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

Hideaki Fujiwara, Yoshinobu Maeda, Koichiro Kobayashi, Hisakazu Nishimori, Ken Ichi Matsuoka, Nobuharu Fujii, Eisei Kondo, Takehiro Tanaka, Lieping Chen, Miyuki Azuma, Hideo Yagita, Mitsune Tanimoto

Research output: Contribution to journalArticle

32 Citations (Scopus)

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-PDL1, 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.Copyright

Original languageEnglish
Pages (from-to)2565-2573
Number of pages9
JournalJournal of Immunology
Volume193
Issue number5
DOIs
Publication statusPublished - Sep 1 2014

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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