title: 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-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.
authors: Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan 700-8558;
authors: Hideaki
authors: H
authors: Fujiwara
authors: Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan 700-8558; yosmaeda@md.okayama-u.ac.jp.
authors: Yoshinobu
authors: Y
authors: Maeda
authors: Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan 700-8558;
authors: Koichiro
authors: K
authors: Kobayashi
authors: Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan 700-8558;
authors: Hisakazu
authors: H
authors: Nishimori
authors: Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan 700-8558;
authors: Ken-Ichi
authors: K
authors: Matsuoka
authors: Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan 700-8558;
authors: Nobuharu
authors: N
authors: Fujii
authors: Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan 700-8558;
authors: Eisei
authors: E
authors: Kondo
authors: Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan 700-8558;
authors: Takehiro
authors: T
authors: Tanaka
authors: Department of Immunobiology and Yale Comprehensive Cancer Center, Yale University, New Haven, CT 06519;
authors: Lieping
authors: L
authors: Chen
authors: Department of Molecular Immunology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan 113-8549; and.
authors: Miyuki
authors: M
authors: Azuma
authors: Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan 113-8421.
authors: Hideo
authors: H
authors: Yagita
authors: Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan 700-8558;
authors: Mitsune
authors: M
authors: Tanimoto
mesh_terms: D064591:Allografts; D000818:Animals; D060890:B7-H1 Antigen / Q000235:genetics / Q000276:immunology; D001565:Benzoates / Q000494:pharmacology; D016026:Bone Marrow Transplantation; D002908:Chronic Disease; D004195:Disease Models, Animal; D005260:Female; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D061027:Programmed Cell Death 1 Ligand 2 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000276:immunology*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D018417:Th1 Cells / Q000276:immunology* / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology* / Q000473:pathology
chemical_list: D060890:B7-H1 Antigen; D001565:Benzoates; C498919:Cd274 protein, mouse; C491383:Pdcd1 protein, mouse; C556978:Pdcd1lg2 protein, mouse; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor; D013764:Tetrahydronaphthalenes; C061133:tamibarotene