Histological changes in the liver in experimental graft-versus-host disease across minor histocompatibility barriers. VI. A light and electron microscopic study of the periportal changes

ABSTRACT— Periportal changes of the liver in experimental graft-versus-host disease (GVHD) across minor histocompatibility barriers were investigated electron-microscopically for up to 14 months after bone marrow transplantation (BMT). In GVHD mice, periportal changes affecting the limiting plate of hepatocytes were relatively mild and, in general, classical piecemeal necrosis was rarely observed. However, around 2 weeks after transplantation disruption of the limiting plate of hepatocytes was transiently observed. At that time, lymphocytes invaded directly into the hepatic parenchyma and were in close contact with hepatocytes mainly through a number of point-contacts of cell membranes. Hepatocytes in close contact with lymphocytes showed minor degenerative changes under electron microscopy. On the other hand, periportal bile ductules and canals of Hering were constantly injured by inflammatory cells during the entire observation period up to 14 months after BMT. They were abutted by lymphocytes, together with other inflammatory cells including eosinophils, neutrophils, plasma cells and monocytes. Infiltration of inflammatory cells into the epithelial layer of the bile ductules and canals of Hering through the basement membrane was frequently found. Inflammatory cells were in contact with duct epithelial cells mainly through a number of point-contacts of cell membranes. Epithelial cells in contact with inflammatory cells exhibited a number of degenerative changes, including condensation of cytoplasm, irregular contour of nucleus, dilatation of endoplasmic reticulum, formation of cytoplasmic vesicles, focal cytoplasmic degeneration, and so on. These results suggest that classical piecemeal necrosis of the limiting plate of hepatocytes is not characteristic for hepatic GVHD, whereas the smaller and smallest periportal bile ductules or canals of Hering are frequently injured by lymphocytes and other inflammatory cells, similar to those seen in the interlobular and septal bile ducts, indicating that not only the interlobular and septal bile ducts but also the smaller or smallest periportal bile ductules and canals of Hering are the major targets in hepatic GVHD, and thus hepatic injury in GVHD may progress along the biliary tree.