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Background: Congestion in the right paramedian sector of a right liver graft without a middle hepatic vein (MHV) may lead to graft dysfunction. To solve this problem, we have developed a technique for reconstructing the MHV tributaries of the right liver grafts by using the preserved recipient's native MHV trunk., Methods: Between 2005 and 2007, among 34 right liver graft liver transplant patients with significant MHV tributaries (>5 mm in diameter), 21 patients underwent right liver graft living-donor liver transplantation: draining MHV tributaries with recipient's native MHV trunk. We evaluated the patency of the reconstructed MHV tributaries, graft regeneration, and graft survival., Results: The 3-month patency rates of the reconstructed V8 and V5 were 92% and 76%, respectively. The 1-year survival rate and the regeneration index of the right paramedian sector 6 months after transplantation were higher in patients with reconstructed MHV tributaries than that for patients without reconstructed MHV tributaries., Conclusion: The use of the recipient's MHV trunk for the reconstruction of the MHV tributaries of the right liver grafts is considered to be a valuable and a feasible strategy in right liver graft living-donor liver transplantation.

Background: Xenogeneic thymus transplantation is an effective approach to achieving T cell tolerance across highly disparate xenogeneic species barriers. We have previously demonstrated that phenotypically normal, specifically tolerant human T cells are generated in porcine thymic grafts. In this study, we assessed the diversity of the human T cell repertoire generated in porcine thymic xenografts. We also examined the ability of porcine thymus grafts to coexist with human thymus grafts., Methods: Fetal swine (SW) or human (HU) thymus with human fetal liver fragments were transplanted under the kidney capsule of 3Gy irradiated NOD/SCID mouse recipients. Thymus tissue was harvested approximately 16 weeks posttransplant for analysis of mixed lymphocyte reactions and spectratyping of human CD4 and CD8 single positive thymocytes., Results: T cell receptor beta genes of human CD4 and CD8 single positive cells developing in HU and SW thymus grafts showed similar, normal CDR3 length distributions. Human T cells developing in SW thymus grafts showed specific unresponsiveness to the major histocompatibility complex of the donor swine in mixed leukocyte reaction assays. In two of three animals receiving SW and HU thymus grafts under opposite kidney capsules, both grafts functioned. In animals with surviving SW grafts, thymocytes from the SW but not the HU grafts showed specific unresponsiveness to the SW donor., Conclusion: Swine thymus grafts support generation of human T cells with a diverse T cell receptor repertoire. Human thymocytes in human thymus grafts are not tolerized by the presence of an additional porcine thymus, but tolerance might be achieved by postthymic encounter with porcine antigens.

Background: Hepatocyte growth factor (HGF) is a growth factor with multiple biologic properties, including mitogenic, morphogenic, anti-apoptotic, and antifibrogenic activities. Long-term administration of the deletion variant of HGF (dHGF) might contribute to the prevention of chronic liver allograft dysfunction, which is attributed to immunologic and nonimmunologic reactions., Methods: Low-dose tacrolimus was administered to rat-liver recipients after transplantation. Effects of dHGF on transplanted livers treated with low-dose tacrolimus were investigated., Results: Rats receiving liver transplants treated with only low-dose tacrolimus administration showed chronic allograft dysfunction. Treatment with dHGF prolonged the survival time of rats that received liver allografts and suppressed fibrosis of liver allograft. Treatment with dHGF also suppressed the expression levels of interleukin (IL)-1beta, caspase-1, and transforming growth factor (TGF)-beta mRNAs in liver allografts., Conclusions: The findings indicate that dHGF may prevent chronic liver-allograft dysfunction and thus may become a novel treatment for chronic liver-allograft dysfunction.

Background: We demonstrated that hepatic stellate cells (HSCs) isolated from rat livers exposed to warm ischemia are significantly contractile when compared with HSCs from intact rat livers. This suggests that ischemia-reperfusion (IR)-induced impairment of sinusoidal microcirculation results, at least in part, from contraction of HSCs., Methods: Rho-associated coiled-coil forming protein serine/threonine kinase (ROCK) is one of the key regulators of HSCs motility. Therefore we investigated whether Y-27632, a p160ROCK-specific inhibitor, has beneficial effects on warm IR injury in an in vivo rat partial liver IR model and a rat orthotopic liver transplantation model., Results: After reperfusion following 90 min of warm ischemia, livers in untreated control rats had persistent congestion and impaired mitochondrial respiration, as demonstrated by increasing deoxy-hemoglobin and reduced cytochrome oxidase contents in the hepatic tissues using in vivo near-infrared spectroscopy. Serum levels of transaminase and endothelin (ET)-1 in these rats were markedly increased 1 hr after reperfusion. In contrast, when Y-27632 (3-30 mg/kg) was administered orally, hepatic tissue contents of deoxy-hemoglobin and cytochrome oxidase rapidly normalized. In such animals, the elevation of serum transaminase levels, but not that of ET-1 levels, was significantly suppressed. This is consistent with in vitro data demonstrating that Y-27632 causes HSCs to undergo relaxation even in the presence of ET-1. Moreover, in a rat orthotopic liver transplantation model, Y-27632 pretreatment dramatically improved the survival of recipients with liver grafts subjected to 45 min of warm ischemia., Conclusions: Y-27632 attenuates IR-induced hepatic microcirculation disruption by inhibiting contraction of HSCs.

Background: Heat shock proteins (HSPs) are well known as cytoprotective proteins. Geranylgeranylacetone (GGA), a nontoxic anti-ulcer drug, was recently shown to have HSP-inducing capacity. In the present study, the activity of GGA was tested in a rat orthotopic liver transplantation (OLT) model to determine whether the compound has beneficial effects in warm ischemia-reperfusion injury., Methods: Either GGA or a control vehicle was orally administered to donor rats before graft harvest. Harvested livers were subjected to 45-min warm ischemia (37 degrees C) followed by OLT. HSP mRNA expressions and HSP syntheses in the graft livers were evaluated by reverse transcriptase polymerase chain reaction and Western blot analysis, respectively., Results: When the donors were treated with a vehicle, all recipients died of primary nonfunction within 2 days after OLT. In contrast, when the donors were treated with GGA (200 mg/kg per day) for 4 weeks, the 7-day survival rate of recipients was dramatically improved (90%). By giving a high dose of GGA (600 mg/kg per day) for 1 week, a similar improvement in recipient survival was seen (83.3%). GGA administration accumulated mRNA for both HSP72 and HSP90 in the livers even before warm ischemia and facilitated the syntheses of HSP72 and HSP90 after warm ischemia. In addition, GGA pretreatment also significantly reduced the serum levels of tumor necrosis factor-alpha (TNF-alpha) after reperfusion., Conclusions: These findings indicate that both the enhanced induction of HSPs and the suppression of a cytotoxic mediator (TNF-alpha) might be involved in the beneficial effects of GGA on ischemia-reperfusion injury. Thus, oral administration of GGA would be a useful tool for preventing primary nonfunction in liver transplantation.

Background: Interleukin- (IL) 10 may be a potent regulator for controlling of allograft rejection. A single administration of IL-10 is not effective for controlling graft rejection. Gene transfer is an attractive vehicle for prolonging the expression of short-lived proteins., Methods: Donor or recipient livers were transduced with 1 x 10(10) p.f.u. of replication-deficient adenovirus vectors harboring human IL-10 cDNA (AdCMVhIL-10) via the ileocecal vein before or after rat orthotopic liver transplantation., Results: DA allografts given AdCMVhIL-10 24-48 hr before donation survived for more than 56 days in Lewis recipients, although DA allografts given the adenovirus vector 7 days or 6 hr before, and 3 days after transplantation were rejected within 30 days in recipients. Serum levels of human IL-10 in gene-transferred rats were maximum from day 2 to 7. The serum level of human IL-10 then decreased gradually, and human IL-10 was not detected by ELISA 30 days after gene-transduction. In gene-transduced long-term surviving liver allografts, IL-10 was expressed, and the expression of IL-4 was also up-regulated on posttransplant day 3, despite the expression of Th1 cytokines (IL-2 and interferon-gamma), although in rejected liver allografts, IL-2 and interferon-gamma were expressed without expression of IL-4 and IL-10., Conclusions: The prolongation of survival of IL-10 cDNA transferred liver allografts might be due to inhibition of the early phase of alloimmune-response by over expression of IL-10, despite the expression of IL-2 and interferon-gamma.