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Eisuke Shimizu, Shin Mukai, Yoko Ogawa, Kazuo Tsubota; Attenuation of Murine Lacrimal Gland Chronic Graft-Versus-Host Disease by Oral Injection of Tranilast. Invest. Ophthalmol. Vis. Sci. 2017;58(8):4726.
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Graft-versus-host disease (GVHD)-related dry eye disease is one of the most frequent complications after allogeneic hematopoietic stem cell transplantation. Tranilast was synthesized for the first time in Japan and then approved for medical use. Over the last decades, this molecule has been utilized to treat asthma, atopic dermatitis and keloid. We have shown a significant role of fibroblasts in cGVHD induced pathogenic fibrosis including the epithelial mesenchymal transition (EMT) in lacrimal gland affected by cGVHD. Using cell-based screening methods, tranilast was found to have a potential to suppress EMT in vitro. The purpose of this study is to investigate whether tranilast is capable of mitigating inflammation, fibrosis and oxidative stress in lacrimal gland disordered by cGVHD.
Whole bone marrow transplantation (BMT) was conducted in order to obtain a mouse model of cGVHD. In the case where the donors are B10.D2 mice and the recipients are BALB/c mice, it is allogeneic transplantation and furnishes a mouse model of cGVHD (Zhang, Y. et al J Immunol. 2002). The allogeneic BMT recipients were treated with tranilast or the solvent-vehicle by oral or intraperitoneal injection. We performed (1) histological investigation, (2) immunohistochemical examination, (3) quantitative PCR (qPCR), (4) immunoblot assays and (5) electron microscopic analysis to explore whether oral or intraperitoneal injection of tranilast could mitigate cGVHD in lacrimal glands.
Histopathological assessments and immunofluorescence staining suggest that oral or intraperitoneal injection of tranilast suppressed cGVHD-induced, inflammatory cell infiltration, fibrosis and oxidative stress in lacrimal glands. In addition, the results of immunoblot analysis and qPCR indicate that the protein or mRNA expression of NF-kB, CXCL9, TGF-b, and thioredoxin interaction protein (TXNIP) was vastly lower in the lacrimal glands treated with TL compared with those treated with the solvent-vehicle. As indicated by our data, oral injection of tranilast can repress lacrimal gland cGVHD in a more effective manner than intraperitoneal injection.
This study suggests that oral administration of tranilast alleviates inflammation and fibrosis caused by ocular cGVHD and therefore can be a promising therapeutic intervention to attenuate cGVHD related dry eye disease.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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