Recombinant human soluble thrombomodulin prevents murine sclerodermatous chronic graft-versus-host disease

Chronic graft-versus-host disease (cGVHD) develops with complex interactions between immune cells and cytokines, leading to irreversible fibrosis. Severe cGVHD impairs quality of life and is associated with nonrelapse mortality; however, effective treatments are limited. Recombinant human soluble thrombomodulin (rTM), a novel anticoagulant consisting of the extracellular domains of thrombomodulin, has shown efficacy in patients with transplantation-associated coagulation disorders and, recently, anti-inflammatory properties in animal studies. Here, we investigated the effects of rTM on cGVHD using a sclerodermatous cGVHD (Scl-cGVHD) mouse model. Prophylactic rTM administration suppressed the development of Scl-cGVHD skin lesions both clinically and histopathologically, prolonging event-free and overall survival. The rTM significantly reduced the infiltration of inflammatory cells, including activated T cells and transforming growth factor β1 (TGFβ1)-producing macrophages into the skin, while inflammation in the draining lymph nodes during priming phase and in spleen during chronic phase was unaffected. TGFβ1 expression in keratinocytes also decreased with rTM. Domain analysis suggested that these effects were mainly attributed to the N-terminal lectin-like domain (domain 1) of rTM, whose functions, including inhibition of inflammatory cell activation and recruitment related to interactions with endothelial cells, has recently been recognized in a limited number of preclinical studies. In conclusion, rTM prevented Scl-cGVHD development, likely by inhibiting the recruitment of inflammatory cells to the skin and subsequent TGFβ1 production by keratinocytes. The rTM may represent a novel prophylactic agent for cGVHD.