Keizo Anzai

Elevated serum soluble Fas ligand in natural killer cell proliferative disorders

We evaluated the serum level of soluble Fas ligand (sFasL) in patients with natural killer lymphocyte proliferative disorders (NK‐ LPD). The serum sFasL level was elevated in neoplastic groups of aggressive NK leukaemia, indolent NK leukaemia and NK lymphoma, all of which contained clonal EBV‐DNA. In NK leukaemia the serum sFasL level was significantly higher than that found in others. However, it was not elevated in the patients with reactive NK‐LPD and in one patient with NK leukaemia in remission. These findings indicate that the serum sFasL level is a useful indicator in evaluating disease activity.

Pilot study of liraglutide effects in non-alcoholic steatohepatitis and non-alcoholic fatty liver disease with glucose intolerance in Japanese patients (LEAN-J)

Non‐alcoholic fatty liver disease (NAFLD), a hepatic manifestation of metabolic syndrome, is associated with an increased risk of developing lifestyle‐related diseases including type 2 diabetes, cardiovascular disease and cerebral vessel disease. No current drug therapy provides the ideal effects of decreasing hepatic inflammation while simultaneously improving liver fibrosis. Liraglutide is a glucagon‐like peptide‐1 receptor agonist that affects the histological findings in patients with non‐alcoholic steatohepatitis (NASH). This study was conducted to evaluate the effect and action of liraglutide for biopsy‐proven NASH.

Successful islet transplantation to two recipients from a single donor by targeting proinflammatory cytokines in mice.

Background. Currently, the inability to achieve successful islet transplantation from one donor to one recipient is a major obstacle facing clinical islet transplantation. We herein determined whether this limitation could be overcome by targeting pro-inflammatory cytokines with the prevention of immediate islet graft loss in association with engraftment in mice. Methods. Isolated islets were grafted into the liver of streptozotocin-induced diabetic mice and the role of proinflammatory cytokines in the engraftment of islets was evaluated with the use of interferon (IFN)-&ggr;−/−mice and monoclonal antibodies against proinflammatory cytokines. Results. Hyperglycemia in streptozotocin-induced diabetic mice receiving 200 syngenic islets, which were isolated from a single mouse pancreas, was ameliorated when IFN-&ggr;−/−, but not wild-type mice, were used as recipients. The treatment with anti-IFN-&ggr; antibody produced normoglycemia in diabetic wild-type mice receiving 200, but not 100 islets. However, when anti–tumor necrosis factor-&agr; and anti-interleukin-1&bgr; antibodies were administered in conjunction with anti-IFN-&ggr; antibody, wild-type diabetic mice receiving 100 islets became normoglycemic after transplantation. In addition, the favorable effect of the combined use of antibodies was similarly achieved in mice receiving islet allografts when rejection was prevented with anti-CD4 antibody treatment. Conclusions. These findings clearly demonstrate that successful islet transplantation from one donor to two recipients is feasible by targeting pro-inflammatory cytokines in mice, thus suggesting a potential application in clinical islet transplantation if similar mechanisms of islet graft loss could be mediated in humans.

Severity of non-alcoholic steatohepatitis is associated with substitution of adipose tissue in skeletal muscle.

The pathogenesis of non‐alcoholic fatty liver disease (NAFLD) is now focusing on its organ cross‐talk with not only adipose tissue but also systemic skeletal muscle. Cross‐sectional and longitudinal studies were conducted to determine the role of intramuscular adipose tissue content (IMAC) measured by computed tomography on the severity of NAFLD/non‐alcoholic steatohepatitis (NASH).

Retinoic acids induce growth inhibition and apoptosis in adult T-cell leukemia (ATL) cell lines

Adult T-cell leukemia (ATL) is a peripheral T-cell neoplasm caused by human T-cell leukemia virus type I (HTLV-I). Despite the administration of combined intensive chemotherapy, the reported survival time of patients with acute and lymphoma types of ATL is less than 10 months. We therefore examine the effects of all-trans-retinoic acid (ATRA), 9-cis-RA and 13-cis-RA and tried to elucidate the mechanisms of inducing growth inhibition and apoptosis by these RAs using four ATL cell lines established in our laboratory. All the investigated RAs inhibited cell growth and the cells were arrested at the G1 phase. Apoptosis was induced in three out of four cell lines. Among the growth regulatory proteins examined, the level of p21Waf1/Cip1 protein was found to increase after RA treatment, thus resulting in pRb hypophosphorylation which also induced the arrest of the cells at the G1 phase. In addition, the p53 level decreased at the same time. Fas-FasL system and the downregulation of CD25 (IL-2R/alpha) expression did not seem to be involved. Based on these findings, the ability of RAs to induce a remission of ATL is thus strongly suggested.

Sarcopenia is a risk factor for the recurrence of hepatocellular carcinoma after curative treatment

Sarcopenia, initially proposed as decreased of muscle mass and strength, is associated with aging and malignant diseases. The aim of the present study was to determine whether there is a correlation between sarcopenia and the recurrence of hepatocellular carcinoma (HCC) after curative treatment.

Lifestyle Intervention Involving Calorie Restriction with or without Aerobic Exercise Training Improves Liver Fat in Adults with Visceral Adiposity

Objective. To evaluate the effect of calorie restriction-induced weight loss with or without aerobic exercise on liver fat. Methods. Thirty-three adults with visceral adiposity were divided into calorie restriction (CR; n = 18) or CR and aerobic exercise (CR + Ex; n = 15) groups. Target energy intake was 25 kcal/kg of ideal body weight. The CR + Ex group had a targeted exercise time of 300 min/wk or more at lactate threshold intensity for 12 weeks. Results. Reductions in body weight (CR, −5.3 ± 0.8 kg; CR + Ex, −5.1 ± 0.7 kg), fat mass (CR, −4.9 ± 0.9 kg; CR + Ex, −4.4 ± 0.6 kg), and visceral fat (CR, −24 ± 5 cm2; CR + Ex, −37 ± 5 cm2) were not statistically different between groups. Liver fat decreased significantly in both groups, with no difference between groups. Change in maximal oxygen uptake was significantly greater in the CR + Ex group than in the CR group (CR, −0.7 ± 0.7 mL/kg/min; CR + Ex, 2.9 ± 1.0 mL/kg/min). Conclusion. Both CR and CR + Ex resulted in an improved reduction in liver fat; however, there was no additive effect of exercise training.

Elevated serum-soluble fas ligand in Histiocytic necrotizing lymphadenitis

Recent studies have indicated that Fas and perforin-based mechanisms seem to induce apoptosis in histiocytic necrotizing lymphadenitis (HNL). In this study, we evaluated the serum levels of soluble Fas ligand (sFasL) in 30 HNL patients using paired sera. Elevations in sFasL levels were detected in 9 patients in the active stage. In the convalescent stage, the levels of sFasL decreased to an undetectable degree after 2 weeks.These findings indicate the possibility that sFasL plays an important role in the constitutional symptoms and pathogenesis of HNL and, furthermore, that it can act as a surrogate marker of the disease activity.

Autoimmune Regulator (AIRE) Gene Is Expressed in Human Activated CD4 T-Cells and Regulated by Mitogen-Activated Protein Kinase Pathway

The autoimmune regulator (AIRE) gene is a gene responsible for autoimmune polyendocrinopathy‐candidiasis‐ectodermal dystrophy. Here we show that AIRE is expressed in human peripheral CD4‐positive T‐cells, and most highly in antigen‐ and interleukin 2‐stimulated T (IL‐2T) cells. Mitogen‐activated protein kinases (MAPKs), including MAPK kinase (MEK) 1/2 and p38 MAPK, were phosphorylated in IL‐2T cells and the expression of the AIRE gene was inhibited by a specific p38 MAPK inhibitor (SB203580), thereby indicating that AIRE gene expression is controlled by the MAPK pathway in IL‐2T cells. These data suggested the possible significance of the AIRE gene in the peripheral immune system.

Reduced Tyk2 gene expression in β-cells due to natural mutation determines susceptibility to virus-induced diabetes

Accumulating evidence suggests that viruses play an important role in the development of diabetes. Although the diabetogenic encephalomyocarditis strain D virus induces diabetes in restricted lines of inbred mice, the susceptibility genes to virus-induced diabetes have not been identified. We report here that novel Tyrosine kinase 2 (Tyk2) gene mutations are present in virus-induced diabetes-sensitive SJL and SWR mice. Mice carrying the mutant Tyk2 gene on the virus-resistant C57BL/6 background are highly sensitive to virus-induced diabetes. Tyk2 gene expression is strongly reduced in Tyk2-mutant mice, associated with low Tyk2 promoter activity, and leads to decreased expression of interferon-inducible genes, resulting in significantly compromised antiviral response. Tyk2-mutant pancreatic β-cells are unresponsive even to high dose of Type I interferon. Reversal of virus-induced diabetes could be achieved by β-cell-specific Tyk2 gene expression. Thus, reduced Tyk2 gene expression in pancreatic β-cells due to natural mutation is responsible for susceptibility to virus-induced diabetes.