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Graft-versus-host Disease

Thrombomodulin alleviates murine GVHD in association with an increase in the proportion of regulatory T cells in the spleen

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Abstract

Recombinant human soluble thrombomodulin (rTM), a potent anticoagulant, has been used for the treatment of disseminated intravascular coagulation in Japan since 2008. Interestingly, rTM possesses anti-inflammatory and cytoprotective functions. This study examined whether rTM alleviates GVHD in a murine hematopoietic SCT (HSCT) model. Use of rTM significantly improved the survival of mice on day 28 of transplantation (survival rate 70% in rTM - treated mice vs 35% in control, P<0.05) in association with a significant decrease in plasma levels of IL-6, IFN-γ and high-mobility group B1 DNA-binding protein on day 7 of HSCT. Intriguingly, the proportion of regulatory T cells in the spleen was significantly increased in rTM-treated mice on day 7 of transplantation compared with control diluent-treated mice. In addition, elevated plasma levels of TM and fibrin/fibrinogen degradation product were noted in HSCT-recipient mice, suggesting coagulopathy caused by endothelial cell damage in this GVHD model. The use of rTM potently decreased these levels. Importantly, rTM did not hamper the anti-GVL and engraftment of hematopoietic cells. Taken together, the use of rTM may prevent GVHD and serve as a potential therapeutic strategy to improve clinical outcomes in individuals who receive HSCT.

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Acknowledgements

This work was supported, in part, by JSPS KAKENHI grant number 23591421 and 26461406, Research for Promoting Technological Seeds, The Uehara Memorial Foundation and The Senshin Medical Research Foundation.

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  1. Department of Hematology and Respiratory Medicine, Kochi University, Nankoku, Japan

    T Ikezoe, J Yang, C Nishioka & A Yokoyama

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  1. T Ikezoe
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  2. J Yang
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Correspondence to T Ikezoe.

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Ikezoe, T., Yang, J., Nishioka, C. et al. Thrombomodulin alleviates murine GVHD in association with an increase in the proportion of regulatory T cells in the spleen. Bone Marrow Transplant 50, 113–120 (2015). https://doi.org/10.1038/bmt.2014.208

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