Localization of apoptosis proteins and lymphocyte subsets in chronic rejection of human liver allograft

Abstract

AbstractIn chronic liver rejection lymphocyte mediated processes lead to chronic inflammation, necrosis and repair mechanisms. The aim of the present study was to investigate the expression of apoptosis related proteins (FAS/APO-1, FAS-L, Bcl-2, Bax, TNF-α, and INF-γ). ApopTag reaction and immunohistochemistry were performed on liver samples of chronically rejected allografts and compared with normal donor livers. In chronic rejection, apoptosis was detected in pericentral hepatocytes and in the biliary epithelium. Bcl-2 was strongly expressed on lymphocytes around the bile ducts, but not on the biliary epithelium itself. Bax, FAS, TNF-αand INF-γwere present in pericentral areas. T-cells showed up around bile ducts, whereas macrophages around pericentral areas. In pericentral areas apoptosis seems to be fostered through TNF-αand INF-γand by the lack of Bcl-2. Based on these results both downregulation and upregulation of apoptotic proteins can be observed in chronic liver allograft rejection: FAS is upregulated in biliary epithelium and zone 2, protein levels of FASL remain unchanged, BAX is upregulated in zone 3, BCL2 is downregulated in both biliary epithelium and zone 1 and both TNFa and IFN are upregulated in zone 3. Our results suggest that the balance between pro- and antiapoptotic patterns was shifted to the proapoptotic side, mainly in the centrilobular area of the hepatic lobule, and in the bile ducts. According to these findings in chronic rejection the predictive sites of apoptosis are the biliary epithelium and the pericentral areas.