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Review

Polysaccharide Immunomodulators as Therapeutic Agents: Structural Aspects and Biologic Function

Arthur O. Tzianabos
Arthur O. Tzianabos
Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115
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DOI: 10.1128/CMR.13.4.523
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    Fig. 1.

    Schematic representation of the balance between pro- and anti-inflammatory cytokines elicited during bacterial sepsis. The onset of bacterial sepsis immediately leads to the production of numerous proinflammatory mediators, such as TNF-α, IL-1β, IL-6, IL-8, and NO. To prevent an overwhelming inflammatory response anti-inflammatory mediators such as IL-10 and MCP-1 are produced a few hours later. These cytokines have pleiotropic effects functioning to directly inhibit proinflammatory cytokine synthesis and promote the synthesis of specific cytokine inhibitors, such as IL-1 receptor antagonist and soluble TNF receptors. In addition, they downregulate chemokine and chemokine receptor production and inhibit Th1 cytokines, such as IL-2 and IFN-γ.

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    Fig. 2.

    Structure of B. fragilis PS A. This repeating unit comprises a trisaccharide backbone with a galactofuranose side chain. PS A has a positively charged free amino group on the 2,4-dideoxy-4-amino-d-FucNAc and a 4,6-pyruvate ring on the galactose moiety.

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    Fig. 3.

    Proposed model of intra-abdominal abscess formation. The CPC of B. fragilis interacts with cells of the host immune system within the peritoneal cavity. This interaction (i) allows for the localization of B. fragilis within the abdominal cavity, thus resulting in enhanced adherence to the mesothelial surface and the ability to resist clearance from the peritoneum, and (ii) stimulates proinflammatory cytokines and chemokines, the production of which stimulates the expression of CAMs (such as ICAM-1) on host cells and the recruitment of PMNs to the abdominal cavity. Infiltration and sequestration of PMNs within the peritoneal cavity are the hallmark of intra-abdominal abscess formation. The CPC of B. fragilisinteracts with T cells, peritoneal macrophages, and PMNs. In response to this interaction, these cells produce TNF-α and IL-8, which serve to recruit activated PMNs to the peritoneal cavity and upregulate ICAM-1 expression on mesothelial cells. The production of ICAM-1 by mesothelial cells serves as a functional ligand for infiltrating PMNs. The recruitment of PMNs into the peritoneal cavity and subsequent adherence of these cells to activated mesothelial tissue form the first stages of intra-abdominal abscess formation in the infected host.

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    Fig. 4.

    Polysaccharide-mediated protection against mortality and abscess formation associated with experimental intra-abdominal sepsis (62). Animals were treated prophylactically with saline, PGG-glucan, PS A, or a combination of these polymers and challenged with rat cecal contents. The challenge inoculum is titrated to yield approximately a 50% mortality rate with 100% abscess formation in surviving animals. Results are taken from two separate experiments. (A) Mortality rates in animals treated with PGG-glucan or with the combination of PGG-glucan and PS A were significantly reduced (∗) compared with the saline-treated control group. (B) Abscess formation was significantly reduced (∗) in animals treated with PS A or the combination of PS A and PGG-glucan compared with the saline-treated controls. These results demonstrate that administration of two polysaccharide immunomodulators can prevent both phases of intra-abdominal sepsis in the absence of antibiotic therapy.

Tables

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  • Table 1.

    Abscess induction by Zpsa

    PolysaccharideAD50b(μg)
    PS A0.67
    PS B25
    CPC22
    C substance5
    S. pneumoniae type 1 CP31
    Group B meningococcal CP>200
    Group B streptococcal type Ia CP>200
    • ↵a Animals were challenged intraperitoneally with 10-fold dilutions of each polysaccharide mixed 1:1 with sterile cecal-content adjuvant (64). Animals were examined for intra-abdominal abscesses 6 days later, and the AD50 was calculated as described (64). Zps were potent abscess-inducing agents, while polysaccharides that did not have this charge motif had AD50s greater than 200 μg.

    • ↵b The dose of polysaccharide calculated to yield abscesses in 50% of animals as previously described (64).

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Polysaccharide Immunomodulators as Therapeutic Agents: Structural Aspects and Biologic Function
Arthur O. Tzianabos
Clinical Microbiology Reviews Oct 2000, 13 (4) 523-533; DOI: 10.1128/CMR.13.4.523

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Polysaccharide Immunomodulators as Therapeutic Agents: Structural Aspects and Biologic Function
Arthur O. Tzianabos
Clinical Microbiology Reviews Oct 2000, 13 (4) 523-533; DOI: 10.1128/CMR.13.4.523
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  • Top
  • Article
    • SUMMARY
    • DEFINITION OF IMMUNOMODULATION
    • POLYSACCHARIDE IMMUNOMODULATORS
    • POTENTIAL CLINICAL APPLICATIONS
    • CONCLUSIONS
    • ACKNOWLEDGMENTS
    • REFERENCES
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KEYWORDS

Adjuvants, Immunologic
Infection
Polysaccharides

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