrolimus, and mycophenolate mofetil. A more recent update of this center’s experience indicates that they have successfully weaned 87 pediatric liver transplants recipients (49*
). As the report was primarily focused on immunologic studies, it provided no updated information as to how many recipients attempted weaning and / or experienced rejection.
While these reports regarding immunosuppression withdrawal in adults and children prove that functional tolerance can occur in liver transplant recipients and create the general context of expectation as to its frequency, they have not yielded definitive data regarding the mechanism(s) of or biomarkers that may predict, characterize, or identify functional tolerance. Intriguing glimpses into the signature of functional tolerance have recently emerged that have yet to be prospectively validated. Two groups, one studying children and the other studying adults, have reported that functionally tolerant liver transplant recipients, compared to immunosuppression-dependent liver transplant recipients and healthy controls, have increased proportion and absolute numbers of circulating γδ T cells (49*
). Moreover, functionally tolerant patients show a predominance of Vγδ1+ over Vγδ2+ cells. One of the two groups has also suggested that the expression patterns of as few as 22 genes can accurately predict the outcome of withdrawal (52**
). Currently, there is an ongoing clinical trial of immunosuppression withdrawal to prospectively test the combination of lymphocyte subsets and gene expression markers for accuracy to identify functionally tolerant adult liver transplant recipients (http://clinicaltrials.gov/ct2/show/NCT00647283?term=immunosuppression+AND+withdrawal&rank=9
In the United States, of the three trials funded by the Immune Tolerance Network / National Institute of Allergy and Infectious Diseases that are actively exploring immunosuppression withdrawal after liver transplantation, one specifically targets pediatric recipients of parental living donor transplants (http://clinicaltrials.gov/ct2/show/NCT00320606?term=immunosuppression+AND+withdrawal&rank=1
). The trial is small, aiming to enroll twenty stable recipients at two centers who will withdraw from immunosuppression over a minimum of 36 weeks. Although the primary endpoint is one of efficacy - the proportion of participants who are successfully withdrawn from immunosuppression, defined as those who remain off immunosuppression for at least one year – there is an overarching emphasis on clarifying the safety of tightly controlled drug withdrawal. An integral part of the study is the serial evaluation of peripheral blood and liver tissue over a five year period before, during, and after withdrawal to identify biomarkers of functional tolerance. If this pilot trial in children proves to be safe and, particularly if a fingerprint of tolerance emerges from this and/or other withdrawal experiences, then the pediatric liver transplant community can look forward to future trials that will enroll a sufficient number of patients to answer critical questions regarding the medical, psychosocial, and immunologic efficacy of immunosuppression withdrawal.