The Role of Programmed Cell Death Ligand-1 (PD-L1/CD274) in the Development of Graft versus Host Disease

Abstract

Programmed cell death ligand-1 (PD-L1/CD274) is an immunomodulatory molecule involved in cancer and complications of bone marrow transplantation, such as graft rejection and graft-versus-host disease. The present study was designed to assess the dynamic expression of this molecule after hematopoietic stem cell transplantation in relation to acute graft-versus-host disease. Female BALB/c mice were conditioned with busulfan and cyclophosphamide and transplanted with either syngeneic or allogeneic (male C57BL/6 mice) bone marrow and splenic cells. The expression of PD-L1 was evaluated at different time points employing qPCR, western blot and immunohistochemistry. Allogeneic- but not syngeneic-transplanted animals exhibited a marked up-regulation of PD-L1 expression in the muscle and kidney, but not the liver, at days 5 and 7 post transplantation. In mice transplanted with allogeneic bone marrow cells, the enhanced expression of PD-L1 was associated with high serum levels of IFNγ and TNFα at corresponding intervals. Our findings demonstrate that PD-L1 is differently induced and expressed after allogeneic transplantation than it is after syngeneic transplantation, and that it is in favor of target rather than non-target organs at the early stages of acute graft-versus-host disease. This is the first study to correlate the dynamics of PD-L1 at the gene-, protein- and activity levels with the early development of acute graft-versus-host disease. Our results suggest that the higher expression of PD-L1 in the muscle and kidney (non-target tissues) plays a protective role in skeletal muscle during acute graft-versus-host disease.

The PD-1 Axis Enforces an Anatomical Segregation of CTL Activity that Creates Tumor Niches after Allogeneic Hematopoietic Stem Cell Transplantation

“…Strong differences were, however, observed in the expression of PD-1 ligands that were highly upregulated in lymph nodes but not in the liver. Interestingly, we observed that PD-1 ligands were upregulated by both hematopoietic APCs and stromal cells in lymph nodes, in accordance with the idea that organ parenchyma contributes to engage the PD-1 axis (Schilbach et al, 2007;Al-Chaqmaqchi et al, 2013). Consistently, blockade of PD-1/PD-1-ligand interactions during allo-HSCT selectively increased CTL activity in lymph nodes.…”

Combined cytotoxic chemotherapy and immunotherapy of cancer: modern times

“…Its efficacy is reinforced when it is combined with the bifunctional DNA-alkylating drug busulfan. In an experimental study in mice transplanted with allogeneic bone marrow cells (model of acute graft-versus-host disease), the alkyl sulfonate busulfan was also found to enhance the expression of PD-L1 in the target organs ( 87 ).…”

Heat Shock Proteins Promote Cancer: It's a Protection Racket

“…Programmed cell death (PCD) is an intrinsic mechanism that all cells are capable of executing, leading to loss of cells that either pose a danger to the organism such as activated T cells or cells sacrificed during tissue remodeling [41]. Such death pathways can also be triggered by stresses.…”