Programmed Death-1 Pathway in Host Tissues Ameliorates Th17/Th1-Mediated Experimental Chronic Graft-versus-Host Disease

Abstract

Chronic graft-versus-host disease (GVHD) is a major cause of late death and morbidity after allogeneic hematopoietic cell transplantation, but its pathogenesis remains unclear. We investigated the role of the programmed death-1 (PD-1) pathway in chronic GVHD using a well-defined mouse model of B10.D2 (H-2d) donor to BALB/c (H-2d) recipients. PD-1 expression on allogeneic donor T cells was upregulated continuously in chronic GVHD development, whereas PD-L1 expression in host tissues was transiently upregulated and declined to basal levels in the late posttransplant period. Blockade of the PD-1 pathway by anti–PD-1, anti–PD-L1, or anti–PD-L2 mAbs exacerbated clinical and pathologic chronic GVHD. Chimeric mice revealed that PD-L1 expression in host tissues suppressed expansion of IL-17+IFN-γ+ T cells, and that PD-L1 expression on hematopoietic cells plays a role in the development of regulatory T cells only during the early transplantation period but does not affect the severity of chronic GVHD. Administration of the synthetic retinoid Am80 overcame the IL-17+IFN-γ+ T cell expansion caused by PD-L1 deficiency, resulting in reduced chronic GVHD damage in PD-L1−/− recipients. Stimulation of the PD-1 pathway also alleviated chronic GVHD. These results suggest that the PD-1 pathway contributes to the suppression of Th17/Th1-mediated chronic GVHD and may represent a new target for the prevention or treatment of chronic GVHD.

Efficacy and tolerability of nivolumab after allogeneic transplantation for relapsed Hodgkin lymphoma

“…Moreover, it did not induce a flare in the 4 patients with controlled cGVHD. These findings conflict with the murine data from Fujiwara et al, 26 who showed that blockade of the PD-1 pathway exacerbated cGVHD. These discrepancies highlight For personal use only.…”

PD-L1 (Programmed Death Ligand 1) Protects Against Experimental Intracerebral Hemorrhage–Induced Brain Injury

“…29,30 PD-L1 administration significantly alleviated symptoms and suppressed disease progression in murine models of autoimmune disorders and graft-versus-host disease by promoting the development of Treg cells and inhibiting the differentiation of Th17 cells. [13][14][15]30,31 Consistent with those reports, we showed that the underlying mechanism for improving the aftermath of ICH involves a change in the balance of Treg/Th17 cells. Although the total number of CD4 + T cells decreased as well, the difference was minimal.…”

Antibodies from donor B cells perpetuate cutaneous chronic graft-versus-host disease in mice

“…[27][28][29][30][31][32][33][34][35] Our previous report showed that B cells augmented Th17 expansion in the lung but not in the skin at 40 days after HCT. 15 Whether donor B cells and their antibodies affect Th17 expansion in the skin beyond 40 days after HCT has not been investigated.…”