@article{bc2d33dddead44a48810e5b1ab3f3a1d,
title = "Novel elucidation and treatment of pancreatic chronic graft-versus-host disease in mice",
abstract = "Chronic graft-versus-host disease (cGVHD) is a severe complication of allogeneic haematopoietic stem cell transplantation. There is a growing understanding of cGVHD, and several effective therapies for cGVHD have been reported. However, pancreatic cGVHD is a potentially untapped study field. Our thought-provoking study using a mouse model of cGVHD suggested that the pancreas could be impaired by cGVHD-induced inflammation and fibrosis and that endoplasmic reticulum (ER) stress was augmented in the pancreas affected by cGVHD. These findings urged us to treat pancreatic cGVHD through reduction of ER stress, and we used 4-phenylbutyric acid (PBA) as an ER stress reducer. A series of experiments has indicated that PBA can suppress cGVHD-elicited ER stress in the pancreas and accordingly alleviate pancreatic cGVHD. Furthermore, we focused on a correlation between epithelial to mesenchymal transition (EMT) and fibrosis in the cGVHD-affected pancreas, because EMT was conceivably implicated in various fibrosis-associated diseases. Our investigation has suggested that the expression of EMT markers was increased in the cGVHD-disordered pancreas and that it could be reduced by PBA. Taken together, we have provided a clue to elucidate the pathogenic process of pancreatic cGVHD and created a potentially effective treatment of this disease using the ER stress alleviator PBA.",
keywords = "4-phenylbutyric acid, Endoplasmic reticulum stress, Fibrosis, Inflammation, Pancreatic graft-versus-host disease",
author = "Shin Mukai and Yoko Ogawa and Fumihiko Urano and Yutaka Kawakami and Kazuo Tsubota",
note = "Funding Information: Date accessibility. The datasets supporting this article have been uploaded as part of the electronic supplementary material. Authors{\textquoteright} contributions. S.M. conceived the study, designed the study, performed the experiments, analysed the data, conducted statistical analyses and drafted the manuscript. Y.O. conceived the study, designed the study, analysed the data and helped draft the manuscript. F.U. coordinated the study and helped draft the manuscript. Y.K. coordinated the study and helped draft the manuscript. K.T. conceived the study and helped draft the manuscript. All the authors gave final approval for publication. Competing interests. F.U. and Y.K. have no conflict of interest. A patent application for {\textquoteleft}Patent no. 62/318, 404. Novel Treatment of Chronic Graft-Versus-Host Disease through Reduction of Endoplasmic Reticulum Stress{\textquoteright} was placed by S.M., Y.O. and K.T. on 5 April 2016. Funding. This research was subsidized by the Japanese Ministry of Education, Science, Sports and Culture, nos. 26462668 and 18K09421. In addition S.M. was a recipient of The Japan Agency for Medical Research and Development (AMED) Translational Research Seeds A Grant. Acknowledgements. Our great appreciation should be given to Dr Toshihiro Nagai and Dr Tetsuya Yano at the Keio University School of Medicine for their assistance. Funding Information: This research was subsidized by the Japanese Ministry of Education, Science, Sports and Culture, nos. 26462668 and 18K09421. In addition S.M. was a recipient of The Japan Agency for Medical Research and Development (AMED) Translational Research Seeds A Grant. Publisher Copyright: {\textcopyright} 2018 The Authors.",
year = "2018",
month = oct,
day = "1",
doi = "10.1098/rsos.181067",
language = "English",
volume = "5",
journal = "Royal Society Open Science",
issn = "2054-5703",
publisher = "The Royal Society",
number = "10",
}