Transplant Immunology in Liver Transplant, Rejection, and Tolerance

Liver transplantation is the most effective treatment for end-stage liver disease. Despite improvements in surgical techniques, transplant rejection remains a significant concern. The liver is considered an immune-privileged organ due to its unique microenvironment and complex interactions among various cell types. Alloimmune responses mediated by T cells and antigen-presenting cells (APCs) play crucial roles in transplant rejection. The liver's dual blood supply and unique composition of its sinusoidal endothelial cells (LSECs), Kupffer cells (KCs), hepatocytes, and hepatic stellate cells (HSCs) contribute to its immune privilege. Alloantigen recognition by T cells occurs through direct, indirect, and semidirect pathways, leading to acute cellular rejection (ACR) and chronic rejection. ACR is a T cell-mediated process that typically occurs within the first few weeks to months after transplantation. Chronic rejection, on the other hand, is a gradual process characterized by progressive fibrosis and graft dysfunction, often leading to graft loss. Acute antibody-mediated rejection (AMR) is less common following surgery compared to other solid organ transplants due to the liver's unique anatomy and immune privilege. However, when it does occur, AMR can be aggressive and lead to rapid graft dysfunction. Despite improvements in immunosuppression, rejection remains a challenge, particularly chronic rejection. Understanding the mechanisms of rejection and immune tolerance, including the roles of regulatory T cells (Tregs) and hepatic dendritic cells (DCs), is crucial for improving transplant outcomes. Strategies to induce immune tolerance, such as modulating DC function or promoting Treg activity, hold promise for reducing rejection and improving long-term graft survival. This review focuses on the liver's unique predisposition to rejection and tolerance, highlighting the roles of individual cell types in these processes. Continued research into the mechanisms of alloimmune responses and immune tolerance in liver transplantation is essential for developing more effective therapies and improving long-term outcomes for patients with end-stage liver disease.