Ryosuke Minagawa

Use of steatotic graft in living-donor liver transplantation.

Background. The degree of fatty infiltration in hepatic grafts is known to be an important risk factor for primary graft nonfunction in cadaveric liver transplantation. However, the effect of hepatic steatosis in living-donor liver transplantation (LDLT) has not yet been well defined. In this study, we evaluated the impact that the degree of hepatic graft steatosis has on the outcome of LDLT. Methods. Sixty consecutive donors and recipients who underwent LDLT between October 1996 and August 2001 at Kyushu University Hospital were the subjects of this study. The pathologic findings of the prereperfusion biopsy of the graft were classified into the following three groups according to the degree of macrovesicular steatosis: None (n=23), 0% steatosis; Mild (n=23), 0% to 20% steatosis; and Moderate (n=6), 20% to 50% steatosis. Liver function tests including total bilirubin (at postoperative day [POD] 7), the peak alanine aminotransferase (ALT) and prothrombin time (at POD 3), and both patient and graft survival were compared among the groups. Furthermore, we also compared the donor parameters including the peak ALT and total bilirubin (at POD 3) and the operative time, blood loss, and length of hospital stay after surgery. Results. The 1-year patient and graft survival were comparable among the groups. The peak ALT was significantly higher in the Moderate group (606±641 IU/L) than in the None (290±190 IU/L) and Mild (376±296 IU/L) groups. Total bilirubin (POD 7) and prothrombin time (POD 3) were comparable among the groups. The donor parameters were comparable among the groups except for the fact that the donor body weight of the Mild and Moderate groups were significantly heavier (P <0.0001) than that of the None group. Conclusions. In conclusion, the use of a fatty liver graft up to the moderate level can be justified in LDLT, even though ischemia-reperfusion injury tends to be severe in such grafts.

Feasibility of duct-to-duct biliary reconstruction in left-lobe adult-living-donor liver transplantation.

A Roux-en-Y choledochojejunostomy (CDJ) has been the sole method of choice for the reconstruction of the bile duct in living-donor liver transplantation (LDLT) using left-lobe grafts. In this study, we evaluated the feasibility of duct-to-duct (DD) biliary reconstruction in adult-to-adult LDLT using left-lobe grafts. Between October 1996 and October 2001, 46 adult-to-adult LDLTs using the left lobe were performed at our institution. The DD biliary reconstruction (hepaticocholedochostomy) over a T-tube was performed for seven of the last nine recipients (DD group, n=7), whereas the conventional Roux-en-Y CDJ was used for the remaining cases (CDJ group, n=39). The technical problems and the incidence of biliary complications were compared between the groups. Bile leakage developed in only 1 of 7 (14%) in the DD group (leakage from a T-tube exit site), whereas it occurred in 8 of 39 (20%) in the CDJ group. Up to now, no patients from the DD group developed anastomotic stricture, whereas twelve (30.7%) patients from the CDJ group did. Other complications included bleeding from the Roux-en-Y jejunojejunostomy (n=1) and anastomotic occlusion caused by an internal stent (n=1), and both complications were associated with CDJ. In conclusion, DD anastomosis is a simple and viable option for biliary reconstruction in left-lobe LDLTs. A long-term follow-up, especially regarding the incidence of biliary stricture, is thus warranted in such patients.

Crucial Fas–Fas ligand interaction in spontaneous acceptance of hepatic allografts in mice

The Fas/Fas ligand (FasL) system plays important roles in the immune system, including host immunoregulation and cytotoxicity. In this study, we investigated the involvement of Fas–FasL interactions in spontaneous acceptance of hepatic allografts in murine orthotopic liver transplantation. Liver transplantation between the C57BL/6 (B6, H‐2b) donor and the MRL/Mp (MRL, H‐2k) recipient was performed in various combinations of donor and recipient mice with wild type (+/+), Fas‐mutant (lpr) or FasL‐mutant (gld) genotypes. The prolongation and spontaneous acceptance of the fully allogeneic grafts in recipients was not observed in either MRL‐lpr recipients with B6+/+ livers or MRL+/+ recipients with B6‐gld livers. Moreover, the serum alanine aminotransferase (ALT) levels and the degree of cell infiltration into hepatic allografts on day 7 after transplantation were inversely correlated with the recipient survival time (in days). The donor‐specific cytotoxic T‐lymphocyte (CTL) activities of the graft‐infiltrating cells (GICs) from MRL‐gld recipients with B6+/+ livers were much lower than those from MRL+/+ or ‐lpr recipients on days 5 and 10 after transplantation. However, the CTL activities of the GICs from MRL+/+ and ‐gld recipients predominately disappeared by day 15 after transplantation. Furthermore, the anti‐donor CTL activities induced in MRL+/+ recipients were ascribed to CD8+ cells, and were not mediated by Fas–FasL interactions. These results strongly suggest that the Fas/FasL system plays a critical role for recipient immunoregulation, enabling recipients in accepting hepatic allografts by deletion of the donor‐specific T cells, but not for CTL/target cell interaction in MRL+/+ recipients.

Heart allograft tolerance without development of posttransplant cardiac allograft vasculopathy in chimerism-based, drug-induced tolerance.

BACKGROUND Recently, we have described a drug (cyclophosphamide [CP] plus busulfan [BU])-induced skin allograft tolerance in mice that can regularly overcome fully H-2-mismatched barriers. Using this method, we have investigated whether or not this regimen can prolong the survival of heart allografts and inhibit the development of posttransplant cardiac allograft vasculopathy (CAV). METHODS The components of the method are intravenous administration of 1 x 108 allogeneic spleen cells on day 0, intraperitoneal injection of 200 mg/kg of CP and 30 mg/kg of BU on day 2, and intravenous injection of T cell-depleted 1 x 107 allogeneic bone marrow cells from the same strain of mice on day 3. Heart grafting was performed on day 28. Chimerism in peripheral blood was followed by flow cytometric analysis, and histological analysis was performed at various times after grafting. RESULTS In a fully major histocompatability complex (MHC)-mismatched combination of B10.D2 (H-2d, IE+)-->B10 (H-2b, IE-), stable, multilineage-mixed chimerism was observed permanently. B10.D2 heart grafts were accepted permanently in a donor-specific manner, and posttransplant CAV did not develop. CONCLUSIONS These results demonstrated that the drug-induced tolerance recently established by us can regularly induce a long-lasting heart allograft tolerance without development of CAV.