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Shin Mukai, Yoko Ogawa, Kazuo Tsubota; Reduction of Endoplasmic Reticulum Stress for Treatment of Ocular Chronic Graft-Versus-Host-Disease. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):308.
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Chronic graft-versus-host disease (cGVHD) is a disabling complication of allogeneic hematopoietic stem cell transplantation and has a highly negative impact on patients’ quality of life. However, no effective treatments for cGVHD have been created. The main focus of the study is on ocular cGVHD, and the ultimate goal is establishing useful therapies for cGVHD. Literature precedent indicates that cellular senescence is involved in ocular cGVHD and that cGVHD can be regarded as an age-associated disease. (Kawai, M. et al. Sci Rep. 2013) Another previous report suggests that endoplasmic reticulum (ER) stress plays a key role in ageing and age-related diseases (Brown et al. Front Physiol. 2012). Based on these findings, we envisage (1) that ER stress is elevated in ocular cGVHD and (2) that mitigation of ER stress using rapamycin can be effective for ocular cGVHD.
1. Whole bone marrow transplantation (BMT) was conducted to obtain a mouse model of cGVHD. (Zhang, Y. et al J Immunol. 2002)<br /> 2. We analyzed mice with and without cGVHD 28 days after BMT. To investigate whether ER stress is elevated in organs affected by cGVHD, we focused on the ER stress marker 78 kDa glucose-regulated protein (GRP78). We compared test and control samples to see the difference in the amount of GRP78, which was done by real-time PCR and immunohistochemistry.<br /> 3. Rapamycin was given to mice with cGVHD from Day 10 to Day 27 after BMT. Immunofluorescence staining and real-time PCR were performed to see whether rapamycin could mitigate ER stress.
Immunofluorescence staining and real-time PCR revealed that ER stress was increased in the murine lacrimal gland (LG) affected by cGVHD. GRP78 was expressed in immune cells and the cytoplasm of endothelial cells. The results of immunofluorescence staining and real-time PCR indicated that the expression of GRP78 in the cGVHD-affected LG was suppressed by rapamycin. Immunofluorescence images also suggested that rapamycin reduced inflammatory cell infiltration and attenuated inflammation.
This study has suggested that ER stress is elevated in the murine LG impaired by cGVHD and that ER stress is linked with ocular cGVHD. Hence, reduction of ER stress using rapamycin can be effective treatment of ocular cGVHD.
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