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.
Highlights
Chronic graft-versus-host disease is an extensive complication of allogeneic hematopoietic stem cell transplantation and can impact patients’ quality of life in a detrimental manner
With respect to fibrosis induced by Chronic graft-versus-host disease (cGVHD), Mallory staining revealed that while the vehicle-treated organs were affected by aberrant fibrosis, their TL-treated equivalents were virtually untouched by cGVHD-triggered fibrosis (Fig 1D, S2C Fig, and S25–S28 Figs)
These findings suggest that TL could suppress systemic inflammation and fibrosis caused by cGVHD without preventing the engraftment of bone marrow cells
Summary
Chronic graft-versus-host disease (cGVHD) is an extensive complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and can impact patients’ quality of life in a detrimental manner. CGVHD appears 6 months or later and its symptoms are similar to those of autoimmune diseases.[1, 2] Virtually all organs are vulnerable to cGVHD, and severe inflammation and fibrosis induced by cGVHD are highly problematic.[3, 4] For example, cGVHD patients can suffer from disabling symptoms such as dry eye, skin rashes, diarrhea and respiratory failure.[3, 4] there is a dearth of information about the exact mechanisms of cGVHD, minor histocompatibility differences between donor and recipient cells are thought to play a detrimental role in the establishment and development of cGVHD.[1] Substantial time and effort have been invested into the creation of effective remedies for cGVHD over the last decades, and several efficacious therapies for cGVHD in mice have recently been reported. Substantial time and effort have been invested into the creation of effective remedies for cGVHD over the last decades, and several efficacious therapies for cGVHD in mice have recently been reported. [5,6,7,8,9] there remains a considerable unfulfilled need in the treatment of cGVHD
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