Galectin-9 suppresses the generation of Th17, promotes the induction of regulatory T cells, and regulates experimental autoimmune arthritis

The effects of galectin-9 on a mouse collagen-induced arthritis (CIA) model were assessed to clarify whether galectin-9 suppresses CIA by regulating T cell immune responses. Galectin-9 suppressed CIA in a dose-dependent manner, and such suppression was observed even when treatment was started on 7 days after the booster, indicating its preventive and therapeutic effects. Galectin-9 induced the decreased levels of pro-inflammatory cytokines, IL-17, IL-12, and IFNgamma in the joint. Galectin-9 induced the decreased number of CD4(+) TIM-3(+) T cells in peripheral blood. Galectin-9-deficient mice became susceptible to CIA may be by increased number of CD4(+) TIM-3(+) T cells and decreased number of Treg cells. We further found that galectin-9 induces differentiation of naive T cells to Treg cells, and it suppresses differentiation to Th17 cells in vitro. The present results suggested that galectin-9 ameliorates CIA by suppressing the generation of Th17, promoting the induction of regulatory T cells.     

Bone marrow cell transfer into fetal circulation can ameliorate genetic skin diseases by providing fibroblasts to the skin and inducing immune tolerance

Recent studies have shown that skin injury recruits bone marrow-derived fibroblasts (BMDFs) to the site of injury to accelerate tissue repair. However, whether uninjured skin can recruit BMDFs to maintain skin homeostasis remains uncertain. Here, we investigated the appearance of BMDFs in normal mouse skin after embryonic bone marrow cell transplantation (E-BMT) with green fluorescent protein-transgenic bone marrow cells (GFP-BMCs) via the vitelline vein, which traverses the uterine wall and is connected to the fetal circulation. At 12 weeks of age, mice treated with E-BMT were observed to have successful engraftment of GFP-BMCs in hematopoietic tissues accompanied by induction of immune tolerance against GFP. We then investigated BMDFs in the skin of the same mice without prior injury and found that a significant number of BMDFs, which generate matrix proteins both in vitro and in vivo, were recruited and maintained after birth. Next, we performed E-BMT in a dystrophic epidermolysis bullosa mouse model (col7a1^−/−) lacking type VII collagen in the cutaneous basement membrane zone. E-BMT significantly ameliorated the severity of the dystrophic epidermolysis bullosa phenotype in neonatal mice. Type VII collagen was deposited primarily in the follicular basement membrane zone in the vicinity of the BMDFs. Thus, gene therapy using E-BMT into the fetal circulation may offer a potential treatment option to ameliorate genetic skin diseases that are characterized by fibroblast dysfunction through the introduction of immune-tolerated BMDFs.     

Stimulatory effect of Shoyu polysaccharides from soy sauce on the intestinal immune system

Soy sauce (Shoyu) is a traditional Japanese fermented seasoning and is available worldwide. We investigated the effect of Shoyu polysaccharides (SPS) prepared from soy sauce on the intestinal immune system of mice. SPS enhanced the production of immunoglobulin A (IgA) from Peyer's patch cells in vitro, and its oral administration to 7-week-old male BALB/c mice for 2 weeks at a dose of 1.5 mg per day significantly (p<0.01) increased the concentration of IgA in the intestine as compared to control mice. Furthermore, experiments on the intestinal transport of SPS in vitro using the human intestinal epithelial cell line Caco-2 confirmed the permeation of uronic acid to be time-dependent. In conclusion, SPS of soy sauce enhanced the production of IgA in vitro and in vivo, and the digested SPS might cross the enterocytic monolayer. Thus, soy sauce is a potentially promising food for enhancing host defenses.     

Study of views on posthumous reproduction, focusing on its relation with views on family and religion in modern Japan

Posthumous reproduction has been performed in Japan several times, without sufficient civic discussion on its appropriateness or legislative regulation. There have even been several lawsuits on posthumous acknowledgment (in which a baby born to a deceased father has the same birthright as a baby born to a living father), and some judgments have proposed the need to develop societal agreement on posthumous reproduction and suggested legislative settlement. With this background, this study aims to clarify the views of the Japanese people regarding posthumous reproduction. In December 2007, we distributed a questionnaire on posthumous reproduction in relation to beliefs about family and religion to 32 universities across the country, and received 3,719 replies. It was found that about 60% of respondents agreed with posthumous reproduction. Statistical analysis was applied to the relationship between this overall position on posthumous reproduction and views on assisted reproduction technologies, family, religion, and so on. The degree of support for posthumous reproduction was strongly correlated with the degree of affirmation of assisted reproduction technologies and a liberal worldview with emphasis on self-determination. On the other hand, there was also a strong correlation with having a traditional view of family, such as family succession. The degree of support for posthumous reproduction was also highly correlated with the intimacy among family members, underlying which was a strong connection to the traditional religious belief in Japan that deceased family members watch the living ones. The view on posthumous reproduction is culturally complex and cannot be explained by a simple dichotomy between traditional conservatives and liberals.     

Neutralizing antibodies decrease the envelope fluidity of HIV-1

For successful penetration of HIV-1, the formation of a fusion pore may be required in order to accumulate critical numbers of fusion-activated gp41 with the help of fluidization of the plasma membrane and viral envelope. An increase in temperature to 40 degrees C after viral adsorption at 25 degrees C enhanced the infectivity by 1.4-fold. The enhanced infectivity was inhibited by an anti-CXCR4 peptide, T140, and anti-V3 monoclonal antibodies (0.5beta and 694/98-D) by post-attachment neutralization, but not by non-neutralizing antibodies (670-30D and 246-D) specific for the C5 of gp120 and cluster I of gp41, respectively. Anti-HLA-II and an anti-HTLV-I gp46 antibody, LAT27, neutralized the molecule-carrying HIV-1(C-2(MT-2)). The anti-V3 antibodies suppressed the fluidity of the HIV-1(C-2) envelope, whereas the non-neutralizing antibodies did not. The anti-HLA-II antibody decreased the envelope fluidity of HIV-1(C-2(MT-2)), but not that of HIV-1(C-2). Therefore, fluidity suppression by these antibodies represents an important neutralization mechanism, in addition to inhibition of viral attachment.     

Learning to recognize visual objects with microstimulation in inferior temporal cortex

The malleability of object representations by experience is essential for adaptive behavior. It has been hypothesized that neurons in inferior temporal cortex (IT) in monkeys are pivotal in visual association learning, evidenced by experiments revealing changes in neural selectivity following visual learning, as well as by lesion studies, wherein functional inactivation of IT impairs learning. A critical question remaining to be answered is whether IT neuronal activity is sufficient for learning. To address this question directly, we conducted experiments combining visual classification learning with microstimulation in IT. We assessed the effects of IT microstimulation during learning in cases where the stimulation was exclusively informative, conditionally informative, and informative but not necessary for the classification task. The results show that localized microstimulation in IT can be used to establish visual classification learning, and the same stimulation applied during learning can predictably bias judgments on subsequent recognition. The effect of induced activity can be explained neither by direct stimulation-motor association nor by simple detection of cortical stimulation. We also found that the learning effects are specific to IT stimulation as they are not observed by microstimulation in an adjacent auditory area. Our results add the evidence that the differential activity in IT during visual association learning is sufficient for establishing new associations. The results suggest that experimentally manipulated activity patterns within IT can be effectively combined with ongoing visually induced activity during the formation of new associations.     

Sepantronium Bromide (YM155) Enhances Response of Human B-Cell Non-Hodgkin Lymphoma to Rituximab

In the treatment of B-cell non-Hodgkin lymphoma (B-NHL) rituximab improves long-term survival in combination with conventional chemotherapy. However, because the majority of patients with B-NHL eventually relapse, the development of more effective therapies is needed. Here, we evaluated the antitumor effects of a combination treatment involving sepantronium bromide (YM155), a first-in-class survivin suppressant, and rituximab in B-NHL xenograft mice models. To determine the efficacy of the combination treatment, YM155- and rituximab-treated B-NHL cell xenografted mice were monitored for tumor size and survival and subjected to 2'-deoxy-2'-(18)F-fluoro-d-glucose ((18)F-FDG) and 3'-(18)F-fluoro-3'-deoxythymidine ((18)F-FLT) positron emission tomography (PET) imaging. In addition, the cell proliferation status of excised tumors was examined by Ki-67 immunohistochemistry. In DB, WSU-DLCL-2, and Mino xenograft-bearing mice, the combination treatment of YM155 and rituximab induced significant tumor growth inhibition and tumor regression compared with either single agent. On day 3 after the initiation of treatment a significant decrease in both (18)F-FDG and (18)F-FLT tumor uptake from pretreatment levels was observed in combination treatment groups. The Ki-67 proliferation index was significantly decreased on day 3 in the xenograft models treated with combination treatment, suggesting that the combination of YM155 and rituximab reduced cell proliferation and glucose metabolism. Furthermore, compared with monotherapy, combination treatment prolonged survival times of severe combined immunodeficient mice with disseminated WSU-FSCCL and Jeko B-NHL tumors. Our findings demonstrate that YM155 and rituximab combination treatment enhances antitumor activity in B-NHL xenografts, and (18)F-FLT and (18)F-FDG PET imaging may allow the early functional evaluation of treatment responses in patients with B-NHL.     

Drug Screening for ALS Using Patient-Specific Induced Pluripotent Stem Cells

Amyotrophic lateral sclerosis (ALS) is a late-onset, fatal disorder in which the motor neurons degenerate. The discovery of new drugs for treating ALS has been hampered by a lack of access to motor neurons from ALS patients and appropriate disease models. We generate motor neurons from induced pluripotent stem cells (iPSCs) from familial ALS patients, who carry mutations in Tar DNA binding protein-43 (TDP-43). ALS patient-specific iPSC-derived motor neurons formed cytosolic aggregates similar to those seen in postmortem tissue from ALS patients and exhibited shorter neurites as seen in a zebrafish model of ALS. The ALS motor neurons were characterized by increased mutant TDP-43 protein in a detergent-insoluble form bound to a spliceosomal factor SNRPB2. Expression array analyses detected small increases in the expression of genes involved in RNA metabolism and decreases in the expression of genes encoding cytoskeletal proteins. We examined four chemical compounds and found that a histone acetyltransferase inhibitor called anacardic acid rescued the abnormal ALS motor neuron phenotype. These findings suggest that motor neurons generated from ALS patient-derived iPSCs may provide a useful tool for elucidating ALS disease pathogenesis and for screening drug candidates.