HISTOPATHOLOGY OF HEPATIC ACUTE GRAFT-VERSUS-HOST DISEASE IN THE DOG A DOUBLE BLIND STUDY CONFIRMS THE SPECIFICITY OF SMALL BILE DUCT LESIONS

Abstract

To test the association of small bile duct destructive lesions in the liver with acute graft-versus-host disease, a blind (coded) histological study was done comparing liver tissue from three groups of dogs given 1,200 R of total-body irradiation: one not given marrow infusions after irradiation, another given autolo-gous hemopoietic grafts, and a third given marrow grafts from DLA-nonidentical unrelated donors. The dogs with unrelated grafts all developed graft-versus-host disease, and their liver histology was distinguished from that of the dogs in the other two groups by three findings: (1) extensive small bile ductule necrosis and atypia; (2) infiltrates of mononuclear cells around and in ductules; and (3) individual hepatocyte necrosis scattered throughout the lobules. Thus, bile duct lesions appear to be a good marker for assessing the presence and severity of hepatic graft-versus-host disease in dogs. Small bile duct proliferation was first reported by de Vries and Vos (2) in mice as a feature of the graft-versus-host reaction of the liver. Subsequent studies in animals showed eosinophilic change, necrosis, and marked atypia of the epithelium of small bile ducts in addition to necrosis of hepatocytes (3, 4, 11, 14, 18). Similar small bile duct lesions have been described in human patients with acute graft-versus-host disease (GVHD) after allogeneic marrow transplantation. Since they seemed to be the only changes distinguishing liver GVHD from other types of hepatitis, small bile duct lesions have been proposed as the basis of a graded assessment of the severity of hepatic GVHD involvement (6, 17). Woodruff et al. (22) have noted bib duct changes in some human marrow graft recipients, but have been reluctant to assign a relationship to graft-versus-host reaction because of concurrent viral infection, especially cyto-megalovirus (CMV). Dogs that are specifically immunized provide a model in which hepatitis is distinctly unusual even after marrow transplantation (8, 10, 11, 13–15). Also, interstitial pneumonia is rare and CMV infection has not been described. This allows one to study the hepatic changes in GVHD under better controlled conditions. In this study we describe the hepatic histology in three groups of dogs given 1,200 R of total-body irradiation (TBI): one given no marrow infusions after irradiation, another given autologous hemopoietic grafts, and a third given marrow grafts from DLA-nonidentical unrelated donors.