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Gordon D. Brown - One of the best experts on this subject based on the ideXlab platform.

  • dectin 1 plays a redundant role in the immunomodulatory activities of β glucan rich ligands in vivo
    Microbes and Infection, 2013
    Co-Authors: Mohlopheni J Marakalala, Gordon D. Brown, David L Williams, Mihai G Netea, Jennifer C Hoving, Rolf E Engstad
    Abstract:

    β-Glucans are known for their ability to trigger both protective and damaging immune responses. Here we have explored the role of the beta-glucan receptor Dectin-1 in archetypical models of protective and non-protective immunomodulation induced by beta-glucan rich ligands. In the first model, we explored the role of Dectin-1 in the ability of soluble purified β-glucans to mediate protection against systemic Staphylococcus aureus infection in mice. In the second model, we explored the role of Dectin-1 in zymosan induced multiple organ dysfunction syndrome. In both cases, these β-glucan rich compounds had marked effects in vivo which were unaltered by Dectin-1 deficiency, suggesting that this receptor has a redundant role in these murine models.

  • β glucans and dectin 1
    Annals of the New York Academy of Sciences, 2008
    Co-Authors: Vicky S Tsoni, Gordon D. Brown
    Abstract:

    Beta-Glucans are naturally occurring carbohydrates that possess immune-modulating activities, but their mechanisms of action are largely unknown. Recent discoveries, however, including identification of beta-glucan receptors, such as dectin-1, have started to shed some light on the mechanisms underlying the properties of these carbohydrates. The characterization of dectin-1, in particular, has revealed some of the processes involved in beta-glucan sensing, intracellular signaling, and induction of cellular responses and has provided new insights into the role of Beta-Glucans in immunity and disease. Here we review both Beta-Glucans and their receptor, dectin-1.

  • soluble dectin 1 as a tool to detect β glucans
    Journal of Immunological Methods, 2006
    Co-Authors: Lisa M Graham, David L Williams, Siamon Gordon, Vicky S Tsoni, Janet A Willment, Philip R Taylor, Kevin M Dennehy, Gordon D. Brown
    Abstract:

    Beta-Glucans are structural components of fungal cell walls which are involved in the immune recognition of fungal pathogens and possess beneficial immunomodulatory activities in isolated form. Here we have developed a soluble chimeric form of the major mammalian beta-glucan receptor, Dectin-1, and demonstrate its application for the detection and characterisation of soluble and insoluble Beta-Glucans, including fungal particles, using ELISA, flow cytometric and fluorescence-based microscopy assays.

  • ligands for the β glucan receptor dectin 1 assigned using designer microarrays of oligosaccharide probes neoglycolipids generated from glucan polysaccharides
    Journal of Biological Chemistry, 2006
    Co-Authors: Angelina S Palma, Siamon Gordon, Ten Feizi, Yibing Zhang, Mark S Stoll, Alexander M Lawson, Esther Diazrodriguez, Maria A Campanerorhodes, Julia Costa, Gordon D. Brown
    Abstract:

    Dectin-1 is a C-type lectin-like receptor on leukocytes that mediates phagocytosis and inflammatory mediator production in innate immunity to fungal pathogens. Dectin-1 lacks residues involved in calcium ligation that mediates carbohydrate-binding by classical C-type lectins; nevertheless, it binds zymosan, a particulate beta-glucan-rich extract of Saccharomyces cerevisiae, and binding is inhibited by polysaccharides rich in beta1,3- or both beta1,3- and beta1,6-linked glucose. The oligosaccharide ligands on glucans recognized by Dectin-1 have not yet been delineated precisely. It is also not known whether Dectin-1 can interact with other types of carbohydrates. We have investigated this, since Dectin-1 shows glucan-independent binding to a subset of T-lymphocytes and is involved in triggering their proliferation. Here we assign oligosaccharide ligands for Dectin-1 using the neoglycolipid-based oligosaccharide microarray technology, a unique approach for constructing microarrays of lipid-linked oligosaccharide probes from desired sources. We generate "designer" microarrays from three glucan polysaccharides, a neutral soluble glucan isolated from S. cerevisiae and two bacterial glucans, curdlan from Alcaligenes faecalis and pustulan from Umbilicaria papullosa, and use these in conjunction with 187 diverse, sequence-defined, predominantly mammalian-type, oligosaccharide probes. Among these, Dectin-1 binding is detected exclusively to 1,3-linked glucose oligomers, the minimum length required for detectable binding being a 10- or 11-mer. Thus, the ligands assigned so far are exogenous rather than endogenous. We further show that Dectin-1 ligands, 11-13 gluco-oligomers, in clustered form (displayed on liposomes), mimic the macromolecular Beta-Glucans and compete with zymosan binding and triggering of tumor necrosis factor-alpha secretion by a Dectin-1-expressing macrophage cell line.

  • the beta glucan receptor dectin 1 recognizes specific morphologies of aspergillus fumigatus
    PLOS Pathogens, 2005
    Co-Authors: Chad Steele, David L Williams, Siamon Gordon, Rekha R Rapaka, Allison E Metz, Shannon M Pop, Jay K Kolls, Gordon D. Brown
    Abstract:

    Alveolar macrophages represent a first-line innate host defense mechanism for clearing inhaled Aspergillus fumigatus from the lungs, yet contradictory data exist as to which alveolar macrophage recognition receptor is critical for innate immunity to A. fumigatus. Acknowledging that the A. fumigatus cell wall contains a high beta-1,3–glucan content, we questioned whether the beta-glucan receptor dectin-1 played a role in this recognition process. Monoclonal antibody, soluble receptor, and competitive carbohydrate blockage indicated that the alveolar macrophage inflammatory response, specifically the production of tumor necrosis factor-α (TNF-α), interleukin-1α (IL-1α), IL-1β, IL-6, CXCL2/macrophage inflammatory protein-2 (MIP-2), CCL3/macrophage inflammatory protein-1α (MIP-1α), granulocyte-colony stimulating factor (G-CSF), and granulocyte monocyte–CSF (GM-CSF), to live A. fumigatus was dependent on recognition via the beta-glucan receptor dectin-1. The inflammatory response was triggered at the highest level by A. fumigatus swollen conidia and early germlings and correlated to the levels of surface-exposed beta glucans, indicating that dectin-1 preferentially recognizes specific morphological forms of A. fumigatus. Intratracheal administration of A. fumigatus conidia to mice in the presence of a soluble dectin-Fc fusion protein reduced both lung proinflammatory cytokine/chemokine levels and cellular recruitment while modestly increasing the A. fumigatus fungal burden, illustrating the importance of beta-glucan–initiated dectin-1 signaling in defense against this pathogen. Collectively, these data show that dectin-1 is centrally required for the generation of alveolar macrophage proinflammatory responses to A. fumigatus and to our knowledge provides the first in vivo evidence for the role of dectin-1 in fungal innate defense.

David L Williams - One of the best experts on this subject based on the ideXlab platform.

  • dectin 1 plays a redundant role in the immunomodulatory activities of β glucan rich ligands in vivo
    Microbes and Infection, 2013
    Co-Authors: Mohlopheni J Marakalala, Gordon D. Brown, David L Williams, Mihai G Netea, Jennifer C Hoving, Rolf E Engstad
    Abstract:

    β-Glucans are known for their ability to trigger both protective and damaging immune responses. Here we have explored the role of the beta-glucan receptor Dectin-1 in archetypical models of protective and non-protective immunomodulation induced by beta-glucan rich ligands. In the first model, we explored the role of Dectin-1 in the ability of soluble purified β-glucans to mediate protection against systemic Staphylococcus aureus infection in mice. In the second model, we explored the role of Dectin-1 in zymosan induced multiple organ dysfunction syndrome. In both cases, these β-glucan rich compounds had marked effects in vivo which were unaltered by Dectin-1 deficiency, suggesting that this receptor has a redundant role in these murine models.

  • soluble dectin 1 as a tool to detect β glucans
    Journal of Immunological Methods, 2006
    Co-Authors: Lisa M Graham, David L Williams, Siamon Gordon, Vicky S Tsoni, Janet A Willment, Philip R Taylor, Kevin M Dennehy, Gordon D. Brown
    Abstract:

    Beta-Glucans are structural components of fungal cell walls which are involved in the immune recognition of fungal pathogens and possess beneficial immunomodulatory activities in isolated form. Here we have developed a soluble chimeric form of the major mammalian beta-glucan receptor, Dectin-1, and demonstrate its application for the detection and characterisation of soluble and insoluble Beta-Glucans, including fungal particles, using ELISA, flow cytometric and fluorescence-based microscopy assays.

  • the beta glucan receptor dectin 1 recognizes specific morphologies of aspergillus fumigatus
    PLOS Pathogens, 2005
    Co-Authors: Chad Steele, David L Williams, Siamon Gordon, Rekha R Rapaka, Allison E Metz, Shannon M Pop, Jay K Kolls, Gordon D. Brown
    Abstract:

    Alveolar macrophages represent a first-line innate host defense mechanism for clearing inhaled Aspergillus fumigatus from the lungs, yet contradictory data exist as to which alveolar macrophage recognition receptor is critical for innate immunity to A. fumigatus. Acknowledging that the A. fumigatus cell wall contains a high beta-1,3–glucan content, we questioned whether the beta-glucan receptor dectin-1 played a role in this recognition process. Monoclonal antibody, soluble receptor, and competitive carbohydrate blockage indicated that the alveolar macrophage inflammatory response, specifically the production of tumor necrosis factor-α (TNF-α), interleukin-1α (IL-1α), IL-1β, IL-6, CXCL2/macrophage inflammatory protein-2 (MIP-2), CCL3/macrophage inflammatory protein-1α (MIP-1α), granulocyte-colony stimulating factor (G-CSF), and granulocyte monocyte–CSF (GM-CSF), to live A. fumigatus was dependent on recognition via the beta-glucan receptor dectin-1. The inflammatory response was triggered at the highest level by A. fumigatus swollen conidia and early germlings and correlated to the levels of surface-exposed beta glucans, indicating that dectin-1 preferentially recognizes specific morphological forms of A. fumigatus. Intratracheal administration of A. fumigatus conidia to mice in the presence of a soluble dectin-Fc fusion protein reduced both lung proinflammatory cytokine/chemokine levels and cellular recruitment while modestly increasing the A. fumigatus fungal burden, illustrating the importance of beta-glucan–initiated dectin-1 signaling in defense against this pathogen. Collectively, these data show that dectin-1 is centrally required for the generation of alveolar macrophage proinflammatory responses to A. fumigatus and to our knowledge provides the first in vivo evidence for the role of dectin-1 in fungal innate defense.

  • the role of signr1 and the beta glucan receptor dectin 1 in the nonopsonic recognition of yeast by specific macrophages
    Journal of Immunology, 2004
    Co-Authors: Philip R Taylor, Gordon D. Brown, David L Williams, Janet A Willment, Jurgen Herre, Siamon Gordon
    Abstract:

    We recently demonstrated that the beta-glucan receptor Dectin-1 (betaGR) was the major nonopsonic beta-glucan receptor on macrophages (Mphi) for the yeast-derived particle zymosan. However, on resident peritoneal Mphi, we identified an additional mannan-inhibitable receptor for zymosan that was distinct from the Mphi mannose receptor (MR). In this study, we have studied the mannose-binding potential of murine Mphi and identified the dendritic cell-specific ICAM-3-grabbing nonintegrin homolog, SIGN-related 1 (SIGNR1), as a major MR on murine resident peritoneal Mphi. Both SIGNR1 and betaGR cooperated in the nonopsonic recognition of zymosan by these Mphi. When SIGNR1 was introduced into NIH3T3 fibroblasts or RAW 264.7 Mphi, it conferred marked zymosan-binding potential on these cells. However, in the nonprofessional phagocytes (NIH3T3), SIGNR1 was found to be poorly phagocytic, suggesting that other receptors such as betaGR may play a more dominant role in particle internalization on professional phagocytes. Binding of zymosan to RAW 264.7 Mphi expressing SIGNR1 resulted in TNF-alpha production. Treatment of RAW 264.7 Mphi expressing SIGNR1, which express low levels of betaGR, with Beta-Glucans had little effect on binding or TNF-alpha production, indicating that there was no absolute requirement for betaGR in this process. These studies have identified SIGNR1 as a major MR for fungal and other pathogens present on specific subsets of Mphi.

  • glucans exhibit weak antioxidant activity but stimulate macrophage free radical activity
    Free Radical Biology and Medicine, 2001
    Co-Authors: Ekaterini Tsiapali, John Kalbfleisch, Harry E Ensley, Sarah Whaley, William I Browder, David L Williams
    Abstract:

    Polymeric carbohydrates have been reported to modulate inflammatory responses in vitro and in vivo. Previous reports suggest that certain carbohydrate polymers, such as (1-->3)-beta-D-glucans, may possess free radical scavenging activity. If glucans are free radical scavengers then it might explain, in part, the ability of these ligands to modulate inflammatory responses. The present study examined the free radical scavenging activity of a variety of carbohydrate polymers and the effect of the polymers on free radical levels in a murine macrophage cell line. All of the carbohydrates exhibited concentration dependent antioxidant effects (EC(50) range = 807 to 43 microg/ml). However, the antioxidant activity for the carbohydrates was modest in comparison with PDTC (EC(50) = 0.13 microg/ml) and the carbohydrate concentration required for antioxidant activity was high (x EC(50) = 283 microg/ml). The antioxidant ability of the polymers was greater (p < .05) than their monosaccharide constituents, i.e., dextrose EC(50) = 807 vs. glucan sulfate EC(50) = 43 microg/ml. Coincubation of glucans with murine J774a.1 cells increased free radical levels when compared to controls. Therefore, the weak free radical scavenging activity of glucan polymers cannot explain their modulatory effect on inflammatory responses in tissue culture and/or disease models of inflammation.

Siamon Gordon - One of the best experts on this subject based on the ideXlab platform.

  • differential high affinity interaction of dectin 1 with natural or synthetic glucans is dependent upon primary structure and is influenced by polymer chain length and side chain branching
    Journal of Pharmacology and Experimental Therapeutics, 2008
    Co-Authors: Elizabeth L Adams, Peter J Rice, Harry E Ensley, Bridget M Graves, Siamon Gordon, Mario A Monteiro, Erzsebet Pappszabo, Douglas W Lowman, Trevor D Power
    Abstract:

    Glucans are structurally diverse fungal biopolymers that stimulate innate immunity and are fungal pathogen-associated molecular patterns. Dectin-1 is a C-type lectin-like pattern recognition receptor that binds glucans and induces innate immune responses to fungal pathogens. We examined the effect of glucan structure on recognition and binding by murine recombinant Dectin-1 with a library of natural product and synthetic (1-->3)-beta/(1-->6)-Beta-Glucans as well as nonglucan polymers. Dectin-1 is highly specific for glucans with a pure (1-->3)-beta-linked backbone structure. Although Dectin-1 is highly specific for (1-->3)-beta-d-glucans, it does not recognize all glucans equally. Dectin-1 differentially interacted with (1-->3)-beta-d-glucans over a very wide range of binding affinities (2.6 mM-2.2 pM). One of the most striking observations that emerged from this study was the remarkable high-affinity interaction of Dectin-1 with certain glucans (2.2 pM). These data also demonstrated that synthetic glucan ligands interact with Dectin-1 and that binding affinity increased in synthetic glucans containing a single glucose side-chain branch. We also observed differential recognition of glucans derived from saprophytes and pathogens. We found that glucan derived from a saprophytic yeast was recognized with higher affinity than glucan derived from the pathogen Candida albicans. Structural analysis demonstrated that glucan backbone chain length and (1-->6)-beta side-chain branching strongly influenced Dectin-1 binding affinity. These data demonstrate: 1) the specificity of Dectin-1 for glucans; 2) that Dectin-1 differentiates between glucan ligands based on structural determinants; and 3) that Dectin-1 can recognize and interact with both natural product and synthetic glucan ligands.

  • soluble dectin 1 as a tool to detect β glucans
    Journal of Immunological Methods, 2006
    Co-Authors: Lisa M Graham, David L Williams, Siamon Gordon, Vicky S Tsoni, Janet A Willment, Philip R Taylor, Kevin M Dennehy, Gordon D. Brown
    Abstract:

    Beta-Glucans are structural components of fungal cell walls which are involved in the immune recognition of fungal pathogens and possess beneficial immunomodulatory activities in isolated form. Here we have developed a soluble chimeric form of the major mammalian beta-glucan receptor, Dectin-1, and demonstrate its application for the detection and characterisation of soluble and insoluble Beta-Glucans, including fungal particles, using ELISA, flow cytometric and fluorescence-based microscopy assays.

  • ligands for the β glucan receptor dectin 1 assigned using designer microarrays of oligosaccharide probes neoglycolipids generated from glucan polysaccharides
    Journal of Biological Chemistry, 2006
    Co-Authors: Angelina S Palma, Siamon Gordon, Ten Feizi, Yibing Zhang, Mark S Stoll, Alexander M Lawson, Esther Diazrodriguez, Maria A Campanerorhodes, Julia Costa, Gordon D. Brown
    Abstract:

    Dectin-1 is a C-type lectin-like receptor on leukocytes that mediates phagocytosis and inflammatory mediator production in innate immunity to fungal pathogens. Dectin-1 lacks residues involved in calcium ligation that mediates carbohydrate-binding by classical C-type lectins; nevertheless, it binds zymosan, a particulate beta-glucan-rich extract of Saccharomyces cerevisiae, and binding is inhibited by polysaccharides rich in beta1,3- or both beta1,3- and beta1,6-linked glucose. The oligosaccharide ligands on glucans recognized by Dectin-1 have not yet been delineated precisely. It is also not known whether Dectin-1 can interact with other types of carbohydrates. We have investigated this, since Dectin-1 shows glucan-independent binding to a subset of T-lymphocytes and is involved in triggering their proliferation. Here we assign oligosaccharide ligands for Dectin-1 using the neoglycolipid-based oligosaccharide microarray technology, a unique approach for constructing microarrays of lipid-linked oligosaccharide probes from desired sources. We generate "designer" microarrays from three glucan polysaccharides, a neutral soluble glucan isolated from S. cerevisiae and two bacterial glucans, curdlan from Alcaligenes faecalis and pustulan from Umbilicaria papullosa, and use these in conjunction with 187 diverse, sequence-defined, predominantly mammalian-type, oligosaccharide probes. Among these, Dectin-1 binding is detected exclusively to 1,3-linked glucose oligomers, the minimum length required for detectable binding being a 10- or 11-mer. Thus, the ligands assigned so far are exogenous rather than endogenous. We further show that Dectin-1 ligands, 11-13 gluco-oligomers, in clustered form (displayed on liposomes), mimic the macromolecular Beta-Glucans and compete with zymosan binding and triggering of tumor necrosis factor-alpha secretion by a Dectin-1-expressing macrophage cell line.

  • the beta glucan receptor dectin 1 recognizes specific morphologies of aspergillus fumigatus
    PLOS Pathogens, 2005
    Co-Authors: Chad Steele, David L Williams, Siamon Gordon, Rekha R Rapaka, Allison E Metz, Shannon M Pop, Jay K Kolls, Gordon D. Brown
    Abstract:

    Alveolar macrophages represent a first-line innate host defense mechanism for clearing inhaled Aspergillus fumigatus from the lungs, yet contradictory data exist as to which alveolar macrophage recognition receptor is critical for innate immunity to A. fumigatus. Acknowledging that the A. fumigatus cell wall contains a high beta-1,3–glucan content, we questioned whether the beta-glucan receptor dectin-1 played a role in this recognition process. Monoclonal antibody, soluble receptor, and competitive carbohydrate blockage indicated that the alveolar macrophage inflammatory response, specifically the production of tumor necrosis factor-α (TNF-α), interleukin-1α (IL-1α), IL-1β, IL-6, CXCL2/macrophage inflammatory protein-2 (MIP-2), CCL3/macrophage inflammatory protein-1α (MIP-1α), granulocyte-colony stimulating factor (G-CSF), and granulocyte monocyte–CSF (GM-CSF), to live A. fumigatus was dependent on recognition via the beta-glucan receptor dectin-1. The inflammatory response was triggered at the highest level by A. fumigatus swollen conidia and early germlings and correlated to the levels of surface-exposed beta glucans, indicating that dectin-1 preferentially recognizes specific morphological forms of A. fumigatus. Intratracheal administration of A. fumigatus conidia to mice in the presence of a soluble dectin-Fc fusion protein reduced both lung proinflammatory cytokine/chemokine levels and cellular recruitment while modestly increasing the A. fumigatus fungal burden, illustrating the importance of beta-glucan–initiated dectin-1 signaling in defense against this pathogen. Collectively, these data show that dectin-1 is centrally required for the generation of alveolar macrophage proinflammatory responses to A. fumigatus and to our knowledge provides the first in vivo evidence for the role of dectin-1 in fungal innate defense.

  • the role of signr1 and the beta glucan receptor dectin 1 in the nonopsonic recognition of yeast by specific macrophages
    Journal of Immunology, 2004
    Co-Authors: Philip R Taylor, Gordon D. Brown, David L Williams, Janet A Willment, Jurgen Herre, Siamon Gordon
    Abstract:

    We recently demonstrated that the beta-glucan receptor Dectin-1 (betaGR) was the major nonopsonic beta-glucan receptor on macrophages (Mphi) for the yeast-derived particle zymosan. However, on resident peritoneal Mphi, we identified an additional mannan-inhibitable receptor for zymosan that was distinct from the Mphi mannose receptor (MR). In this study, we have studied the mannose-binding potential of murine Mphi and identified the dendritic cell-specific ICAM-3-grabbing nonintegrin homolog, SIGN-related 1 (SIGNR1), as a major MR on murine resident peritoneal Mphi. Both SIGNR1 and betaGR cooperated in the nonopsonic recognition of zymosan by these Mphi. When SIGNR1 was introduced into NIH3T3 fibroblasts or RAW 264.7 Mphi, it conferred marked zymosan-binding potential on these cells. However, in the nonprofessional phagocytes (NIH3T3), SIGNR1 was found to be poorly phagocytic, suggesting that other receptors such as betaGR may play a more dominant role in particle internalization on professional phagocytes. Binding of zymosan to RAW 264.7 Mphi expressing SIGNR1 resulted in TNF-alpha production. Treatment of RAW 264.7 Mphi expressing SIGNR1, which express low levels of betaGR, with Beta-Glucans had little effect on binding or TNF-alpha production, indicating that there was no absolute requirement for betaGR in this process. These studies have identified SIGNR1 as a major MR for fungal and other pathogens present on specific subsets of Mphi.

Gordon D Ross - One of the best experts on this subject based on the ideXlab platform.

  • mechanism by which orally administered 1 3 glucans enhance the tumoricidal activity of antitumor monoclonal antibodies in murine tumor models 1
    Journal of Immunology, 2004
    Co-Authors: Feng Hong, Jun Yan, Jarek T Baran, Daniel J Allendorf, Richard Hansen, Gary R Ostroff, Pei Xiang Xing, Naikong V Cheung, Gordon D Ross
    Abstract:

    Antitumor mAb bind to tumors and activate complement, coating tumors with iC3b. Intravenously administered yeast beta-1,3;1,6-glucan functions as an adjuvant for antitumor mAb by priming the inactivated C3b (iC3b) receptors (CR3; CD11b/CD18) of circulating granulocytes, enabling CR3 to trigger cytotoxicity of iC3b-coated tumors. Recent data indicated that barley beta-1,3;1,4-glucan given orally similarly potentiated the activity of antitumor mAb, leading to enhanced tumor regression and survival. This investigation showed that orally administered yeast beta-1,3;1,6-glucan functioned similarly to barley beta-1,3;1,4-glucan with antitumor mAb. With both oral beta-1,3-glucans, a requirement for iC3b on tumors and CR3 on granulocytes was confirmed by demonstrating therapeutic failures in mice deficient in C3 or CR3. Barley and yeast beta-1,3-glucan were labeled with fluorescein to track their oral uptake and processing in vivo. Orally administered beta-1,3-glucans were taken up by macrophages that transported them to spleen, lymph nodes, and bone marrow. Within the bone marrow, the macrophages degraded the large beta-1,3-glucans into smaller soluble beta-1,3-glucan fragments that were taken up by the CR3 of marginated granulocytes. These granulocytes with CR3-bound beta-1,3-glucan-fluorescein were shown to kill iC3b-opsonized tumor cells following their recruitment to a site of complement activation resembling a tumor coated with mAb.

  • beta glucan a specific biologic response modifier that uses antibodies to target tumors for cytotoxic recognition by leukocyte complement receptor type 3 cd11b cd18
    Journal of Immunology, 1999
    Co-Authors: Jun Yan, Vaclav Vetvicka, Yu Xia, Angela Coxon, Michael C Carroll, Tanya N Mayadas, Gordon D Ross
    Abstract:

    Beta-Glucans were identified 36 years ago as a biologic response modifier that stimulated tumor rejection. In vitro studies have shown that Beta-Glucans bind to a lectin domain within complement receptor type 3 (CR3; known also as Mac-1, CD11b/CD18, or alphaMbeta2-integrin, that functions as an adhesion molecule and a receptor for factor I-cleaved C3b, i.e., iC3b) resulting in the priming of this iC3b receptor for cytotoxicity of iC3b-opsonized target cells. This investigation explored mechanisms of tumor therapy with soluble beta-glucan in mice. Normal mouse sera were shown to contain low levels of Abs reactive with syngeneic or allogeneic tumor lines that activated complement, depositing C3 onto tumors. Implanted tumors became coated with IgM, IgG, and C3, and the absent C3 deposition on tumors in SCID mice was reconstituted with IgM or IgG isolated from normal sera. Therapy of mice with glucan- or mannan-rich soluble polysaccharides exhibiting high affinity for CR3 caused a 57-90% reduction in tumor weight. In young mice with lower levels of tumor-reactive Abs, the effectiveness of beta-glucan was enhanced by administration of a tumor-specific mAb, and in SCID mice, an absent response to beta-glucan was reconstituted with normal IgM or IgG. The requirement for C3 on tumors and CR3 on leukocytes was highlighted by therapy failures in C3- or CR3-deficient mice. Thus, the tumoricidal function of CR3-binding polysaccharides such as beta-glucan in vivo is defined by natural and elicited Abs that direct iC3b deposition onto neoplastic cells, making them targets for circulating leukocytes bearing polysaccharide-primed CR3. Therapy fails when tumors lack iC3b, but can be restored by tumor-specific Abs that deposit iC3b onto the tumors.

D Hoole - One of the best experts on this subject based on the ideXlab platform.

  • dietary β glucan stimulate complement and c reactive protein acute phase responses in common carp cyprinus carpio during an aeromonas salmonicida infection
    Fish & Shellfish Immunology, 2013
    Co-Authors: Nicolas Pionnier, Alberto Falco, Patrick Frost, Joanna J Miest, Ilgiz Irnazarow, Annette K Shrive, D Hoole
    Abstract:

    The effect of Beta-Glucans as feed additive on the profile of C-reactive protein (CRP) and complement acute phase responses was studied in common carp Cyprinus carpio after exposition to a bacterial infection with Aeromonas salmonicida. Carp were orally administered with beta-glucan (MacroGard (R)) for 14 days with a daily beta-glucan intake of 6 mg per kg body weight. Fish were then intraperitoneally injected with either PBS or 1 x 10(8) bacteria per fish and sampled at time 0, 6, 12, 24, 48, 72, 96 and 120 h post-injection (p.i.) for serum and head kidney, liver and mid-gut tissues. CRP levels and complement activity were determined in the serum samples whilst the gene expression profiles of CRP and complement related genes (crp1, crp2, c1r/s, bf/c2, c3 and masp2) were analysed in the tissues by quantitative PCR. Results obtained showed that oral administration of beta-glucan for 14 days significantly increased serum CRP levels up to 2 fold and serum alternative complement activity (ACP) up to 35 fold. The bacterial infection on its own (i.e. not combined with a beta-glucan feeding) did have significant effects on complement response whilst CRP was not detectably induced during the carp acute phase reaction. However, the combination of the infection and the beta-glucan feeding did show significant effects on both CRP and complement profiles with higher serum CRP levels and serum ACP activity in the beta-glucan fed fish than in the control fed fish. In addition, a distinct organ and time dependent expression profile pattern was detected for all the selected genes: a peak of gene expression first occurred in the head kidney tissue (6 h p.i. or 12 h p.i.), then an up-regulation in the liver several hours later (24 h p.i.) and finally up- or down-regulations in the mid-gut at 24 h p.i. and 72 h p.i. In conclusion, the results of this study suggest that MacroGard (R) stimulated CRP and complement responses to A. salmonicida infection in common carp.

  • reduced inflammatory response to aeromonas salmonicida infection in common carp cyprinus carpio l fed with β glucan supplements
    Fish & Shellfish Immunology, 2012
    Co-Authors: Alberto Falco, Patrick Frost, Joanna J Miest, Nicolas Pionnier, Ilgiz Irnazarow, D Hoole
    Abstract:

    The objective of the present study was to determine the action of Beta-Glucans as feed additives on the gene expression profile of some inflammatory-related cytokines from common carp (Cyprinus carpio L) during the early stages of a non-lethal bacterial infection with Aeromonas salmonicida. beta-glucan (MacroGard (R)), was administered daily to carp (6 mg per kg body weight) in the form of supplemented commercial food pellets for 14 days prior to infection. Control and treated fish were then intraperitoneally injected with PBS or 4 x 10(8) bacteria per fish and were sampled at time 0 and 6 h, 12 h, I day, 3 days and 5 days post-injection. Head kidney and gut were collected and the gene expression patterns for tnf alpha 1, tnf alpha 2, il1 beta, il6 and il10 were analyzed by quantitative PCR. Results obtained showed that treatment with Beta-Glucans generally down-regulated the expression of all measured genes when compared to their corresponding controls. After injection, highest changes in the gene expression levels were obtained at 6 h: particularly, in head kidney there was higher up-regulation of tnfa1 and tnfa2 in infected fish fed Beta-Glucans in comparison to control feed: however, in gut there was a significant down-regulation of tnf alpha 1, tnf alpha 2, il1 beta and il6 in infected fish fed Beta-Glucans. Analysis of carp specific antibodies against A. salmonicida 30 days after injection revealed their levels were reduced in the infected beta-glucan group. In conclusion, a diet supplemented with beta-glucan (MacroGard (R)) reduced the gene expression levels of some inflammation-related cytokines in common carp. Such a response appears to be dependent of organ studied and therefore the immunostimulant may be preventing an acute and potential dangerous response in gut, whilst enhancing the inflammatory response in head kidney when exposed to A. salmonicida