Expression of tumor necrosis factor-α gene during allograft rejection following rat liver transplantation

: Background/Aims: Tumor necrosis factor‐α (TNF‐α) is believed to play a role in hepatic allograft rejection. However, the specific cellular population responsible for TNF‐α production during hepatic allograft rejection is not known. Circulating monocyte‐macrophage cells are the primary systemic sources of TNF‐α. In the liver, Kupffer cells are the main producers of TNF‐α. In this study, we determined which cells are involved in TNF‐α production during allograft rejection after orthotopic liver transplantation. Methods: In situ hybridization was used to identify cells with TNF‐α mRNA in the liver. Immunohistochemical staining with ED2 and ED3 was used to differentiate between cellular types (Kupffer cells versus infiltrating monocytes). To detect DNA fragmentation in liver cells, TdT‐mediated biotin‐dUTP nick‐end labeling (TUNEL) was done. Studies were performed in the rat liver transplant model using rejecting (ACI to LEW) and non‐rejecting (ACI to ACI) donor/recipient combinations. Results: In the control group, cells with TNF‐α mRNA were rarely observed. In the rejection group, TNF‐α mRNA was observed in mononuclear cells that were mainly within the vessels of the portal region and occasionally in the sinusoids. The cells with the signals for TNF‐α mRNA were ED2‐negative and ED3‐positive. DNA fragementation was observed in hepatocytes as well as infiltrating mononuclear cells. Conclusions: The main producer of TNF‐α may be infiltrating mononuclear cells such as monocyte‐macrophage cells rather than Kupffer cells during allograft rejection after liver transplantation. Circulating monocyte‐macrophages may play a role in the control of allograft rejection.