Factors affecting operational tolerance after pediatric living-donor liver transplantation: impact of early post-transplant events and HLA match*

Abstract

Summary Pediatric recipients of living‐donor liver transplants (LDLT) can often discontinue immunosuppression (IS). We examined factors affecting development of operational tolerance (OT), defined as off IS for >1 year, in this population. A historic cohort analysis was conducted in 134 pediatric primary semi‐allogeneic LDLT. Multivariate logistic regression analysis was used. The frequency of peripheral regulatory T cells (Tregs) was determined at >10 years post‐Tx by FACS analysis. IS was successfully discontinued in 84 tolerant patients (Gr‐tol), but not in 50 intolerant patients (Gr‐intol). The Gr‐intol consisted of 24 patients with rejection (Gr‐rej) and 26 with fibrosis of grafts (Gr‐fib). The absence of early rejection [odds ratio (OR) 2.79, 95% CI 1.11–7.02, P = 0.03], was a positive independent predictor, whereas HLA‐A mismatch (0.18, 0.03–0.91, P = 0.04) was a negative predictor. HLA‐DR mismatches did not affect OT. The Treg frequency was significantly decreased in Gr‐intol (4.9%) compared with Gr‐tol (7.6%) (P = 0.003). There were increased levels of tacrolimus in the first week in Gr‐Tol (P = 0.02). Although HLA‐B mismatch (8.73, 1.09–70.0, P = 0.04) was a positive independent predictor of OT, its clinical significance remains doubtful. In this large cohort of pediatric LDLT recipients, absence of early rejection, HLA‐A match and the later predominance of Tregs are factors associated with OT.

Immunosuppression in pediatric liver transplant recipients: Unique aspects

“…Normal liver function was initially observed in some patients after required immunosuppression withdrawal due to complications such as PTLD or noncompliance . Multiple studies have examined this phenomenon, although pediatric‐specific studies have been limited (Table ) . These reports demonstrated that a proportion of carefully selected LT recipients (15%‐60%) can be successfully weaned off immunosuppression with normal allograft function 14‐120 months after medication discontinuation .…”

Tolerance signatures in transplant recipients

“…This is particularly surprising given the widely held belief that relative to other transplanted organs livers are more resistant to the long-term injurious effects of rejection and more predisposed to the development of tolerance. However, a number of investigators have examined spontaneously tolerant patients or conducted trials in which patients have undergone closely supervised drug withdrawal; a scenario in which several studies have suggested that in carefully selected cohorts of liver transplant recipients the incidence of spontaneous tolerance may approach or even exceed fifty percent (19, 26, 27). These studies have led to the description of a number of potential biomarkers of liver allograft tolerance.…”

Association of interleukin4 gene polymorphisms of recipients and donors with acute rejection following living donor liver transplantation

“…In our cohort, the patients had received similar immunosuppression in early phase after LT. On the other hand, the immunosuppression was individualized for the renal or infectious complication, or for the operational tolerance after the early postoperative period [46][47][48]. In addition, a large number of HCV patients who underwent LT were treated for recurrent HCV with IFN-based therapy, which is reported to contribute to develop ACR [49].…”