B. Handan Özdemir, M.D. MSc is a medical professor and is currently the head of the pathology department at Başkent University. She specializes in Nephropathology, Transplant Pathology, Uropathology, Surgical Pathology, Hematopathology, Immunopathology, Pulmonary Pathology, and Digital Pathology She has received many awards and certifications internationally and has held administrative positions and board memberships in medical associations worldwide. Prof. Özdemir has also been interested in investigating the meeting point between the fields of medicine and the humanities.
Unexpected role of programmed death-ligand 1 (PD-L1) in renal allografts with antibody-mediated rejection
B. Handan Ozdemir1, Bilkay Basturk2, Aysen Terzi1, C. Burak Sayin3, Mehmet A. Haberal4.
1Department of Pathology, Baskent University, Ankara, Turkey; 2Department of Immunology, Baskent University, Ankara, Turkey; 3Department of Nephrology , Baskent University, Ankara, Turkey; 4Department of General Surgery, Division of Transplantation, Baskent University, Ankara, Turkey
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 antibody-mediated rejection (ABMR) is unknown. While some studies show that PD-1/PD-L1 interaction is crucial for graft tolerance, its impact on immune cells in renal allografts with ABMR may vary. We sought to investigate the status of PD-1/PD-L1 interaction on endothelial cells and immune cells in peritubular capillaries (PTCs), considering that the vasculature serves as the initial interface between immune cells and the target graft.
Materials and Methods: In a study involving 110 patients, 68 had pure ABMR (Group 1), while 42 exhibited both acute ABMR and TCMR (Group 2). Diagnostic biopsies were re-evaluated, assessing glomerular, PTC, interstitial leukocyte, macrophage, CD4, and CD8 positive lymphocyte infiltration, as well as HLA-DR positive cells. Loss of HLA-DR on PTCs indicated PTC destruction. Expression of PD-1 and PD-L1 on tubular, endothelial, and inflammatory cells was examined, along with TGF-β, IFN-γ, and TNF-α expressions in tubules and inflammatory cells. Follow-up biopsies were evaluated for diffuse interstitial fibrosis (IF).
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 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 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 66,1% in patients without inflammatory cell PD-1/PD-L1 (p<0.001).
Conclusion: Our findings reveal that the heightened immunological nature of ABMR may explain the unconventional roles of PD-L1 in renal allografts. Previous organ transplantation studies demonstrating the protective effect of the PD-1/PD-L1 pathway primarily involved models with limited T-cell reactivity. We propose that the inhibitory functions of the PD-1/PD-L1 pathway may not be effective under intense T-cell activation with high immunological costimulation, as seen in ABMR.
[1] PD-L1, PD-1, Antibody-mediated rejection, T-cell mediated rejection, Graft survival
