Although livers transplanted across MHC barriers in mice are normally accepted without recipient immune suppression, the underlying mechanisms remain to be clarified. To identify the cell type that contributes to induction of such a tolerance state, we established a mixed hepatic constituent cell-lymphocyte reaction (MHLR) assay. Irradiated C57BL/6 (B6) or BALB/c mouse hepatic constituent cells (HCs) and CFSE-labeled B6 splenocytes were cocultured. In allogeneic MHLR, whole HCs did not promote T cell proliferation. When liver sinusoidal endothelial cells (LSECs) were depleted from HC stimulators, allogeneic MHLR resulted in marked proliferation of reactive CD4+ and CD8+ T cells. To test the tolerizing capacity of the LSECs toward alloreactive T cells, B6 splenocytes that had transmigrated through monolayers of B6, BALB/c, or SJL/j LSECs were restimulated with irradiated BALB/c splenocytes. Nonresponsiveness of T cells that had transmigrated through allogeneic BALB/c LSECs and marked proliferation of T cells transmigrated through syngeneic B6 or third-party SJL/j LSECs were observed after the restimulation. Transmigration across the Fas ligand-deficient BALB/c LSECs failed to render CD4+ T cells tolerant. Thus, we demonstrate that Fas ligand expressed on naive LSECs can impart tolerogenic potential upon alloantigen recognition via the direct pathway. This presents a novel relevant mechanism of liver allograft tolerance. In conclusion, LSECs are capable of regulating a polyclonal population of T cells with direct allospecificity, and the Fas/Fas ligand pathway is involved in such LSEC-mediated T cell regulation.

A portal venous injection of allogeneic donor cells is known to prolong the survival of subsequently transplanted allografts. In this study, we investigated the role of liver sinusoidal endothelial cells (LSECs) in immunosuppressive effects induced by a portal injection of allogeneic cells on T cells with indirect allospecificity. To eliminate the direct CD4+ T cell response, C57BL/6 (B6) MHC class II-deficient C2tatm1Ccum (C2D) mice were used as donors. After portal injection of irradiated B6 C2D splenocytes into BALB/c mice, the host LSECs that endocytosed the irradiated allogeneic splenocytes showed enhanced expression of MHC class II molecules, CD80, and Fas ligand (FasL). Due to transmigration across the LSECs from BALB/c mice treated with a portal injection of B6 C2D splenocytes, the naive BALB/c CD4+ T cells lost their responsiveness to stimulus of BALB/c splenic APCs that endocytose donor-type B6 C2D alloantigens, while maintaining a normal response to stimulus of BALB/c splenic APCs that endocytose third-party C3H alloantigens. Similar results were not observed for naive BALB/c CD4+ T cells that transmigrated across the LSECs from BALB/c FasL-deficient mice treated with a portal injection of B6 C2D splenocytes. Adaptive transfer of BALB/c LSECs that had endocytosed B6 C2D splenocytes into BALB/c mice via the portal vein prolonged the survival of subsequently transplanted B6 C2D hearts; however, a similar effect was not observed for BALB/c FasL-deficient LSECs. These findings indicate that LSECs that had endocytosed allogeneic splenocytes have immunosuppressive effects on T cells with indirect allospecificity, at least partially via the Fas/FasL pathway.

Summary Currently, patients are prescribed lifelong treatment with hepatitis B immunoglobulin (HBIg) after liver transplantation (LT) for hepatitis B virus (HBV)‐related diseases in order to prevent reinfection with HBV. Active immunization with an HBV vaccine would be a preferable alternative; however, the immunosuppressive environment in LT recipients is believed to elicit a poor response to vaccination. Minimizing the exposure of the HBV‐infected LT recipients to immunosuppressants would be beneficial in inducing adaptive immunity against HBV by vaccination. In this study, in addition to efforts to minimize immunosuppression, prophylaxis with HBV vaccination combined with continuous HBIg administration was performed in 17 LT recipients who had undergone transplantation attributable to HBV‐related diseases. During the observation period, the overall response rate to HBV vaccination was 64.7%. The immune status of the recipients was evaluated by a mixed lymphocyte reaction assay in response to allostimulation. Patients showing a donor‐specific hyporesponse with a well‐maintained response to the third‐party stimulus always achieved a sustained immune response to the vaccine, whereas patients showing a hyporesponse to both the donor and the third‐party stimulus were unable to do so. Thus, inducing an anti‐donor‐specific immunosuppressive status by minimizing immunosuppression should enable post‐transplant HBV vaccination to be a promising prophylactic strategy.

Summary We have described our experience with arterial reconstruction during living‐donor liver transplantation by using Varioscope® AF3 – a head‐mounted surgical binocular system with automatic focusing and continuous zoom magnification from 3.6× to 7.2×. From July 1996 to December 2006, 91 grafts were implanted in 89 living‐donor liver transplantation recipients, including two that required retransplantation. For microsurgical reconstruction of the graft hepatic artery, a conventional operating microscope was used in the first 10 transplants and Varioscope, in the subsequent 81. The time required to complete arterial reconstruction while using a conventional operating microscope and Varioscope was 78.6 ± 44.6 min and 35.5 ± 15.5 min, respectively. No arterial complications, including hepatic artery thrombosis, occurred in any of the 89 patients during the observation period. In living‐donor liver transplantation, successful hepatic artery reconstruction can be safely carried out using Varioscope.

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The present paper describes a case of hemorrhagic cholecystitis in a patient on maintenance dialysis. The patient presented with right upper quadrant abdominal pain. Computed tomography revealed swelling of the gallbladder, high- and isodensity contents of the gallbladder, and high-density stone in the gallbladder neck. He was hospitalized for suspected acute cholecystitis. After hospitalization, his levels of total bilirubin, aspartate aminotransferase, and alanine aminotransferase increased. T2-weighted magnetic resonance imaging showed low-intensity contents expanded to include a wide area from the common bile duct to the cystic duct and gallbladder neck. Endoscopic retrograde cholangiopancreatography revealed clotting from the duodenal papilla. After cannulation of the bile duct, old blood and pus began to flow from the mammary papilla, and an endoscopic nasobiliary drainage tube was placed. After his liver function had improved, the patient underwent laparoscopic cholecystectomy. His sample revealed that the gallbladder was filled with blood clots and stones. His postoperative course was uneventful and he was discharged on day 19 after the procedure. Although hemorrhagic cholecystitis is rare, it should be considered as a differential diagnosis for patients on dialysis who have acute abdominal symptoms.

Although it is well known that liver allografts are often accepted by recipients, leading to donor-specific tolerance of further organ transplants, the underlying mechanisms remain unclear. We had previously used an in vitro model and showed that mouse liver sinusoidal endothelial cells (LSECs) selectively suppress allospecific T-cells across major histocompatibility complex (MHC) barriers. In the present study, we established an in vivo model for evaluating the immunomodulatory effects of allogeneic LSECs on corresponding T-cells. Allogeneic BALB/cA LSECs were injected intraportally into recombination activating gene 2 g-chain doubleknockout (RAG2/gc-KO, H-2 b ) mice lacking T, B, and natural killer (NK) cells. In order to facilitate LSEC engraftment, the RAG2/gc-KO mice were injected intraperitoneally with monocrotaline 2 days before the adoptive transfer of LSECs; this impaired the host LSECs, conferring a proliferative advantage to the transplanted LSECs. After orthotopic allogeneic LSEC engraftment, the RAG2/gc-KO mice were immune reconstituted intravenously with C57BL/6 splenocytes. After immune reconstitution, mixed lymphocyte reaction (MLR) assay using splenocytes from the recipients revealed that specific inhibition of host CD4 + and CD8 + T-cell proliferation was greater in response to allostimulation with irradiated BALB/cA splenocytes rather than to stimulation with irradiated third party SJL/jorllco splenocytes. This inhibitory effect was attenuated by administering anti-programmed death ligand 1 (PD-L1) monoclonal antibody during immune reconstitution in the above-mentioned mice, but not in RAG2/gc-KO mice engrafted with Fas ligand (FasL)-deficient BALB/ cA LSECs. Furthermore, engraftment of allogeneic BALB/cA LSECs significantly prolonged the survival of subsequently grafted cognate allogeneic BALB/cA hearts in RAG2/gc-KO mice immune reconstituted with bone marrow transplantation from C57BL/6 mice. In conclusion, murine LSECs have been proven capable of suppressing T-cells with cognate specificity for LSECs in an in vivo model. The programmed death 1/PD-L1 pathway is likely involved in these suppressive effects.

Background: The prognostic prolongation effect of reduction surgery for asymptomatic stage IV gastric cancer (GC) is unfavorable; however, its prognostic effect for symptomatic stage IV GC remains unclear. We aimed to compare the prognosis of gastrectomy and gastrojejunostomy for symptomatic stage IV GC. Methods: This multicenter retrospective study analyzed record-based data of patients undergoing palliative surgery for symptomatic stage IV GC in the middle or lower-third regions between January 2015 and December 2019. Patients were divided into distal gastrectomy and gastrojejunostomy groups. We compared clinicopathological features and outcomes after propensity score matching (PSM). Results: Among the 126 patients studied, 46 and 80 underwent distal gastrectomy and gastrojejunostomy, respectively. There was no difference in postoperative complications between the groups. Regarding prognostic factors, surgical procedures and postoperative chemotherapy were significantly different in multivariate analysis. Each group was further subdivided into groups with and without postoperative chemotherapy. After PSM, the data of 21 well-matched patients with postoperative chemotherapy and 8 without postoperative chemotherapy were evaluated. Overall survival was significantly longer in the distal gastrectomy group (p = 0.007 [group with postoperative chemotherapy], p = 0.02 [group without postoperative chemotherapy]). Conclusions: Distal gastrectomy for symptomatic stage IV GC contributes to prognosis with acceptable safety compared to gastrojejunostomy.