Effects of Trichostatin A in a Rat Model of Acute Graft-Versus-Host Disease After Liver Transplantation

Abstract

Acute graft-versus-host disease (aGVHD) is a rare but serious and life-threatening complication of liver transplantation (LTx). Previously, we have demonstrated that the development of aGVHD after LTx (LTx-aGVHD) is associated with a decreased percentage of regulatory T cells (Tregs) in the peripheral blood of recipients. Histone deacetylase inhibitors promote the production of Tregs and some, such as suberoylanilide hydroxamic acid and trichostatin A (TSA), are used to treat autoimmune diseases, including GVHD after bone marrow transplantation. In this study, LTx-aGVHD rats were treated with TSA continuously for 7 days from day 8 to 14 after LTx. Subsequently, splenic T cells were used for in vitro investigations of the mechanism of action of transplantation. All LTx-aGVHD rats developed typical LTx-aGVHD symptoms after TSA treatment and died from LTx-aGVHD. The percentage frequency of Tregs in peripheral blood mononuclear cells was slightly up-regulated after TSA treatment, whereas TSA dramatically down-regulated Foxp3 protein and mRNA levels both in vivo and in vitro. Furthermore, TSA impaired T-cell proliferation and production of proinflammatory and anti-inflammatory cytokines in vitro. TSA does not abrogate LTx-aGVHD in rats due to down-regulation of Tregs.