Novel elucidation and treatment of pancreatic chronic graft-versus-host disease in mice

• Main Authors: Shin Mukai, Yoko Ogawa, Fumihiko Urano, Yutaka Kawakami, Kazuo Tsubota
• Format: Article
• Language: English
• Published: The Royal Society 2018-01-01
• Series: Royal Society Open Science
• Subjects: pancreatic graft-versus-host disease; endoplasmic reticulum stress; 4-phenylbutyric acid; inflammation; fibrosis
• Online Access: https://royalsocietypublishing.org/doi/pdf/10.1098/rsos.181067

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.