Chronic Antibody-Mediated Rejection in Rat Orthotopic Liver Transplantation

Abstract

Introduction: In chronic rejection in Banff schema for liver allograft rejection, the early and late chronic rejection has been defined. However, the pathological characteristics of chronic antibody-mediated rejection in liver allogarfts have not been fully investigated. In the present study, we examined the pathology of chronic antibody-mediated rejection using rat liver transplantation. Method: Orthotopic liver transplantation was performed from Lewis (RT1l) to BN (RT1n) rats without immunosspression. In this allogenic combination, the liver grfts transplantated with hepatic artery reconstruction could survive more than 100 days, although the grafts transplanted without hepatic artery reconstruction were rejected by day 35 with extensive T cell-mediated and antibody-mediated rejection. We studied Lewis liver grafts that were transplnated into BN rats with hepatic artery reconstruction, focusing on the pathological characteristics of chronic rejection accompanied with chronic antibody-mediated rejection in liver grafts. Results: The grafts transplanted with hepatic artery reconstruction could survived more than 100 days with mild graft dysfunction (T-Bil 0.4 ± 0.1 mg/dl, AST 198.1 ± 19.9 mg/dl), after the eraly severe T cell- and antibody-mediated rejection and graft dysfunction (T-Bil 4.9 ± 1.4 mg/dl, AST 420.8 ± 134.4 mg/dl). Between day 7 and day 28, in addition to the development of T cell-mediated rejection, the deposition of IgM and IgG was detected on endothelial cells in portal veins and hepatic arteries, epithelial cells in bile ducts, and hepatic cells in lobules. After day 28, T cell-mediated rejection gradually subsided but continued more than day 100. The deposition of IgM and IgG was also contnued mainly on endothelial cells in portal veins and hepatic arteries, suggesting the development of chronic antibody-mediated rejection. In light and electron microscopic studies at more than day 100, most prominent features were persistent endothelial cell injuries in portal veins and hepatic arteries with obliterative vasculopathy, diffuse sinusoidal fibrosis, and obstructive cholangiopathy and ductopenia. Conclusion: In chronic liver allograft rejection, chronic antibodymediated rejection could develop with graft dysfunction. The pathological characteristics of chronic rejection accompanied with chronic antibodymediated rejection were similar features as late chronic rejection, but they progressed within short periods with typical obliterative vasculopathy and ductopenia. This animal model is useful for the evaluation of the mechanism and pathological characteristics of chronic antibodymediated liver allograft rejection.