Published online before print September 6, 2007

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(American Journal of Pathology. 2007;171:1499-1508.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.070027

FasL Expression in Hepatic Antigen-Presenting Cells and Phagocytosis of Apoptotic T Cells by FasL⁺ Kupffer Cells Are Indicators of Rejection Activity in Human Liver Allografts

Aya Miyagawa-Hayashino^*, Tatsuaki Tsuruyama^*, Hiroto Egawa, Hironori Haga^*, Hiromi Sakashita^*, Tomoko Okuno^*, Shinya Toyokuni, Keiji Tamaki, Hirohiko Yamabe^*, Toshiaki Manabe^* and Shinji Uemoto

From the Departments of Diagnostic Pathology^* and Surgery, Kyoto University Hospital, Kyoto; and the Departments of Legal Medicine and Molecular Genetics and Pathology and Biology of Diseases, Kyoto University Graduate School of Medicine, Kyoto, Japan

Fas-Fas ligand (FasL) interaction and apoptosis are important in the mechanism of allograft rejection. However, the interaction between donor and recipient cells, specifically focusing on antigen-presenting cells (APCs), under various conditions is poorly understood in human liver allografts. FasL expression on APCs, its association with apoptosis, and the origin of apoptotic lymphocytes in human liver allografts were assessed by immunohistochemistry and in situ hybridization. We found increased expression of FasL on Kupffer cells (KCs) and endothelium in acute cellular rejection (n = 20) and to lesser extent in chronic rejection (n = 6) and septic cholangitis (n = 5) compared with stable grafts and normal controls. In addition, the graft specificity of infiltrating T cells was confirmed by polymerase chain reaction examination of T-cell receptor- loci. T-cell apoptosis occurred at a higher rate in acute cellular rejection than in chronic rejection or septic cholangitis. The number of apoptotic bodies derived from recipient lymphocytes correlated with the severity of rejection and was reversed by treatment. FasL⁺ KCs phagocytosed CD4⁺ interferon-⁺ T cells, rather than CD4⁺ interleukin-4⁺ T cells, suggesting a role of KCs in regulating CD4⁺ T-cell subset differentiation. In conclusion, our data suggest that FasL expression on APCs and phagocytosis of apoptotic T cells by FasL⁺ KCs are indicators of rejection activity in human liver allografts.