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Background To evaluate the role of the oral glucose tolerance test (OGTT) before transplantation and to examine the risk factors for new-onset diabetes after transplantation (NODAT) during long-term follow-up of renal transplant recipients receiving FK-based therapy. Methods The study evaluated 378 patients pre-transplantation using the OGTT and assigned them to one of three groups: Group 1, normal pattern; Group 2, impaired fasting glucose (IFG)/impaired glucose tolerance (IGT) pattern (IFG/IGT); and Group 3, DM pattern. Results Although the incidence of NODAT was higher in Group 3 than in groups 1 and 2, no significant difference was found between the three groups with regard to graft survival during long-term follow-up. Multivariate analysis showed that only a family history of diabetes was a significant factor determining NODAT progression. Conclusions Impaired glucose tolerance appears to be a threshold influencing NODAT; however, it was not a significant factor in graft survival. Careful monitoring and management based on the result of the pre-transplantation OGTT appear to prevent the deterioration of impaired glucose tolerance in renal transplant recipients receiving FK-based therapy, even when a pre-operative OGTT shows impaired glycemic control.

For many years, cellular assays, including mixed leukocyte reactions, cell-mediated lympholysis, and T helper and T cytotoxic cell precursor frequency analyses, have been used to monitor the immune response status of organ allograft recipients. The predictive value, sensitivity, and specificity of such assays have often been questioned. In addition, no in vitro assay has been shown to correlate reliably with or to predict operational tolerance. As tolerogenic strategies are introduced into clinical testing, the need for development and validation of “tolerance” assays is great. Herein, we survey contemporary and emerging technologic approaches to confront this challenge.

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.

We demonstrated that an indirect pathway of alloantigen presentation via liver sinusoidal endothelial cells (LSEC) is involved in alloreactive T-cell tolerance induced by portal venous injection (PI) of donor cells. Thirty million C57BL/6 (B6) splenocytes that were either untreated or treated with 30-Gy irradiation were injected via the portal vein into Balb/c mice. Host LSEC expressing major histocompatibility complex class II actively endocytosed the allogeneic naive splenocytes as well as irradiated splenocytes after PI. Using a transendothelial migration assay, it was demonstrated that host-type Balb/c CD4(+) T cells that transmigrated across LSEC that had captured irradiated B6 splenocytes were rendered tolerant to subsequent alloantigen presentation by host professional antigen-presenting cells. Consistently, PI of irradiated donor-type splenocytes led to remarkable prolongation of the survival of subsequently transplanted heart allografts. These results indicate that indirect antigen presentation by LSEC significantly contributes to alloreactive T-cell tolerance induced by PI of irradiated donor splenocytes.

Livers transplanted across major histocompatibility complex (MHC) barriers in mice are normally accepted without recipient immune suppression. To identify the cell type that contributes to induction of such a tolerance state, we established an allogeneic mixed hepatic constituent cell-lymphocyte reaction (MHLR) assay. Hepatic constituent cells were isolated from C57BL/6 (B6) and Balb/c mice as stimulators, and splenocytes were isolated from B6 mice as responders. Irradiated hepatic constituent cells were co-cultured with fluorescent dye (CFSE)-labeled B6 splenocytes. In the allogeneic MHLR using either whole hepatic constituent cells or parenchymal hepatocytes as stimulators, a lack of T-cell proliferation was observed. Only when CD105(+) cells, which are exclusively liver sinusoidal endothelial cells (LSECs), were depleted from hepatic constituent cell stimulators, the MHLR resulted in marked proliferation of both allo-reactive CD4(+) and CD8(+) T cells. These results indicate that CD105(+) LSECs have the capacity to induce nonresponsiveness of T cells across MHC barriers.

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.

Poor bone marrow (BM) engraftment in a xenogeneic combination results at least in part from the limited engraftment capacity of BM-derived stromal cells, which support hematopoietic repopulation in a species-specific fashion. We attempted to construct a BM stromal microenvironment by engraftment of BM plug fragments into kidney capsules in a rat-to-mouse combination. BM plugs from F344/N Jcl-rnu/rnu (F344 nu) rats were transplanted into the kidney capsules of C.B-17 scid/scid (C.B-17 scid) mice treated with rabbit anti-asialo-GM1 serum to deplete natural killer (NK) cells and then with 3 Gy of whole body irradiation. As a conventional control, an equivalent amount of F344 nu bone marrow cells (BMCs) was intravenously injected into C.B-17 scid mice treated with a similar conditioning regimen. In both mouse recipients of rat BM plug engraftment in the kidney capsules and recipients of intravenous injection of rat BMC suspension, comparable extents of donor rat class I+ cells were persistently detected in the peripheral blood. However, the differentiation of rat-derived B cells in the mouse recipients of rat BM plugs was more rapid than that in the recipients of rat BMC suspension. In the late phase (10 weeks after BM transplantation), the percentage of rat-derived T cells (CD4+ cells) in the mouse recipients of rat BM plugs was significantly higher than that in the recipients of rat BMC suspension. At this time point, ectopic BM structure consisting of bone, mesenchymal cells, and hematopoietic progenitors was constructed in the kidney capsules of mice that received rat BM plugs. Most of the cells in the ectopic BM were derived from the donor rat. Thus, engraftment of BM plugs into the kidney capsules results in the construction of a donor-derived BM microenvironment, facilitating multilineage mixed xenogeneic chimerism.

当センターでこの12年間に経験したpositive selectionのCAPD症例59例中, 死亡15例, 血液透析 (HD) への移行23例の計38例 (64.4%) が, CAPD脱落症例であった.これらの脱落原因の50%がCAPDに関連したもので, 中でもHD移行の主な理由は, 限外濾過不全, 難治性・頻回のCAPD腹膜炎, 硬化性被嚢性腹膜炎 (SEP) であった. また, 開腹手術を要した6例中5例がHDへ移行した. 脱落関連因子として, CAPD施行期間の長さ, CAPD腹膜炎罹患が有意に相関があると考えられた.SEP症例は, 59例中3例, 5.1%であった. 限外濾過不全のためHD移行後, この前段階と考えられる著明な腹水貯留4症例に, 発症早期からのステロイド治療が有効であった.CAPD排液中のamylase値は, 平常時およびCAPD腹膜炎時には, それぞれ, 5.6±2.7, 19.3±22.6mU/mlで, 後者で有意に高値を呈した. 穿孔性腹膜炎2例 (S状結腸, 回腸) と急性膵炎1例に緊急開腹手術を施行したが, 術前のこれらの値はさらに著明な高値を示し, 一般のCAPD腹膜炎との鑑別に極めて有用であった. 回腸穿孔例では, 術後に縫合不全を合併し手術死亡となったが, このような後期の腹膜硬化症を呈する症例においては, 腸管吻合に重大な危険性が存在すると考えられた.脱落症例38例中16例に, カテーテル抜去時や開腹手術時に腹膜のサンプリングが行われ, 病理組織学的検索がなされた. CAPD施行期間が8-18か月の3例では, いずれも腹膜線維症の所見であった. しかし, 60か月以上の13例中12例, 92.3%では, 腹膜機能障害が非可逆性といわれる中期以後の腹膜硬化症の所見 (中期5例, 後期7例) が認められ, 極めて注目すべき結果が得られた. この事実は, かかる長期CAPD症例においては, SEPとの関連から, その中止時期も含めて, 注意深い経過観察が必要であると考えられた.

症例は60歳, 女性. 1986年12月9日慢性糸球体腎炎による慢性腎不全と診断され, 持続腹膜透析 (CAPD) 導入. その直後の1987年2月12日両側手根管症候群にて開放術施行. 以後9年間で腹膜炎を2回発症. 徐々に除水能の低下をきたし, 1995年12月より血液濾過透析に移行. 透析低血圧および, 凝固能異常の合併によると思われる内シャントの閉塞を反復した. 1996年11月より悪心, 嘔吐, 腹部膨満等の腸閉塞症状出現, 保存的療法にて-時軽快. 消化管透視腹部超音波検査, 腹部CT検査で, 腸管の拡張, 腸蠕動の著明な低下が認められ, 硬化性被嚢性腹膜炎と診断された. 同年12月再び腸閉塞出現, 保存的加療施行するも症状遷延. 内シャント再建術中, 突然ショック状態を呈し, 急性心不全状態持続したのち, 重篤な心筋伝導障害で12月16日死亡した. 病理剖検所見では, 化膿性腹膜炎および腹膜の線維性硬化像に加えて, 全身骨・関節, 消化管, 心, 肺, その他諸臓器にアミロイド沈着を認め, 硬化性被嚢性腹膜炎およびアミロイドーシスの合併が判明した. 本例のアミロイドは, β2-microglobulin由来であったが, AA抗体陽性, 過マンガン酸カリ抵抗性で, 従来の文献とは異なっていた.透析に伴う重篤な合併症を重複した, 貴重な剖検例を経験した. 透析療法の進歩で, 慢性腎不全患者の長期生存が可能となった現在, 同様の症例の出現が今後も予想され, 本例を長期透析患者の全身管理の指針について, 貴重な布石としたい.

症例は63歳の男性で, 主訴は下血. 血清CA19-9異常高値 (830U/ml), CT, Gaシンチなどから, 悪性腸間膜腫瘍を疑い開腹した. 回盲部より80cmの部位にMeckel憩室を認め, 同部に腫瘍および腸間膜リンパ節の腫脹を認めたため, リンパ節郭清を含めた回腸切除を行った. 病理組織学的にはMeckel憩室から発生した中分化型腺癌で, 憩室内には迷入組織を認めなかった. 術後血清CA19-9は速やかに低下し, また抗CA19-9抗体を用いた免疫染色で陽性であり, CA19-9産生腫瘍と診断した. Meckel憩室癌は本邦22例目と極めてまれである. 本症は予後不良であるが, 自験例は1年6か月経過した現在も再発の兆候を認めず, CA19-9の上昇も認めていない.

Leiomyosarcoma of the inferior vena cava (IVC) is a rare neoplasm of venous smooth muscle. A case of leiomyosarcoma of the IVC which was successfully resected by early detection is described. A 63-year-old woman was seen at the hospital because of right abdominal pain, and abdominal ultrasonography revealed a 26×21mm sized tumor in S1 portion of the fiver. The correct diagnosis was not made even by computed tomographic scan, magnetic resonance imaging and transhepatic biopsy of the tumor. An exploratory laparotomy was carried out and the tumor was resected together with the hepatic IVC by using the femoro-axillary V-V bypass. We reconstructed the IVC by a EPTFE graft with rings. Pathologically this tumor was leiomyosarcoma of the IVC. The tumor was 4.0×2.5×2.0cm in size, protruded to the surface of the lumen of inferior vena cava, and its outside was adjacent of the liver through capsula fibrosa. The postoperative course was uneventful. There has been no sign of recurrence as of 6 months after the operation.

Recipients of spousal donor transplantation (SDT) have poorer histocompatibility and higher human leukocyte antigen (HLA) sensitization due to pregnancy than those receiving related donor transplantation (RDT). Thus, SDT carries a higher risk of acute rejection (AR). In our department, patients at a high immunological risk, such as those with ABO incompatibility and HLA sensitization, were considered for desensitization by double filtration plasmapheresis and preoperative administration of rituximab. In this study we compared the AR incidence rates between SDT and RDT according to their immunological risk. We performed RDT in 279 and SDT in 100 patients, a total of 379 cases, between 2000 and 2008; 48.7% of RDT and 67.0% of SDT cases were considered to be at a high immunological risk and underwent preoperative desensitization (P=0.002). Even though the AR incident rate of SDT was higher than RDT in the low immunological risk group, in which the patients had undergone transplantation without desensitization (RDT 24.4%, SDT 37.0%, P=0.012), there was no significant difference between the two donor type groups in the high immunological risk group, in which transplantation with desensitization occurred (RDT 21.3%, SDT 31.3%, P>0.05). Preoperative administration of rituximab significantly reduced AR from 37.4% to 10.6% (P

Proinflammatory responses play critical roles in hepatic ischemia/reperfusion (I/R) injury associating with liver transplantation (LTx), and carbon monoxide (CO) can effectively down-regulate them. Using wild-type (WT) to enhanced green fluorescent protein (EGFP)-transgenic rat LTx with 18-hour cold preservation in University of Wisconsin solution, this study analyzed the relative contribution of donor and host cells during early posttransplantation period and elucidated the mechanism of hepatic protection by CO. CO inhibited hepatic I/R injury and reduced peak alanine aminotransferase levels at 24 hours and hepatic necrosis at 48 hours. Abundant EGFP+ host cells were found in untreated WT liver grafts at 1 hour and included nucleated CD45+ leukocytes (myeloid, T, B, and natural killer cells) and EGFP+ platelet-like depositions in the sinusoids. However, reverse transcription polymerase chain reaction (RT-PCR) analysis of isolated graft nonparenchymal cells (NPCs) revealed that I/R injury-induced proinflammatory mediators [for example, tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and inducible nitric oxide synthase (iNOS)] were not up-regulated in purified CD45+ cells of donor or host origin. Instead, TNF-α and IL-6 messenger RNA (mRNA) elevation was exclusively seen in isolated CD68+ cells, whereas iNOS mRNA up-regulation was seen in hepatocytes. Nearly all CD68+ cells at 1 hour after LTx were EGFP− donor Kupffer cells, and CO efficiently inhibited TNF-α and IL-6 up-regulation in the CD68+ Kupffer cell fraction. When graft Kupffer cells were inactivated with gadolinium chloride, activation of inflammatory mediators in liver grafts was significantly inhibited. Furthermore, in vitro rat primary Kupffer cell culture also showed significant down-regulation of lipopolysaccharide (LPS)-induced inflammatory responses by CO. Conclusion: These results indicate that CO ameliorates hepatic I/R injury by down-regulating graft Kupffer cells in early postreperfusion period. The study also suggests that different cell populations play diverse roles by up-regulating distinctive sets of mediators in the acute phase of hepatic I/R injury. (HEPATOLOGY 2008;48:1608–1620.)

Graft-versus-host disease (GVHD) after liver transplantation is uncommon but is a serious complication that can be fatal. Hemophagocytic syndrome (HPS), which is caused by activation of autologous T lymphocytes, is also a serious complication that can occur after liver transplantation. Because these complications share the clinical triad of skin rash, marrow failure, and diarrhea, differential diagnosis is difficult. We describe a case of severe GVHD resembling HPS in clinical features that occurred after living-related liver transplantation. The patient who had undergone the transplantation had high fever, pancytopenia, and skin rash 3 wk after the operation. Examination of a bone-marrow biopsy sample revealed the presence of abundant monocytes with phagocytosis, suggesting either GVHD or HPS. Donor human leukocyte antigens were detected in the peripheral blood of the patient by polymerase chain reaction, but this finding is not specific for GVHD. A definitive diagnosis was made by demonstration of remarkable anti-self response and undetectable anti-donor response in a mixed lymphocyte reaction assay using carboxyfluorescein diacetate succinimidyl ester.

Background Portal vein reconstruction is still a crucial problem in living-donor liver transplantation. Vascular closure staples (VCS) have been applied for small peripheral and large vessels because of the technical ease with which they can be employed. We describe here our experience with portal vein reconstruction in living donor-liver transplantation and compare VCS with conventional sutures in portal vein reconstruction. Methods The anastomosis between the donor portal vein and recipient portal vein or the right external iliac vein graft was created using either VCS or conventional sutures. Results The stenotic ratios were .51 ± .15 and .79 ± .25 for the conventional sutures and VCS, respectively. The stenotic ratio was significantly lower in VCS compared with conventional sutures. Conclusions VCS compared with conventional sutures has the advantage of low risk of anastomotic stenosis.

The pathway leading to cell death in clinical liver transplantation is not known. Eight liver transplant recipients and eight donors were enrolled in this study. Postoperative serum levels of alanine transferase had significantly increased in the recipients compared with those in the donors. Mild centri-lobular necrosis was observed in only liver tissues taken from the recipients. Tumor necrosis factor (TNF)-R1 and death receptor 5 expression levels had increased in liver tissues taken from the recipients. There were no changes in the levels of Fas/Fas ligand expression in liver tissues from either the donors or recipients. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression was down-regulated in donor liver after hepatectomy and liver allograft after implantation. The results suggest that, although ischemic liver injury was not serious, due to the short ischemia time, TNF and TRAIL signals are associated with liver ischemic injury in live-donor liver transplantation but Fas signal is not.