The Experts below are selected from a list of 261 Experts worldwide ranked by ideXlab platform
Alice L Yu - One of the best experts on this subject based on the ideXlab platform.
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tailored design of nkt stimulatory Glycolipids for polarization of immune responses
Journal of Biomedical Science, 2017Co-Authors: Jungtung Hung, Jingrong Huang, Alice L YuAbstract:Natural killer T (NKT) cell is a distinct population of T lymphocytes that can rapidly release massive amount of Th1 and Th2 cytokines upon the engagement of their T cell receptor with Glycolipids presented by CD1d. The secreted cytokines can promote cell-mediated immunity to kill tumor cells and intracellular pathogens, or suppress autoreactive immune cells in autoimmune diseases. Thus, NKT cell is an attractive target for developing new therapeutics to manipulate immune system. The best-known glycolipid to activate NKT cells is α-galactosylceramide (α-GalCer), which has been used as a prototype for designing new NKT stimulatory Glycolipids. Many analogues have been generated by modification of the galactosyl moiety, the acyl chain or the phytosphingosine chain of α-GalCer. Some of the analogues showed greater abilities than α-GalCer in polarizing immune responses toward Th1 or Th2 dominance. Among them, several analogues containing phenyl groups in the lipid tails were more potent in inducing Th1-skewed cytokines and exhibited greater anticancer efficacy than α-GalCer. Analyses of the correlation between structure and activity of various α-GalCer analogues on the activation of iNKT cell revealed that CD1d–glycolipid complexes interacted with the same population of iNKT cell expressing similar T-cell receptor Vβ as α-GalCer. On the other hand, those phenyl Glycolipids with propensity for Th1 dominant responses showed greater binding avidity and stability than α-GalCer for iNKT T-cell receptor when complexed with CD1d. Thus, it is the avidity and stability of the ternary complexes of CD1d-glycolipid-iNKT TCR that dictate the polarity and potency of immune responses. These findings provide a key to the rationale design of immune modulating Glycolipids with desirable Th1/Th2 polarity for clinical application. In addition, elucidation of α-GalCer-induced anergy, liver damage and accumulation of myeloid derived suppressor cells has offered explanation for its lacklustre anti-cancer activities in clinical trials. On other hand, the lack of such drawbacks in glycolipid analogues containing phenyl groups in the lipid tails of α-GalCer coupled with the greater binding avidity and stability of CD1d-glycolipid complex for iNKT T-cell receptor, account for their superior anti-cancer efficacy in tumor bearing mice. Further clinical development of these phenyl Glycolipids is warranted.
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potent immune modulating and anticancer effects of nkt cell stimulatory Glycolipids
Proceedings of the National Academy of Sciences of the United States of America, 2007Co-Authors: Yajen Chang, Jingrong Huang, Yichien Tsai, Jungtung Hung, Douglass Wu, Masakazu Fujio, Chihuey Wong, Alice L YuAbstract:α-Galactosylceramide (α-GalCer), a glycolipid that stimulates natural killer T (NKT) cells to produce both T helper (Th)1 and Th2 cytokines, has shown antitumor effects in mice but failed in clinical trials. We evaluated 16 analogs of α-GalCer for their CD1-mediated T cell receptor (TCR) activation of naive human NKT cells and their anticancer efficacy. In vitro, Glycolipids containing an aromatic ring in their acyl tail or sphingosine tail were more effective than α-GalCer in inducing Th1 cytokines/chemokines, TCR activation, and human NKT cell expansion. None of these Glycolipids could directly stimulate human dendritic cell maturation, except for a glycolipid with an aromatic ring on the sphingosine tail. Here, we show that Glycolipids activated the TCR of NKT cells with phosphorylation of CD3e, ERK1/2, or CREB, which correlated with their induction of Th1 cytokines. Notably, the extent of NKT cell activation when glycolipid was presented by antigen-presenting cells was greater than when glycolipid was presented by non-antigen-presenting cells. In vivo, in mice bearing breast or lung cancers, the Glycolipids that induced more Th1-biased cytokines and CD8/CD4 T cells displayed significantly greater anticancer potency than α-GalCer. These findings indicate that α-GalCer analogs can be designed to favor Th1-biased immunity, with greater anticancer efficacy and other immune-enhancing activities than α-GalCer itself.
Narayanaswamy Jayaraman - One of the best experts on this subject based on the ideXlab platform.
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synthetic arabinomannan heptasaccharide Glycolipids inhibit biofilm growth and augment isoniazid effects in mycobacterium smegmatis
ChemBioChem, 2017Co-Authors: Krishnagopal Maiti, Kirtimaan Syal, Dipankar Chatterji, Narayanaswamy JayaramanAbstract:Biofilm formation, involving attachment to an adherent surface, is a critical survival strategy of mycobacterial colonies in hostile environmental conditions. Here we report the synthesis of heptasaccharide Glycolipids based on mannopyranoside units anchored on to a branched arabinofuranoside core. Two types of Glycolipids2,3-branched and 2,5-branchedwere synthesized and evaluated for their efficacies in inhibiting biofilm growth by the non-pathogenic mycobacterium variant Mycobacterium smegmatis. Biofilm formation was inhibited at a minimum biofilm growth inhibition concentration (MBIC) of 100gmL(-1) in the case of the 2,5-branched heptasaccharide glycolipid. Further, we were able to ascertain that a combination of the drug isoniazid with the branched heptasaccharide glycolipid (50gmL(-1)) potentiates the drug, making it three times more effective, with an improved MBIC of 30gmL(-1). These studies establish that synthetic Glycolipids not only act as inhibitors of biofilm growth, but also provide a synergistic effect when combined with significantly lowered concentrations of isoniazid to disrupt the biofilm structures of the mycobacteria.
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Synthetic arabinomannan Glycolipids impede mycobacterial growth, sliding motility and biofilm structure
Glycoconjugate Journal, 2016Co-Authors: Kirtimaan Syal, Krishnagopal Maiti, Dipankar Chatterji, Kottari Naresh, Prakash Gouda Avaji, Narayanaswamy JayaramanAbstract:Mycobacterium has evolved distinct cell wall and strategies such as biofilm formation, which helps it to survive in hostile conditions. We have reported previously that arabinofuranoside containing Glycolipids exhibit inhibition activities against the above functions of the mycobacterial species M. smegmatis . In search for activities mediated by oligosaccharide Glycolipids, we report herein the inhibitory activities of a linear and a branched pentasaccharides having arabinan and mannan moieties. In the presence of the pentasaccharide Glycolipids, a significant reduction in mycobacterial growth is observed, concomitant with reductions in sliding motility and colonization through biofilm formation, at the optimal glycolipid concentrations of 50–100 μg mL^−1. Especially the biofilm coat is ruptured by ~80–85 % in the presence of Glycolipids. Pentasaccharides alone without the lipidic chain show only a weak effect. The Glycolipids are non-toxic, as evaluated through their effect on RBCs. Analysis of the mycolic acid profile of glycolipid treated biofilm shows that α- and epoxy mycolic acids are downregulated significantly, in comparison to glycolipid untreated biofilms. Lipidomics profile analysis through mass spectrometry further reveals profound downregulation of phosphatidylinositol mannosides, acylatedphosphoglycerols and mycolic acid family, namely, keto-, alpha- and methoxymycolic acids.
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Synthesis of β-arabinofuranoside Glycolipids, studies of their binding to surfactant protein-A and effect on sliding motilities of M. smegmatis
Glycoconjugate Journal, 2012Co-Authors: Kottari Naresh, Krishnagopal Maiti, Kirtimaan Syal, Dipankar Chatterji, Prakash Gouda Avaji, Binod K. Bharati, Narayanaswamy JayaramanAbstract:Surfactant protein A (SP-A), which is a lung innate immune system component, is known to bind Glycolipids present at the cell surface of a mycobacterial pathogen. Lipoarabinomannan (LAM), a component of mycobacterial thick, waxy cell wall, is one of the glycolipid ligands for SP-A. In order to assess binding of synthetic Glycolipids with SP-A and the glycosidic linkage preferences for the interaction, β-arabinofuranoside trisaccharide Glycolipids constituted with β-(1→2), β-(1→3) and β-(1→2), β-(1→5) linkages relevant to LAM were synthesized through chemical glycosylations. The efficacies of synthetic Glycolipids to interact with SP-A were assessed by using the surface plasmon resonance (SPR) technique, from which association-dissociation rate constants and equilibrium binding constants were derived. The equilibrium binding constants of the interaction of two constitutionally varying β-arabinofuranoside Glycolipids with SP-A were found to be in the millimolar range. A comparison of the results with few α-anomeric arabinofuranoside Glycolipids showed that Glycolipids with β-anomeric linkages were having relatively lower equilibrium binding constants than those with α-anomeric linkages in binding to the protein, whereas oligosaccharides alone, without lipidic chains, exhibited higher equilibrium binding constants. Further, the synthetic compounds inhibited the growth of mycobacteria and affected sliding motilities of the bacteria, although to an extent relatively lesser than that of synthetic compounds constituted with α-anomeric linkages.
Jungtung Hung - One of the best experts on this subject based on the ideXlab platform.
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tailored design of nkt stimulatory Glycolipids for polarization of immune responses
Journal of Biomedical Science, 2017Co-Authors: Jungtung Hung, Jingrong Huang, Alice L YuAbstract:Natural killer T (NKT) cell is a distinct population of T lymphocytes that can rapidly release massive amount of Th1 and Th2 cytokines upon the engagement of their T cell receptor with Glycolipids presented by CD1d. The secreted cytokines can promote cell-mediated immunity to kill tumor cells and intracellular pathogens, or suppress autoreactive immune cells in autoimmune diseases. Thus, NKT cell is an attractive target for developing new therapeutics to manipulate immune system. The best-known glycolipid to activate NKT cells is α-galactosylceramide (α-GalCer), which has been used as a prototype for designing new NKT stimulatory Glycolipids. Many analogues have been generated by modification of the galactosyl moiety, the acyl chain or the phytosphingosine chain of α-GalCer. Some of the analogues showed greater abilities than α-GalCer in polarizing immune responses toward Th1 or Th2 dominance. Among them, several analogues containing phenyl groups in the lipid tails were more potent in inducing Th1-skewed cytokines and exhibited greater anticancer efficacy than α-GalCer. Analyses of the correlation between structure and activity of various α-GalCer analogues on the activation of iNKT cell revealed that CD1d–glycolipid complexes interacted with the same population of iNKT cell expressing similar T-cell receptor Vβ as α-GalCer. On the other hand, those phenyl Glycolipids with propensity for Th1 dominant responses showed greater binding avidity and stability than α-GalCer for iNKT T-cell receptor when complexed with CD1d. Thus, it is the avidity and stability of the ternary complexes of CD1d-glycolipid-iNKT TCR that dictate the polarity and potency of immune responses. These findings provide a key to the rationale design of immune modulating Glycolipids with desirable Th1/Th2 polarity for clinical application. In addition, elucidation of α-GalCer-induced anergy, liver damage and accumulation of myeloid derived suppressor cells has offered explanation for its lacklustre anti-cancer activities in clinical trials. On other hand, the lack of such drawbacks in glycolipid analogues containing phenyl groups in the lipid tails of α-GalCer coupled with the greater binding avidity and stability of CD1d-glycolipid complex for iNKT T-cell receptor, account for their superior anti-cancer efficacy in tumor bearing mice. Further clinical development of these phenyl Glycolipids is warranted.
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potent immune modulating and anticancer effects of nkt cell stimulatory Glycolipids
Proceedings of the National Academy of Sciences of the United States of America, 2007Co-Authors: Yajen Chang, Jingrong Huang, Yichien Tsai, Jungtung Hung, Douglass Wu, Masakazu Fujio, Chihuey Wong, Alice L YuAbstract:α-Galactosylceramide (α-GalCer), a glycolipid that stimulates natural killer T (NKT) cells to produce both T helper (Th)1 and Th2 cytokines, has shown antitumor effects in mice but failed in clinical trials. We evaluated 16 analogs of α-GalCer for their CD1-mediated T cell receptor (TCR) activation of naive human NKT cells and their anticancer efficacy. In vitro, Glycolipids containing an aromatic ring in their acyl tail or sphingosine tail were more effective than α-GalCer in inducing Th1 cytokines/chemokines, TCR activation, and human NKT cell expansion. None of these Glycolipids could directly stimulate human dendritic cell maturation, except for a glycolipid with an aromatic ring on the sphingosine tail. Here, we show that Glycolipids activated the TCR of NKT cells with phosphorylation of CD3e, ERK1/2, or CREB, which correlated with their induction of Th1 cytokines. Notably, the extent of NKT cell activation when glycolipid was presented by antigen-presenting cells was greater than when glycolipid was presented by non-antigen-presenting cells. In vivo, in mice bearing breast or lung cancers, the Glycolipids that induced more Th1-biased cytokines and CD8/CD4 T cells displayed significantly greater anticancer potency than α-GalCer. These findings indicate that α-GalCer analogs can be designed to favor Th1-biased immunity, with greater anticancer efficacy and other immune-enhancing activities than α-GalCer itself.
Kazuo Oshimi - One of the best experts on this subject based on the ideXlab platform.
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multifocal motor neuropathy caused by a b cell lymphoma producing a monoclonal igm autoantibody against peripheral nerve myelin Glycolipids gm1 and gd1b
British Journal of Haematology, 2003Co-Authors: Masaaki Noguchi, Kiyoshi Mori, Shigetaka Yamazaki, Kouichi Suda, Naotake Sato, Kazuo OshimiAbstract:Summary. Various data support the pathogenetic significance of serum IgM autoantibodies against glycolipid GM1 in patients with multifocal motor neuropathy. Although some patients with this neuropathy have an extraneural lymphoma, IgM anti-GM1 glycolipid autoantibodies have not been investigated in these cases. We found IgM anti-GM1 autoantibody in the serum of a 52-year-old man who developed multifocal motor neuropathy that was associated with an extraneural diffuse large B-cell lymphoma. An autopsy showed severe widespread demyelination without lymphoma cell infiltration in the peripheral nerves. Immunofluorescent flow cytometry and thin-layer chromatographic immunostaining demonstrated that most of the anti-GM1 antibody in the serum was monoclonal IgM of λ type, which was also demonstrable in secretory form on lymphoma cells. The antibody showed affinity for the Galβ1-3GalNAc terminal disaccharide of Glycolipids GM1 and GD1b, which both are widespread in peripheral nerve myelin. Enzyme-linked immunosorbent assay demonstrated that this antibody was much more abundant in lymphoma cell culture supernatant than in normal lymphocyte culture supernatant. Thus, our patient's B-cell lymphoma cells produced a monoclonal IgM λ autoantibody against this terminal disaccharide residue. This antibody bound to Glycolipids GM1 and GD1b in peripheral motor nerve myelin, presumably initiating formation of destructive immune complexes that caused multifocal motor neuropathy.
Douglass Wu - One of the best experts on this subject based on the ideXlab platform.
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potent immune modulating and anticancer effects of nkt cell stimulatory Glycolipids
Proceedings of the National Academy of Sciences of the United States of America, 2007Co-Authors: Yajen Chang, Jingrong Huang, Yichien Tsai, Jungtung Hung, Douglass Wu, Masakazu Fujio, Chihuey Wong, Alice L YuAbstract:α-Galactosylceramide (α-GalCer), a glycolipid that stimulates natural killer T (NKT) cells to produce both T helper (Th)1 and Th2 cytokines, has shown antitumor effects in mice but failed in clinical trials. We evaluated 16 analogs of α-GalCer for their CD1-mediated T cell receptor (TCR) activation of naive human NKT cells and their anticancer efficacy. In vitro, Glycolipids containing an aromatic ring in their acyl tail or sphingosine tail were more effective than α-GalCer in inducing Th1 cytokines/chemokines, TCR activation, and human NKT cell expansion. None of these Glycolipids could directly stimulate human dendritic cell maturation, except for a glycolipid with an aromatic ring on the sphingosine tail. Here, we show that Glycolipids activated the TCR of NKT cells with phosphorylation of CD3e, ERK1/2, or CREB, which correlated with their induction of Th1 cytokines. Notably, the extent of NKT cell activation when glycolipid was presented by antigen-presenting cells was greater than when glycolipid was presented by non-antigen-presenting cells. In vivo, in mice bearing breast or lung cancers, the Glycolipids that induced more Th1-biased cytokines and CD8/CD4 T cells displayed significantly greater anticancer potency than α-GalCer. These findings indicate that α-GalCer analogs can be designed to favor Th1-biased immunity, with greater anticancer efficacy and other immune-enhancing activities than α-GalCer itself.
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bacterial Glycolipids and analogs as antigens for cd1d restricted nkt cells
Proceedings of the National Academy of Sciences of the United States of America, 2005Co-Authors: Douglass Wu, Guowen Xing, Michael A Poles, Amir Horowitz, Yuki Kinjo, Barbara A Sullivan, Vera Bodmernarkevitch, Oliver Plettenburg, Mitchell Kronenberg, Moriya TsujiAbstract:The CD1 family of proteins binds self and foreign Glycolipids for presentation to CD1-restricted T cells. To identify previously uncharacterized active CD1 ligands, especially those of microbial origin, numerous Glycolipids were synthesized and tested for their ability to stimulate mouse and human natural killer T (NKT) cells. They included analogs of the well known NKT cell agonist α-galactosyl ceramide (α-GalCer), bacterial Glycolipids, and variations of the self-glycolipid, sulfatide. Bacterial Glycolipids, α-galacturonosyl-ceramides from Sphingomonas wittichii, although structurally similar to α-GalCer, have significant differences in the sugar head group as well as the ceramide portion. The Sphingomonas glycosphingolipids (GSLs) and sulfatide variants were shown to activate human NKT cells as measured by IL-4 and IFN-γ secretion. Moreover, CD1d-dimer staining revealed human NKT cell reactivity toward these GSLs and to the sulfatides in a fashion comparable with α-GalCer. Because α-GalCer is a marine-sponge-derived ligand, our study here shows that bacterium-derived antigens are also able to stimulate mouse and human NKT cells.