Toshiro Niki

Kagawa University, Takamatu, Kagawa, Japan

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Publications (53)227.2 Total impact

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    ABSTRACT: Biologics to TNF family receptors are prime candidates for therapy of immune disease. Whereas recent studies have highlighted a requirement for Fcγ receptors in enabling the activity of CD40, TRAILR, and GITR when engaged by antibodies, other TNFR molecules may be controlled by additional mechanisms. Antibodies to 4-1BB (CD137) are currently in clinical trials and can both augment immunity in cancer and promote regulatory T cells that inhibit autoimmune disease. We found that the action of agonist anti-4-1BB in suppressing autoimmune and allergic inflammation was completely dependent on Galectin-9 (Gal-9). Gal-9 directly bound to 4-1BB, in a site distinct from the binding site of antibodies and the natural ligand of 4-1BB, and Gal-9 facilitated 4-1BB aggregation, signaling, and functional activity in T cells, dendritic cells, and natural killer cells. Conservation of the Gal-9 interaction in humans has important implications for effective clinical targeting of 4-1BB and possibly other TNFR superfamily molecules.
    The Journal of experimental medicine. 06/2014;
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    ABSTRACT: Galectin-9 (Gal-9) is a β-galactosidase-binding lectin that promotes apoptosis, tissue inflammation, T cell immune exhaustion, and alters HIV infection in part through engagement with the T cell immunoglobulin mucin domain-3 (Tim-3) receptor and protein disulphide isomerases (PDI). Gal-9 was initially thought to be an eosinophil attractant, but is now known to mediate multiple complex signaling events that affect T cells in both an immunosuppressive and inflammatory manner. To understand the kinetics of circulating Gal-9 levels during HIV infection we measured Gal-9 in plasma during HIV acquisition, in subjects with chronic HIV infection with differing virus control, and in uninfected individuals. During acute HIV infection, circulating Gal-9 was detected as early as 5 days after quantifiable HIV RNA and tracked plasma levels of IL-10, TNF-α, and IL-1β. In chronic HIV infection, Gal-9 levels positively correlated with plasma HIV RNA levels (r= 0.29; p= 0.023), and remained significantly elevated during suppressive anti-retroviral therapy (median: 225.3 pg/ml) and in elite controllers (263.3 pg/ml) compared to age-matched HIV-uninfected controls (54 pg/ml). Our findings identify Gal-9 as a novel component of the first wave of the cytokine storm in acute HIV infection that is sustained at elevated levels in virally suppressed subjects and suggest that Gal-9:Tim-3 crosstalk remains active in elite controllers and ARV suppressed subjects, potentially contributing to ongoing inflammation and persistent T cell dysfunction.
    AIDS research and human retroviruses 04/2014; · 2.18 Impact Factor
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    ABSTRACT: Anti-glomerular basement membrane glomerulonephritis (anti-GBM GN) is a Th1- and Th17-predominant autoimmune disease. Galectin-9 (Gal-9), identified as the ligand of Tim-3, functions in diverse biological processes and leads to the apoptosis of CD4+Tim-3+ T cells. It is still unclear how Gal-9 regulates the functions of Th1 and Th17 cells and prevents renal injury in anti-GBM GN. In this study, Gal-9 was administered to anti-GBM GN mice for 7 days. We found that Gal-9 retarded the increase of Scr, ameliorated renal tubular injury and reduced the formation of crescents. The infiltration of Th1 and Th17 cells into the spleen and kidneys significantly decreased in Gal-9-treated nephritic mice. The reduced infiltration of Th1 and Th17 cells might be associated with the down-regulation of CCL-20, CXCL-9 and CXCL-10 mRNAs in the kidney. In parallel, the blood levels of IFN-γ and IL-17A declined in Gal-9-treated nephritic mice at day 21 and day 28. In addition, an enhanced Th2 cell-mediated immune response was observed in the kidneys of nephritic mice after a 7-day injection of Gal-9. In conclusion, the protective role of Gal-9 in anti-GBM GN is associated with the inhibition of Th1 and Th17 cell-mediated immune responses and enhanced Th2 immunity in the kidney.
    AJP Renal Physiology 01/2014; · 4.42 Impact Factor
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    ABSTRACT: Galectin-9 (Gal-9), a lectin having a β-galactoside-binding domain, can induce apoptosis of Th1 cells by binding to TIM-3. In addition, Gal-9 inhibits IgE/Ag-mediated degranulation of mast cell/basophilic cell lines by binding to IgE, thus blocking IgE/Ag complex formation. However, the role of Gal-9 in mast cell function in the absence of IgE is not fully understood. Here, we found that recombinant Gal-9 directly induced phosphorylation of Erk1/2 but not p38 MAPK in a human mast cell line, HMC-1, which does not express FcεRI. Gal-9 induced apoptosis and inhibited PMA/ionomycin-mediated degranulation of HMC-1 cells. On the other hand, Gal-9 induced cytokine and/or chemokine production by HMC-1 cells, dependent on activation of ERK1/2 but not p38 MAPK. In addition, the lectin activity of Gal-9 was required for Gal-9-mediated cytokine secretion by HMC-1 cells. These observations suggest that Gal-9 has dual properties as both a regulator and an activator of mast cells.
    PLoS ONE 01/2014; 9(1):e86106. · 3.73 Impact Factor
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    ABSTRACT: Galectin-9 ameliorates various inflammatory conditions including autoimmune diseases by regulating T cell and macrophage/dendritic cell (DC) functions. However, the effect of galectin-9 on polymicrobial sepsis has not been assessed. We induced polymicrobial sepsis by cecal ligation and puncture (CLP) in mice. The survival rate was compared between galectin-9- and PBS-treated CLP mice. An ELISA was used to compare the levels of various cytokines in the plasma and culture supernatants. Fluorescence-activated cell sorting analysis was further performed to compare the frequencies of subpopulations of spleen cells. Galectin-9 exhibited a protective effect in polymicrobial sepsis as demonstrated in galetin-9 transgenic mice and therapeutic galectin-9 administration. In contrast, such effect was not observed in nude mice, indicating the involvement of T cells in galectin-9-mediated survival prolongation. Galectin-9 decreased TNFalpha, IL-6, IL-10 and, high mobility group box 1 (HMGB1) and increased IL-15 and IL-17 plasma and spleen levels. Galectin-9 increased the frequencies of natural killer T (NKT) cells and PDCA-1+ CD11c+ macrophages (pDC-like macrophages) but did not change the frequency of CD4 or CD8 T cells, [unknown][unknown]T cells or conventional DC. As expected, galectin-9 decreased the frequency of Tim-3+ CD4 T cells, most likely Th1 and Th17 cells. Intriguingly, many spleen NK1.1+ NKT cells and pDC-like macrophages expressed Tim-3. Galectin-9 increased the frequency of Tim-3-expressing NK1.1+ NKT cells and pDC-like macrophages. Galectin-9 further increased IL-17+ NK1.1+ NKT cells. These data suggest that galectin-9 exerts therapeutic effects on polymicrobial sepsis, possibly by expanding NKT cells and pDC-like macrophages and by modulating the production of early and late proinflammatory cytokines.
    Critical care (London, England) 12/2013; 17(6):R284. · 4.72 Impact Factor
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    ABSTRACT: ABSTRACT Background. Viral respiratory infection is the most common cause of acute asthma exacerbation in patients with stable asthma. The replication of most respiratory viruses requires the generation of double-stranded RNA (dsRNA), resulting in the activation of host immune responses. Synthetic dsRNA, polyinosinic-polycytidylic acid (PolyIC), mimics the effects of viruses in various cell types. To evaluate new therapies for mite antigen-induced chronic asthma, we developed an acute exacerbation model of mouse chronic asthma using mite antigen and PolyIC. We also examined the preventive effects of recombinant galectin-9 (Gal-9) on acute asthma exacerbation in this model. Methods. Airway hyperresponsiveness (AHR) was examined to evaluate the exacerbation of chronic asthma. To analyze airway inflammation, the numbers of inflammatory cells and concentrations of cytokines in the bronchoalveolar lavage fluid (BALF) were estimated by flow cytometry and enzyme-linked immunosorbent assay, respectively. Results. AHR was accelerated by intranasal administration of PolyIC in addition to mite antigen. Levels of cytokines that contribute to AHR, including interferon-γ, tumor necrosis factor-α, and RANTES (CCR5), and of Gal-9 in the BALF were elevated in this acute asthma exacerbation mouse model. Intranasal administration of recombinant Gal-9 reduced the PolyIC-induced AHR and levels of these cytokines in the BALF. Further, Gal-9 suppressed the production of cytokines induced by PolyIC in the alveolar macrophages. Conclusions. Our findings demonstrated that exogenous Gal-9 suppressed dsRNA-induced AHR in an acute exacerbation model of chronic asthma in mice, and suggest that recombinant Gal-9 could be therapeutically effective for preventing acute asthma exacerbation.
    Experimental Lung Research 11/2013; · 1.47 Impact Factor
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    ABSTRACT: Dengue virus (DENV) infection remains a major public health burden worldwide. Soluble mediators may play a critical role in the pathogenesis of acute DENV infection. Galectin-9 (Gal-9) is a soluble β-galactoside-binding lectin, with multiple immunoregulatory and inflammatory properties. To investigate plasma Gal-9 levels as a biomarker for DENV infection. We enrolled 65 DENV infected patients during the 2010 epidemic in the Philippines and measured their plasma Gal-9 and cytokine/chemokine levels, DENV genotypes, and copy number during the critical and recovery phases of illness. During the critical phase, Gal-9 levels were significantly higher in DENV infected patients compared to healthy or those with non-dengue febrile illness. The highest Gal-9 levels were observed in dengue hemorrhagic fever (DHF) patients (DHF: 2464pg/ml; dengue fever patients (DF): 1407pg/ml; non-dengue febrile illness: 616pg/ml; healthy: 196pg/ml). In the recovery phase, Gal-9 levels significantly declined from peak levels in DF and DHF patients. Gal-9 levels tracked viral load, and were associated with multiple cytokines and chemokines (IL-1α, IL-8, IP-10, and VEGF), including monocyte frequencies and hematologic variables of coagulation. Further discriminant analyses showed that eotaxin, Gal-9, IFN-α2, and MCP-1 could detect 92% of DHF and 79.3% of DF, specifically (P<0.01). Gal-9 appears to track DENV inflammatory responses, and therefore, it could serve as an important novel biomarker of acute DENV infection and disease severity.
    Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology 10/2013; · 3.12 Impact Factor
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    ABSTRACT: Galectin-9 serves opposing roles in the innate and adaptive immune systems. Galectin-9 triggers T-cell immunoglobulin mucin-3 (Tim-3) on T helper type 1 (Th1) cells, thereby terminating Th1 immunity and protecting allografts from host immune attacks. Meanwhile, galectin-9 promotes the maturation of dendritic cells (DCs) that deliver proinflammatory signals. We previously showed that galectin-9 significantly prolongs cardiac allograft survival in mice but failed to induce tolerance. This study aimed at improving the administration protocol to induce allograft tolerance. We examined whether rapamycin can reverse the proinflammatory effects of galectin-9 on DCs and whether rapamycin synergizes with galectin-9 to induce cardiac allograft tolerance. Monocytes/DCs from cardiac allografts were assessed for Tim-3 expression by flow cytometry. Costimulatory molecules CD80/CD86 were measured on galectin-9/rapamycin-treated bone marrow-derived DCs by flow cytometry. We performed heterotopic cervical cardiac transplantation using BALB/c donors and C57BL/6 recipients and assessed graft survival time. T cells of long-term surviving recipients were immunoassayed for interferon-γ and interleukin-4 secretion. Allograft-infiltrating monocytes/DCs expressed high Tim-3 levels (47.3%±5.6%). Expression of CD80/CD86 was up-regulated on galectin-9-treated bone marrow-derived DCs, which was reversed by rapamycin. Combined treatment with galectin-9 and rapamycin promoted the permanent acceptance of fully mismatched grafts (survival time >180 days; n=6). However, treatment with galectin-9 or rapamycin alone was not sufficient to induce tolerance. Galectin-9/rapamycin-induced tolerance was associated with low donor-specific interferon-γ and interleukin-4 secretion. Rapamycin inhibits proinflammatory effects of galectin-9 on DCs. Combined treatment of galectin-9 and rapamycin promotes allografts tolerance, which is associated with reduced Th1 and Th2 responses.
    Transplantation 07/2013; · 3.78 Impact Factor
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    ABSTRACT: Galectin-9 (Gal-9) inhibited the infection of H1N1, H3N2 and H5N1 influenza A viruses in vitro and in vivo. Fifty percent effective doses (ED50) of Gal-9 were 0.1-0.5 μM depending on virus strains in the plaque reduction assay. Gal-9 but not Gal-1 bound to the virus particles of A/Puerto Rico/8/34 (H1N1) (PR/8), resulting in inhibition of virus attachment to the host cells. Lactose but not sucrose inhibited the binding of Gal-9 to the viruses. Endogenous Gal-9 expression was detected and increased with the course of infection with influenza A viruses in mice. Fifty percent of Gal-9-transgenic mice survived after the challenge with PR/8, while all of the wild-type mice died. Gal-9 treatment of mice affected diminishing influenza virus replication in the lungs, body weight loss and the expression level of inflammatory cytokines. Combined administration of Gal-9 and oseltamivir was more effective than the use of single compound in mouse model. The present results indicate that Gal-9 is a candidate compound for influenza A virus infection therapy.
    The Japanese journal of veterinary research 05/2013; 61((1&2):):5-18. · 0.65 Impact Factor
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    ABSTRACT: Galectin-9 is a tandem-repeat type galectin with two carbohydrate-recognition domains, and it was first identified as an eosinophil chemoattractant and activation factor. Subsequent studies revealed that galectin-9, similar to other galectins, modulates a variety of biological functions including cell aggregation and adhesion, as well as apoptosis of tumor cells. Galectin-9 has recently been shown to have an anti-proliferative effect on cancer cells. Recent studies have uncovered additional mechanisms by which T cell immunoglobulin mucin-3 (Tim-3), a receptor for galectin-9, negatively regulates T cell responses by promoting CD8+ T cell exhaustion and inducing expansion of myeloid-derived suppressor cells. These mechanisms are involved in tumor growth and escape from immunity. In many solid cancers, the loss of galectin-9 expression is closely associated with metastatic progression, and treatment with recombinant galectin-9 prevents metastatic spread in various preclinical cancer models. Here, we review the biology and physiological role of galectin-9, and discuss the therapeutic potential of galectin-9 in cancer as well as relevant patents.
    Recent Patents on Endocrine Metabolic & Immune Drug Discovery 03/2013;
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    ABSTRACT: Galectin-9 is a pleiotropic immune modulator affecting numerous cell types of innate and adaptive immunity. Patients with chronic infection with either HCV or HIV have elevated circulating levels. Limited data exist on the regulation of natural killer (NK) cell function through interaction with galectin-9. We found that galectin-9 ligation down-regulates multiple immune activating genes including eight involved in the NK cell-mediated cytotoxicity pathway, impairs lymphokine-activated killing, and decreases the proportion of IFN-γ producing NK cells that had been stimulated with IL-12/IL-15. We demonstrate that the transcriptional and functional changes induced by galectin-9 are independent of Tim-3. Consistent with these human results, we find that the genetic absence of galectin-9 in mice is associated with greater IFN-γ production by NK cells and enhanced degranulation. We also show that in the setting of a short-term (4-Day) MCMV infection; terminally differentiated NKs accumulate in the livers of galectin-9 KO mice and that hepatic NKs spontaneously produce significantly more IFN-γ in this setting. Taken together, our results indicate that galectin-9 engagement impairs the function of NK cells, including cytotoxicity and cytokine production.
    Journal of Virology 02/2013; · 5.08 Impact Factor
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    ABSTRACT: Galectin-9 (Gal-9) is known for induction of apoptosis in IFN-γ and IL-17 producing T-cells and amelioration of autoimmunity in murine models. On the other hand, Gal-9 induced IFN-γ positive T-cells in a sarcoma mouse model and in food allergy, suggesting that Gal-9 can have diametric effects on T-cell immunity. Here, we aimed to delineate the immunomodulatory effect of Gal-9 on human resting and ex vivo activated peripheral blood lymphocytes. Treatment of resting lymphocytes with low concentrations of Gal-9 (5-30 nM) induced apoptosis in ∼60% of T-cells after 1 day, but activated the surviving T-cells. These viable T-cells started to expand after 4 days with up to 6 cell divisions by day 7 and an associated shift from naïve towards central memory and IFN-γ producing phenotype. In the presence of T-cell activation signals (anti-CD3/IL-2) Gal-9 did not induce T-cell expansion, but shifted the CD4/CD8 balance towards a CD4-dominated T-cell response. Thus, Gal-9 activates resting T-cells in the absence of typical T-cell activating signals and promotes their transition to a TH1/C1 phenotype. In the presence of T-cell activating signals T-cell immunity is directed towards a CD4-driven response by Gal-9. Thus, Gal-9 may specifically enhance reactive immunological memory.
    PLoS ONE 01/2013; 8(5):e65616. · 3.73 Impact Factor
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    ABSTRACT: Human monocytes/macrophages (M/MФ) of the innate immunity sense and respond to microbial products via specific receptor coupling with stimulatory (such as TLR) and inhibitory (such as Tim-3) receptors. Current models imply that Tim-3 expression on M/MØ can deliver negative signaling to TLR-mediated IL-12 expression through trans association with its ligand Galectin-9 (Gal-9) presented by other cells. However, Gal-9 is also expressed within M/MØ, and the effect of intracellular Gal-9 on Tim-3 activities and inflammatory responses in the same M/MØ remains unknown. In this study, our data suggest that Tim-3 and IL-12/IL-23 gene transcriptions are regulated by enhanced or silenced Gal-9 expression within monocytes through synergizing with TLR signaling. Additionally, TLR activation facilitates Gal-9/Tim-3 cis association within the same M/MØ to differentially regulate IL-12/IL-23 expressions through STAT-3 phosphorylation. These results reveal a ligand (Gal-9) compartment-dependent regulatory effect on receptor (Tim-3) activities and inflammatory responses via TLR pathways-a novel mechanism underlying cellular responses to external or internal cues.
    PLoS ONE 01/2013; 8(8):e72488. · 3.73 Impact Factor
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    ABSTRACT: Galectin-9 ameliorates various murine autoimmune disease models by regulating T cells and macrophages, although it is not known what role it may have in B cells. The present experiment shows that galectin-9 ameliorates a variety of clinical symptoms, such as proteinuria, arthritis, and hematocrit in MRL/lpr lupus-prone mice. As previously reported, galectin-9 reduces the frequency of Th1, Th17, and activated CD8(+) T cells. Although anti-dsDNA antibody was increased in MRL/lpr lupus-prone mice, galectin-9 suppressed anti-dsDNA antibody production, at least partly, by decreasing the number of plasma cells. Galectin-9 seemed to decrease the number of plasma cells by inducing plasma cell apoptosis, and not by suppressing BAFF production. Although about 20% of CD19(-/low) CD138(+) plasma cells expressed Tim-3 in MRL/lpr lupus-prone mice, Tim-3 may not be directly involved in the galectin-9-induced apoptosis, because anti-Tim-3 blocking antibody did not block galectin-9-induced apoptosis. This is the first report of plasma cell apoptosis being induced by galectin-9. Collectively, it is likely that galectin-9 attenuates the clinical severity of MRL lupus-prone mice by regulating T cell function and inducing plasma cell apoptosis.
    PLoS ONE 01/2013; 8(4):e60807. · 3.73 Impact Factor
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    ABSTRACT: Hepatitis C virus (HCV) is remarkable at disrupting human immunity to establish chronic infection. The accumulation of regulatory T (Treg) cells at the site of infection and up-regulation of inhibitory signaling pathways (such as Tim-3/Gal-9) play pivotal roles in suppressing antiviral effector T (Teff) cells that are essential for viral clearance. While Tim-3/Gal-9 interactions have been shown to negatively regulate Teff cells, their role in regulating Treg cells is poorly understood. To explore how Tim-3/Gal-9 interactions regulate HCV-mediated Treg cell development, here we provide pilot data showing that HCV-infected human hepatocytes express higher levels of Gal-9 and TGF-β, and up-regulate Tim-3 expression and regulatory cytokines TGF-β/IL-10 in co-cultured human CD4(+) T cells, driving conventional CD4(+) T cells into CD25(+) Foxp3(+) Treg cells. Additionally, recombinant Gal-9 protein can transform TCR-activated CD4(+) T cells into Foxp3(+) Treg cells in a dose-dependent manner. Importantly, blocking Tim-3/Gal-9 ligations abrogates HCV-mediated Treg-cell induction by HCV-infected hepatocytes, suggesting that Tim-3/Gal-9 interactions may regulate human Foxp3(+) Treg-cell development and function during HCV infection.
    European Journal of Immunology 11/2012; · 4.97 Impact Factor
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    ABSTRACT: Ocular infection with herpes simplex virus 1 (HSV-1) results in a chronic immunoinflamammtory reaction in the cornea, which is primarily orchestrated by CD4(+) T cells. Hence, targeting proinflammatory CD4(+) T cells or increasing the representation of cells that regulate their function is a relevant therapeutic strategy. In this report, we demonstrate that effective therapeutic control can be achieved using a combination of approaches under circumstances where monotherapy is ineffective. We use a convenient and highly effective monoclonal antibody (MAb) approach with MAbT25 to expand cells that express the tumor necrosis factor receptor superfamily member 25 (TNFRSF25). In naïve animals, these are predominantly cells that are Foxp3-positive regulatory T cells. MAbT25 treatment before or at the time of initial HSV infection was an effective means of reducing the severity of subsequent stromal keratitis lesions. However, MAbT25 treatment was not effective if given 6 days after infection since it expanded proinflammatory effector T cells, which also express TNFRSF25. Therefore, the MAbT25 procedure was combined with galectin-9 (Gal-9), an approach that compromises the activity of T cells involved in tissue damage. The combination therapy provided highly effective lesion control over that achieved by treatment with one of them. The beneficial outcome of the combination therapy was attributed to the expansion of the regulatory T cell population that additionally expressed activation markers such as CD103 needed to access inflammatory sites. Additionally, there was a marked reduction of CD4(+) gamma interferon-producing effector T cells responsible for orchestrating the tissue damage. The approach that we describe has potential application to control a wide range of inflammatory diseases, in addition to stromal keratitis, an important cause of human blindness.
    Journal of Virology 07/2012; 86(19):10606-20. · 5.08 Impact Factor
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    ABSTRACT: Galectin-9 is a mammalian lectin which possesses immunosuppressive properties. Excessive production of galectin-9 has been reported in two types of human virus-associated diseases chronic hepatitis C and nasopharyngeal carcinoma associated to the Epstein-Barr virus. The objective of this study was to produce new monoclonal antibodies targeting galectin-9 in order to improve its detection in clinical samples, especially on tissue sections analysed by immunohistochemistry. Hybridomas were produced through immunization of mice with the recombinant c-terminus part of galectin-9 (residues 191 to 355 of the long isoform) and semi-solid fusion of spleen cells with Sp2/0 cells. Monoclonal antibodies were characterized using ELISA, epitope mapping, western blot and immunohistochemistry. We selected seven hybridomas producing antibodies reacting with our recombinant c-terminus galectin-9 in ELISA. Five of them reacted with the epitope "TPAIPPMMYPHPA" (common to all isoforms, residues 210 to 222 of the long isoform) and stained all three isoforms of galectin-9 analysed by western blot. One of them, 1G3,demonstrated very good sensitivity and specificity when used for immunohistochemistry. Using 1G3, we could confirm the intense and constant expression of galectin-9 by Epstein-Barr virus positive malignant cells from nasopharyngeal carcinomas. In most samples, specific staining was detected in both cytoplasm and nuclei. Galectin-9 was also detected in liver biopsies from patients infected by the human hepatitis C or B viruses with expression not only in inflammatory leucocytes and Kupffer cells, but also in hepatocytes. In contrast, galectin-9 was virtually absent in non-infected liver specimens. The 1G3 monoclonal antibody will be a powerful tool to assess galectin-9 expression and distribution especially in diseases related to oncogenic viruses.
    Infectious Agents and Cancer 07/2012; 7(1):16.
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    Journal of Investigative Dermatology 05/2012; 132(9):2302-5. · 6.19 Impact Factor
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    ABSTRACT: Galectin-9 (Gal-9) is a tandem repeat-type member of the galectin family and is a ligand for T-cell immunoglobulin mucin domain 3 (Tim-3), a type-I glycoprotein that is persistently expressed on dysfunctional T cells during chronic infection. Studies in autoimmune diseases and chronic viral infections show that Tim-3 is a regulatory molecule that inhibits Th1 type immune responses. Here we show that soluble Gal-9 interacts with Tim-3 expressed on the surface of activated CD4(+) T cells and renders them less susceptible to HIV-1 infection and replication. The Gal-9/Tim-3 interaction on activated CD4(+) T cells, leads to down-regulation of HIV-1 coreceptors and up-regulation of the cyclin-dependent kinase inhibitor p21 (also known as cip-1 and waf-1). We suggest that higher expression of Tim-3 during chronic infection has evolved to limit persistent immune activation and associated tissue damage. These data demonstrate a novel mechanism for Gal-9/Tim-3 interactions to induce resistance of activated CD4(+) T cells to HIV-1 infection and suggest that Gal-9 may play a role in HIV-1 pathogenesis and could be used as a novel microbicide to prevent HIV-1 infection.
    Blood 03/2012; 119(18):4192-204. · 9.06 Impact Factor
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    ABSTRACT: The cytokine IL-12 induces IFN-γ production by T and NK cells. In preclinical models, it contributes to antitumor immunity. However, in clinical testing, it has shown limited benefit in patients with any one of a variety of malignancies. Moreover, in a clinical trial testing a combination of IL-12 and rituximab in patients with follicular B cell non-Hodgkin lymphoma (FL), those treated with IL-12 showed a lower response rate, suggesting that IL-12 actually plays a detrimental role. Here, we investigated whether the failure of IL-12 treatment for FL was due to T cell exhaustion, a condition characterized by reduced T cell differentiation, proliferation, and function, which has been observed in chronic viral infection. We found that extended exposure to IL-12 induced T cell exhaustion and contributed to the poor prognosis in FL patients. Long-term exposure of freshly isolated human CD4+ T cells to IL-12 in vitro caused T cell dysfunction and induced expression of TIM-3, a T cell immunoglobulin and mucin domain protein with a known role in T cell exhaustion, via an IFN-γ-independent mechanism. TIM-3 was required for the negative effect of IL-12 on T cell function. Importantly, TIM-3 also was highly expressed on intratumoral T cells that displayed marked functional impairment. Our findings identify IL-12- and TIM-3-mediated exhaustion of T cells as a mechanism for poor clinical outcome when IL-12 is administered to FL patients.
    The Journal of clinical investigation 03/2012; 122(4):1271-82. · 15.39 Impact Factor

Publication Stats

801 Citations
227.20 Total Impact Points

Institutions

  • 2007–2014
    • Kagawa University
      • • Faculty of Medicine
      • • Department of Immunology
      Takamatu, Kagawa, Japan
  • 2013
    • University of Colorado
      • Division of Gastroenterology and Hepatology
      Denver, CO, United States