Yasuhiro Nakayama

Telmisartan attenuates progression of steatohepatitis in mice: role of hepatic macrophage infiltration and effects on adipose tissue.

Background/Aims: Non‐alcoholic fatty liver disease and non‐alcoholic steatohepatitis (NASH) are the hepatic manifestation of metabolic syndrome. However, its therapeutic strategy has not been established. Recently, an angiotensin II type 1 receptor blocker, telmisartan (Tel), has received a great deal of attention as a therapeutic tool for metabolic syndrome. The aim of this study was to investigate the efficacy and mechanisms of Tel on a murine NASH model.

Immature NK Cells Suppress Dendritic Cell Functions during the Development of Leukemia in a Mouse Model

To analyze the mechanisms by which cancer cells escape from hosts’ immune surveillance, we investigated the changes in immune status during the progression of leukemia induced by injecting mice with WEHI-3B cells. In the bone marrow (BM) of leukemic mice, only DX5+CD3− cells were continuously increased, despite the progression of leukemia. In addition, DX5+CD3− cells were rapidly increased in peripheral blood (PB) 20 days after inoculation. We also found that myeloid dendritic cells (DCs) expressing low levels of I-Ad and having low allo-T cell stimulatory activity were markedly increased in PB and spleen. The increase in DX5+ cells in BM was thought to be induced by soluble factors from leukemic cells. DX5+ cells from leukemic mice were CD3−, B220−, Gr-1−, CD14−, CD94−, Ly-49C/F−, asialo GM1+, CD25+, CD122+, Thy-1bright, and c-kitdim and showed low killing activity against YAC-1 cells, suggesting that those DX5+ cells were immature NK cells. NK cells from leukemic PB down-regulated the expression of I-Ad on DCs, an effect mediated by TGF-β. Moreover, these NK cells significantly suppressed the allo-T cell stimulatory activity of DCs, an effect requiring cell-to-cell contact between NK cells and DCs and thought to involve CD25. Importantly, NK cells from leukemic PB inhibited generation of autotumor-specific CTL induced by DCs in primary MLR or by DC immunization. In conclusion, we identified circulating immature NK cells with immunosuppressive activities. These cells may be important for understanding the involvement of the host immune system during the development of leukemia.

Development of osteomalacia in a post-liver transplant patient receiving adefovir dipivoxil

We report the case of a patient treated with living donor-related liver transplantation who suffered from osteomalacia during adefovir dipivoxil (ADV)-containing antiviral therapy for lamivudine-resistant hepatitis B virus infection. The patient had generalized bone pain, with severe hypophosphatemia after 20 mo of ADV therapy. Radiographic studies demonstrated the presence of osteomalacia. The peak plasma ADV level was 38 ng/mL after administration of ADV at 10 mg/d. It was also found that ADV affected the metabolism of tacrolimus, a calcineurin-inhibitor, and caused an increase in the plasma levels of tacrolimus. The disability was reversed with the withdrawal of ADV and with mineral supplementation. ADV can cause an elevation of plasma tacrolimus levels, which may be associated with renal dysfunction. High levels of ADV and tacrolimus can cause nephrotoxicity and osteomalacia. This case highlights the importance of considering a diagnosis of osteomalacia in liver transplantation recipients treated with both ADV and tacrolimus.

CTLA-4Ig suppresses liver injury by inhibiting acquired immune responses in a mouse model of fulminant hepatitis†

Expression of costimulatory molecules is significantly upregulated in various organs in an animal model of severe hepatitis induced by injection of Propionibacterium acnes (P. acnes) and lipopolysaccharide (LPS). In the present study, we examined whether blockade of costimulatory signals by CTLA‐4Ig can suppress the liver injury in this model. We injected an adenovirus encoding CTLA‐4Ig (AdCTLA‐4Ig) into mice 7 days before, on the same day, or 3 days after P. acnes priming. The virus was found to infect the liver preferentially, and CTLA‐4Ig was detected in the serum as early as 2 days after viral injection. After injection of LPS, liver injury and survival rates were examined. Most of the mice not injected with AdCTLA‐4Ig died within 12 hours after injection of LPS. In contrast, all the AdCTLA‐4Ig–injected mice survived when the virus was injected 7 days before or on the same day as P. acnes priming. Importantly, hemorrhagic liver injury and serum alanine aminotransferase levels were significantly reduced after LPS injection even when AdCTLA‐4Ig was injected 3 days after P. acnes priming. Immunological analyses showed that CTLA‐4Ig inhibited the activation and expansion of P. acnes–specific CD4+ T cells in the hepatic lymph nodes, leading to a reduction in the recruitment of the cells to the liver. The total amounts of interferon‐γ, interleukin‐12, and various chemokines in the liver were then decreased, resulting in inhibition of the secondary recruitment of not only T cells but also macrophages. In conclusion, CTLA‐4Ig could be useful for treatment of severe liver injury. Supplementary material for this article can be found on the HEPATOLOGY website (http://www.interscience.wiley.com/jpages/0270‐9139/suppmat/index.html). (HEPATOLOGY 2005;42:915–924.)

Preferential accumulation of CD103+ T cells in human livers; its association with extrathymic T cells

BACKGROUND/AIMS CD103, a mucosal integrin alphaEbeta7, binds to E-cadherin expressed on hepatocytes and bile duct epithelium in the liver. Although CD103+ T cells are enriched in intestinal intraepithelial lymphocytes, the localization of those cells in the liver is unknown. METHODS We investigated whether CD103+ cells are present in human livers, and how they are associated with the intrahepatic development of T cells by flow cytometry and immunohistochemistry. RESULTS Human livers contain significantly (P<0.001) higher percentages of CD103+ cells in CD4+ and CD8+ T cells (25.7+/-13.5 and 27.1+/-19.3%, respectively) than peripheral blood lymphocytes. Moreover, CD103+ cells in the liver, but not in peripheral blood, contained T cells with intermediate expression level of T cell receptor alphabeta. Those cells consist of mostly CD4+ and CD4-CD8- cells, and expressed low level of CD56 and interleukin-2 receptor beta chain in most of the population. These characteristics are distinct from natural killer T cells, which have been thought to be extrathymic T cells in human livers. Moreover, intrahepatic CD103+ cells expressed mRNA for recombination-activating gene-1, -2 and pre T cell receptor-alpha detected by reverse transcription-polymerase chain reaction. CONCLUSIONS CD103+ T cells are preferentially accumulated in human livers, and those T cells show characteristics of extrathymic T cells.

Overexpression of granulocyte-macrophage colony-stimulating factor in mouse liver enhances the susceptibility of lipopolysaccharide leading to massive apoptosis of hepatocytes

Abstract: Background/Aims: We examined whether antigen‐nonspecific accumulation of dendritic cells (DCs) and macrophages in the liver by the overexpression of granulocyte macrophage‐colony stimulating factor (GM‐CSF) could prime severe liver injury after LPS injection.