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.
Highlights
Acute graft-versus-host disease (GVHD) is one of the most disturbing complications following allogeneic hematopoietic stem cell transplantation [1]
We studied the dynamic expression of programmed cell death ligand 1 (PD-L1) in different organs during the development of murine acute GVHD following transplantation with allogeneic BM and splenic cells
Our observation that the relative expression of PD-L1 mRNA in the skeletal muscle of untreated control mice (D-7) was higher than that in the liver and kidney strongly suggests that skeletal muscle constitutively expresses more PD-L1
Summary
Acute graft-versus-host disease (GVHD) is one of the most disturbing complications following allogeneic hematopoietic stem cell transplantation [1]. It occurs in 40–70% of all patients transplanted with allogeneic stem cells [2,3]. GVHD develops when alloreactive donor T cells migrate into peripheral tissues. Acute GVHD has been proposed to be mediated by Th1-type cells and their inflammatory cytokines including IFN-c, IL-2 and TNFa [8,9,10]. Donor T cells lacking IFN-c still exacerbate GVHD [11]. Th2-type cells have been reported to suppress acute GVHD [12]
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