Tolerance after liver transplantation: Where are we?

Area of Science:

• Immunology
• Transplantation Medicine
• Pediatric Gastroenterology

Background:

• Long-term outcomes in liver transplantation depend on meticulous immunosuppression management, especially for pediatric recipients requiring decades of graft survival.
• Both insufficient and excessive immunosuppression pose risks: subclinical allo-immune injury and cumulative toxicities, respectively.
• Historically, immunosuppression minimization and withdrawal have been explored to enhance graft and patient longevity.

Purpose of the Study:

• To evaluate the safety and efficacy of immunosuppression withdrawal in highly selected adult and pediatric liver transplant recipients.
• To assess the robustness of operational tolerance through extended biochemical and histological follow-up.
• To highlight the need for noninvasive biomarkers to guide immunosuppression management.

Main Methods:

• Multicenter trials involving immunosuppression withdrawal in stable, long-term liver transplant recipients (adult and pediatric).
• Assessment of operational tolerance using biochemical and histological criteria.
• Extended follow-up, including over 8 years for pediatric patients off immunosuppressive drugs.

Main Results:

• Successful immunosuppression withdrawal demonstrated operational tolerance in 40% of adults and 60% of pediatric liver transplant recipients.
• Extended follow-up confirmed the robustness of operational tolerance in children.
• A subset of clinically ideal recipients eligible for withdrawal trials exhibited concerning inflammation and/or fibrosis, suggesting potential unresolved immune responses.

Conclusions:

• Complete and safe immunosuppression withdrawal is feasible in highly selected adult and pediatric liver transplant recipients.
• Liver histology remains the gold standard for assessing allograft health and guiding immunosuppression due to the lack of definitive noninvasive biomarkers.
• Further research is needed to develop accurate biomarkers for personalized immunosuppression management to avoid both under- and over-immunosuppression.