Cellular strategies to induce immune tolerance after liver transplantation: Clinical perspectives

Abstract

Liver transplantation (LT) has become the most efficient treatment for pediatric and adult end-stage liver disease and the survival time after transplantation is becoming longer due to the development of surgical techniques and perioperative management. However, long-term side-effects of immunosuppressants, like infection, metabolic disorders and malignant tumor are gaining more attention. Immune tolerance is the status in which LT recipients no longer need to take any immunosuppressants, but the liver function and intrahepatic histology maintain normal. The approaches to achieve immune tolerance after transplantation include spontaneous, operational and induced tolerance. The first two means require no specific intervention but withdrawing immunosuppressant gradually during follow-up. No clinical factors or biomarkers so far could accurately predict who are suitable for immunosuppressant withdraw after transplantation. With the understanding to the underlying mechanisms of immune tolerance, many strategies have been developed to induce tolerance in LT recipients. Cellular strategy is one of the most promising methods for immune tolerance induction, including chimerism induced by hematopoietic stem cells and adoptive transfer of regulatory immune cells. The safety and efficacy of various cell products have been evaluated by prospective preclinical and clinical trials, while obstacles still exist before translating into clinical practice. Here, we will summarize the latest perspectives and concerns on the clinical application of cellular strategies in LT recipients.

Keywords: Cellular therapy; Induced tolerance; Liver transplantation; Regulatory T cells; Regulatory dendritic cells

Core Tip: Immune tolerance after liver transplantation could significantly reduce the long-term side-effects of immunosuppressants. Compared with operational and spontaneous tolerance, induced tolerance by cellular therapy could reduce immunosuppressant dosage at early stage after transplantation. Regulatory immune cells could suppress the inflammatory response, which are widely explored in preclinical and clinical trials. So far, regulatory CD4+ T cells, mesenchymal stromal cells and regulatory dendritic cells are mostly studied. However, even the safety and tolerability of cellular therapy in transplantation recipients have been validated, the overall efficacy of tolerance induction is unsatisfactory. Detailed exploration is required in the future.