Operational tolerance is not always permanent: A 10-year prospective study in pediatric liver transplantation recipients

Immunosuppression withdrawal can be safely performed in select liver transplantation recipients, but the long-term outcomes and sustainability of tolerance have not been well studied. We completed a 10-year prospective, observational study of 18 pediatric liver transplantation recipients with operational tolerance to (1) assess the sustainability of tolerance over time, (2) compare the clinical characteristics of patients who maintained versus lost tolerance, (3) characterize liver histopathology findings in surveillance liver biopsies; and (4) describe immunologic markers in patients with tolerance. Comparator patients from two clinical phenotype groups termed “stable” and “nontolerant” patients were used as controls. Of the 18 patients with operational tolerance, the majority of patients were males (n = 14, 78%) who were transplanted for cholestatic liver disease (n = 12, 67%). Median age at transplantation was 1.9 (range, 0.6–8) years. Median time after transplantation that immunosuppression had been discontinued was 13.1 (range, 2.9–22.1) years. As many as 11 (61%) maintained tolerance for a median of 10.4 (range, 1.9–22.1) years, whereas 7 (39%) lost tolerance after a median of 3.2 (range, 1.5–18.6) years. Populations of T regulatory cells (%CD4⁺ CD25^hi CD127^lo) were significantly higher in patients with tolerance (p = 0.02). Our results emphasize that spontaneous operational tolerance is a dynamic and nonpermanent state. It is therefore essential for patients who are clinically stable off immunosuppression to undergo regular follow-up and laboratory monitoring, as well as surveillance biopsies to rule out subclinical rejection.