Therapeutic potential of tranilast for the treatment of chronic graft-versus-host disease in mice

Shin Mukai, Yoko Ogawa, Hideyuki Saya, Yutaka Kawakami, Kazuo Tsubota

Research output: Contribution to journalArticle

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Abstract

Chronic graft-versus-host disease (cGVHD) is a marked complication of hematopoietic stem cell transplantation, and multiple organs can be affected by cGVHD-induced inflammation and fibrosis. In clinical settings, immunosuppressive agents have been the last resort to treat cGVHD. However, it has been only partially effective for cGVHD. Hence, efficacious treatment of cGVHD is eagerly awaited. Our previous work suggested that oxidative stress was elevated in cGVHD-disordered lacrimal glands and that epithelial-To-mesenchymal transition (EMT) was implicated in fibrosis caused by ocular cGVHD. In addition, our recent article demonstrated that thioredoxin interaction protein (TXNIP) and transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) were associated with the development of cGVHD. After our search for effective drugs, we chose tranilast to combat systemic cGVHD. Tranilast is known to (1) act as an inhibitor of the inflammatory molecules TXNIP and NF-κB and (2) exert anti-fibrotic, anti-EMT and anti-oxidative effects. To investigate the effectiveness of tranilast for cGVHD, we used an MHC-compatible, multiple minor histocompatibility antigen-mismatched murine model of cGVHD. Tranilast or a solvent-vehicle were orally given to the allogeneic bone marrow transplantation (allo-BMT) recipients from the day before allo-BMT (Day-1) to Day 27 after allo-BMT. Their cGVHD-vulnerable organs were collected Day 28 after allo-BMT and analyzed by using various methods such as histology, immunohistochemistry and immunoblotting. As indicated by our results, tranilast alleviated cGVHD-elicited inflammation and fibrosis by suppressing the expression and/or activation of TXNIP and NF-κB and preventing EMT. Taken together, although this strategy may not be a complete cure for cGVHD, tranilast could be a promising medication to ameliorate cGVHD-Triggered disabling symptoms.

Original languageEnglish
Article numbere0203742
JournalPLoS One
Volume13
Issue number10
DOIs
Publication statusPublished - 2018 Oct 1

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Graft vs Host Disease
Grafts
therapeutics
mice
bone marrow transplant
Homologous Transplantation
Bone Marrow Transplantation
Therapeutics
fibrosis
Thioredoxins
Epithelial-Mesenchymal Transition
Bone
Fibrosis
tranilast
inflammation
histocompatibility antigens
lacrimal apparatus
immunosuppressive agents
cell transplantation
proteins

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Therapeutic potential of tranilast for the treatment of chronic graft-versus-host disease in mice. / Mukai, Shin; Ogawa, Yoko; Saya, Hideyuki; Kawakami, Yutaka; Tsubota, Kazuo.

In: PLoS One, Vol. 13, No. 10, e0203742, 01.10.2018.

Research output: Contribution to journalArticle

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