Makoto Ochi

Liver NK cells expressing TRAIL are toxic against self hepatocytes in mice.

Although it is known that activation of natural killer (NK) cells causes liver injury, the mechanisms underlying NK cell‐induced killing of self‐hepatocytes are not clear. We demonstrated that liver NK cells have cytotoxicity against normal syngeneic hepatocytes in mice. Polyinosinic‐polycytidylic acid (poly I:C) treatment enhanced hepatocyte toxicity of liver NK cells but not that of spleen NK cells. Unlike NK cells in other tissues, approximately 30%–40% of liver NK cells constitutively express tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL). An in vitro NK cell cytotoxic assay revealed that hepatocyte toxicity of liver NK cells from both naïve and poly I:C‐treated mice was inhibited partially by an anti‐TRAIL monoclonal antibody (mAb) alone and completely by the combination with anti‐Fas ligand (FasL) mAb and a perforin inhibitor, concanamycin A, indicating contribution of TRAIL to NK cell‐mediated hepatocyte toxicity. The majority of TRAIL+ NK cells lacked expression of Ly‐49 inhibitory receptors recognizing self‐major histocompatibility complex class I, indicating a propensity to targeting self‐hepatocytes. Poly I:C treatment significantly upregulated the expression of Ly‐49 receptors on TRAIL− NK cells. This might be a compensatory mechanism to protect self‐class I‐expressing cells from activated NK cell‐mediated killing. However, such compensatory alteration was not seen at all in the TRAIL+ NK cell fraction. Thus, liver TRAIL+ NK cells have less capacity for self‐recognition, and this might be involved in NK cell‐dependent self‐hepatocyte toxicity. In conclusion, our findings are consistent with a model in which TRAIL‐expressing NK cells play a critical role in self‐hepatocyte killing through poor recognition of MHC. (HEPATOLOGY 2004;39:1321–1331.)

Intraoperative near-infrared spectroscopy for evaluating hepatic venous outflow in living-donor right lobe liver

Background. This study was performed to determine the usefulness of intraoperative near-infrared spectroscopy (NIRS) for evaluating the extent of congestion in the anterior segment of the graft after living-donor liver transplantation using right lobe grafts that do not have the middle hepatic vein. Methods. Fifteen patients undergoing living-donor liver transplantation using a right lobe graft without the middle hepatic vein were enrolled in this study. During the course of harvesting and implantation, in vivo NIRS was performed on the liver grafts to determine hemoglobin (Hb) and cytochrome oxidase content in the hepatic tissues. Results. The 15 cases were divided into three groups according to the caliber of the middle hepatic vein tributaries in the right lobe grafts: the small group (<4 mm), the intermediate group (4–7 mm), and the large group (>7 mm). After implantation, congestion (increase in tissue Hb) in the anterior segment was more severe than that in the posterior segment in the intermediate and large groups. However, well-preserved mitochondrial cytochrome oxidase redox state was observed in both segments except for two cases in the large group with severe congestion in the anterior segment. The extent of postoperative congestion in the anterior segment was significantly correlated with the tissue content of remaining Hb in that segment after ex vivo flushing. Conclusions. Intraoperative NIRS enables quantification of the extent of congestion in the anterior segment after implantation of a right lobe liver graft and even enables prediction of such congestion at the phase of ex vivo perfusion.

Indication of Hepatectomy for Cirrhotic Patients with Hepatocellular Carcinoma Classified as Child-Pugh Class B

We clarified the indication of partial hepatectomy in hepatocellular carcinoma (HCC) patients with liver cirrhosis classified as Child-Pugh class B. Univariate analysis revealed that adverse prognostic factors were (1) the presence of ascites, (2) elevated total bilirubin (1.5 mg/dl or higher), (3) reduced choline esterase (160 IU/ or lower), (4) elevated alpha-fetoprotein (AFP) (400 ng/ml or higher), (5) microscopic vascular invasion, and (6) non-curative hepatectomy. Microvascular invasion was excluded in the multivariate analysis because this factor could not be predicted before hepatectomy. Multivariate analysis revealed that independent adverse prognostic factors were (1) elevated total bilirubin (1.5 mg/dl or higher), (2) presence of ascites, (3) elevated AFP (400 ng/ml or higher), and (4) non-curative hepatectomy. The overall 5-year survival rate of patients with none of or only one of the four adverse prognostic factors was 45.8%. The overall 5-year survival rate of patients with two or more adverse prognostic factors was only 7.0%. Partial hepatectomy is the first choice of treatment for patients with none of or only one of the four adverse prognostic factors, whereas orthotopic liver transplantation or other conservative treatment should be considered for patients with two or more adverse prognostic factors.