Programmed death-1 pathway in host tissues ameliorates Th17/Th1-mediated experimental chronic graft-versus-host disease

J Immunol. 2014 Sep 1;193(5):2565-73. doi: 10.4049/jimmunol.1400954. Epub 2014 Jul 30.

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-2(d)) donor to BALB/c (H-2(d)) 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allografts
  • Animals
  • B7-H1 Antigen / genetics
  • B7-H1 Antigen / immunology
  • Benzoates / pharmacology
  • Bone Marrow Transplantation
  • Chronic Disease
  • Disease Models, Animal
  • Female
  • Graft vs Host Disease / genetics
  • Graft vs Host Disease / immunology*
  • Graft vs Host Disease / pathology
  • Graft vs Host Disease / prevention & control
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Programmed Cell Death 1 Ligand 2 Protein / antagonists & inhibitors
  • Programmed Cell Death 1 Ligand 2 Protein / genetics
  • Programmed Cell Death 1 Ligand 2 Protein / immunology
  • Programmed Cell Death 1 Receptor / genetics
  • Programmed Cell Death 1 Receptor / immunology*
  • Tetrahydronaphthalenes / pharmacology
  • Th1 Cells / immunology*
  • Th1 Cells / pathology
  • Th17 Cells / immunology*
  • Th17 Cells / pathology

Substances

  • B7-H1 Antigen
  • Benzoates
  • Cd274 protein, mouse
  • Pdcd1 protein, mouse
  • Pdcd1lg2 protein, mouse
  • Programmed Cell Death 1 Ligand 2 Protein
  • Programmed Cell Death 1 Receptor
  • Tetrahydronaphthalenes
  • tamibarotene