Involvement of PDL1 and Foxp3 Expression in Human Liver Transplantation Tolerance

Abstract

Background: Operational tolerance after liver transplantation (LT) characterized by successful immunosuppression withdrawal (ISW) without rejection has been reported but its underlying mechanisms are unknown. Programmed cell death protein 1 (PD-1)/its ligand PD-L1 pathway, concomitant with forkhead box protein P3 (Foxp3), may play a specific role in operational tolerance after LT. Methods: Tolerance and control recipients are defined as recipients maintained without and with standard dose of immunosuppression (IS) without episodes of rejection for at least one year. Liver biopsies from 38 tolerant, 35 non-tolerant (including 16 samples that triggered reintroduction of IS and 19 samples after IS reintroduction) and 38 control LT patients were studied. Expression of PD-1, PD-L1, Foxp3, CD4 and CD8 were determined by immunohistochemical staining. Results: PD-1 was hardly detectable while PD-L1 was expressed in the cytoplasm of hepatocytes and Foxp3 was localized in the nucleus. CD4 and CD8 were expressed in the periportal area. Tolerant and control patients exhibited a higher PD-L1 level (median[interquartile]: 20.8[16.2-26] relative units (RU) and 19.8[11.2-30.8]RU vs. 13.3[8-19.3]RU; p=0.0008 and p=0.0036) and higher Foxp3/CD8 ratio (4[0.8-11.8] and 3[1-11.8] vs. 0[0-2.5]; p=0.0001 and p=0.0013) in compared to non-tolerant patients at the moment of triggering IS reintroduction; whereas CD4 expression was comparable between the three groups. A weak but significant correlation between PDL1 and Foxp3 was identified (r=0.2401, p=0.0211). Conclusion: PD-L1 and Foxp3 might concomitantly contribute to the regulation of immune-tolerant in LT patients. Further studies regarding PD-1/PD-L1 pathway may shed light on the mechanisms for operational tolerance after LT.