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.
Highlights
Chronic graft-versus-host disease is an immunologically mediated complication and hampers success in allogeneic haematopoietic stem cell transplantation (HSCT)
The degree of inflammation and fibrosis was determined by immunoblot assays for the inflammatory markers IL-6 and connective tissue growth factor (CTGF) [28,29]
Our data indicated that these two markers were expressed at higher level in the Chronic graft-versus-host disease (cGVHD)-affected pancreas compared with its syngeneic control partner (IL-6: p 1⁄4 6.9 Â 1025, CTGF: p 1⁄4 1.2 Â 1024)
Summary
Chronic graft-versus-host disease (cGVHD) is an immunologically mediated complication and hampers success in allogeneic haematopoietic stem cell transplantation (HSCT). CGVHD typically occurs in allogeneic HSCT recipients six months or later after transplantation, and they can suffer from multisystem disorders which resemble those induced by autoimmune diseases [1,2]. Despite the recent advancement of therapies for cGVHD, to the best of our knowledge, no comprehensive biological investigation into pancreatic cGVHD has been reported far. This fact urged us to gain more insights into cGVHD in the pancreas. CGVHD patients can be affected by diabetes, and it has been conceived to arise from corticosteroid therapies, not from disorders in the pancreas [8,9]. We envisaged that it would be of great medical importance to focus on the state of the pancreas in cGVHD sufferers
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