The effect of programmed death-ligand 1 (DP-l1) on graft survival in renal allografts with antibody-mediated rejection

Introduction: Despite the critical role of PD-L1 in T-cell biology and increasing knowledge of the function of PD-L1 in solid organ transplantation, its role in ABMR is unknown. Although some studies demonstrated that PD-1/PD-L1 interaction is essential for maintaining graft tolerance, PD-1/PD-L1 interaction in renal allografts with ABMR might exert different effects on immune cells. Since the vasculature is the first interface between the immune cells and the target graft, we aimed to understand the status of PD-1/PD-L1 interaction on endothelial cells and immune cells in peritubular capillaries (PTCs). Materials and Methods: Pure ABMR was present in 68 out of 110 patients (Group 1), and both acute ABMR and acute TCMR were present in 42 patients (Group 2). Initial biopsy samples were re-evaluated, and the degree of glomerular, PTC, interstitial leukocyte, macrophage, CD4, and CD8 positive lymphocyte infiltration was classified. HLA-DR expression on PTCs, tubules, and interstitial leukocytes was examined. Loss of PTC-DR expression was considered PTC destruction. Expression of PD-1 and PD-L1 on tubular, endothelial, and inflammatory cells was evaluated. CD80, CD86, TGF-β, IFN-γ, and TNF-α expressions were investigated in tubules and inflammatory cells. Follow-up biopsies were assessed for diffuse interstitial fibrosis (IF) development. Results: In Group 2 patients, endothelial and inflammatory cell PD-1/PD-L1 showed higher expression rates compared to Group 1 (p<0.001). The interaction of endothelial and inflammatory cell PD-1/PD-L1 increased along with the increase in interstitial, glomerular, PTC leukocytes, macrophages, CD4, and CD8 positive lymphocytes (p<0.001). There was an inverse relationship between PTC-DR expression and PD-1/PD-L1 interaction and a positive relationship with tubular HLA-DR expression (p<0.001). The development of IF was 52.3% in patients with endothelial PD-1/PD-L1 interaction, while it was 12.1% in patients without endothelial PD-1/PD-L1 interaction (p<0.001). The overall 10-year survival was 27.3% in patients with endothelial PD-1/PD-L1, whereas it was 66.7% in patients without endothelial PD-1/PD-L1 (p<0.001). Similarly, the overall 10-year survival was 31.3% in patients with inflammatory cell PD-1/PD-L1, while it was 66,1% in patients without inflammatory cell PD-1/PD-L1 (p<0.001). Conclusion: Our findings demonstrate that the high immunological nature of ABMR may underlie the unexpected functions of PD-L1 in renal allografts. Indeed, most experimental organ transplantation studies demonstrating the protective effect of the PD-1/PD-L1 pathway have used transplantation models with limited T-cell reactivity due to concurrent immunosuppression. We suggest that the inhibitory functions of the PD-1/PD-L1 pathway may not be effective under strong T cell activation with high immunological costimulation such as ABMR.