Modulation of surgical fibrosis by microbial zwitterionic polysaccharides

Ruiz-Perez, Begonia; Chung, Doo Ryeon; Sharpe, Arlene H.; Yagita, Hideo; Kalka-Moll, Wiltrud M.; Sayegh, Mohamed H.; Kasper, Dennis L.; Tzianabos, Arthur O.

doi:10.1073/pnas.0505688102

Cited by 38 publications

(34 citation statements)

References 38 publications

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“…In mouse models of abscess formation and surgical adhesion development, the immunostimulatory activity of PSA and related zwitterionic polysaccharides depends on co-stimulatory molecules of the B7 family (Stephen et al, 2005). Immunoprotection by PSA in those models also depends on ICOS–ICOSL interaction (Ruiz-Perez et al, 2005), although a specific APC mediating these interactions with T cells was not identified. Antigen presentation and co-stimulation alone are not sufficient for PSA-induced immunoprotection; innate immune pathways, particularly those mediated through TLR2, are also required.…”

Section: Discussionmentioning

confidence: 99%

Plasmacytoid Dendritic Cells Mediate Anti-inflammatory Responses to a Gut Commensal Molecule via Both Innate and Adaptive Mechanisms

Dasgupta

Ertürk-Hasdemir

Ochoa‐Repáraz

et al. 2014

Cell Host & Microbe

250

246

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Summary Polysaccharide A (PSA), the archetypical immunomodulatory molecule of the gut commensal Bacteroides fragilis, induces regulatory T cells to secrete the anti-inflammatory cytokine interleukin 10 (IL-10). The cellular mediators of PSA’s immunomodulatory properties are incompletely understood. In a mouse model of colitis, we find that PSA requires both innate and adaptive immune mechanisms to generate protection. Plasmacytoid DCs (PDCs) exposed to PSA do not produce proinflammatory cytokines but instead they specifically stimulate IL-10 secretion by CD4+ T cells and efficiently mediate PSA-afforded immunoprotection. PSA induces and preferentially ligates Toll-like receptor 2 on PDCs but not on conventional DCs. Compared with other TLR2 ligands, PSA is better at enhancing PDC expression of co-stimulatory molecules required for protection against colitis. PDCs can thus orchestrate the beneficial immunoregulatory interaction of commensal microbial molecules, such as PSA, through both innate and adaptive immune mechanisms.

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Section: Discussionmentioning

confidence: 99%

Plasmacytoid Dendritic Cells Mediate Anti-inflammatory Responses to a Gut Commensal Molecule via Both Innate and Adaptive Mechanisms

Dasgupta

Ertürk-Hasdemir

Ochoa‐Repáraz

et al. 2014

Cell Host & Microbe

250

246

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“…Detection of not only IgG3, the predominant isotype produced in response to T-cell-independent TI-2 polysaccharide antigens (19), but also a significant IgG1 titer promotes our hypothesis of T-cell-mediated isotype switching and suggests a humoral memory response. Subcutaneous ZPS application without adjuvant has been shown to induce regulatory IL-10-secreting CD4 ϩ CD45Rb low CD25 Ϫ T cells that protect from disease (20). Thus, it is conceivable that subcutaneous Sp1 administration in the presence of adjuvant induces regulatory CD4 ϩ T cells that contribute to the low IgG titer and the shift to a predominant IgG1 (TH2) isotype.…”

Section: Discussionmentioning

confidence: 99%

“…Yet ZPS-specific clones in mice have not been established. The difficulties observed so far in obtaining and culturing polysaccharide-reactive T cells might be explained by complex immunomodulatory features, such as the polysaccharide-mediated T-cell anergy and the induction of IL-10-producing regulatory T cells, which may inhibit clonal expansion (20,23). In light of these difficulties, clonotype mapping, which is a highly sensitive method to detect clonotypic TCR transcripts making up as little as 0.1% of a mixed T-cell population, seems to be a suitable method for analysis of the clonality of in vitro ZPS-activated CD4 ϩ T cells without the need for long-term expansion (21,26).…”

Section: Discussionmentioning

confidence: 99%

Oligoclonal CD4⁺T Cells Promote Host Memory Immune Responses to Zwitterionic Polysaccharide ofStreptococcus pneumoniae

et al. 2009

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Zwitterionic polysaccharides of the normal flora bacteria represent a novel class of antigens in that they correct systemic CD4؉ T-cell deficiencies and direct lymphoid organogenesis during colonization of the host. Presentation of these polysaccharides to CD4؉ T cells depends on major histocompatibility complex class IIand DM-dependent retrograde transport from lysosomes to the cell surface. Yet the phenotype and clonality of the immune response to the polysaccharide in the mature host immune system have not been studied. Capsular polysaccharides of the human physiologic bacterial flora are immunogenic components that first encounter the human immune system during initial colonization and at the time that the immune system is developing and maturing. As opposed to common negatively charged polysaccharides, the biologic activities of certain commensal bacterial polysaccharides are unique in their ability to stimulate CD4 ϩ T cells in vivo and in vitro. They direct the development of the systemic cellular immune response by correcting CD4 ϩ T-cell deficiencies and TH1/TH2 imbalances toward a TH1 immune response. Responses to the polysaccharides are conferred by CD4 ϩ T cells, not B cells or other T cells (14,18,28,(31)(32)(33). Examples of such bacteria are the ubiquitous anaerobic member of the gut flora Bacteroides fragilis, Staphylococcus aureus as a temporary member of the skin and mucosal flora, and Streptococcus pneumoniae of the upper respiratory tract flora. CD4 ϩ T-cell activation induced by these polysaccharides depends on their unique electrical charge: each repeating unit has a minimum of one positive and one negative charge, leading to their common three-dimensional configuration characterized by a right-handed helix with repeating negatively charged grooves, with the positive charges being on the outer surface of the lateral boundaries (5,14,31,36). Presentation of the so-called zwitterionic polysaccharide (ZPS) from S. pneumoniae serotype 1 (Sp1) by major histocompatibility complex (MHC) class II molecules requires its retrograde transport from lysosomes to the cell surface within tubules as a ZPS-MHC class II complex and also requires the DM molecule (12,22). DM is known to catalyze and edit the exchange of the self-peptide CLIP with processed antigen in MHC class II compartments. The requirement of DM for Sp1 presentation via MHC class II suggests presentation within the antigen binding groove, which is supported by recent studies demonstrating that binding of the ZPS PS A1 from B. fragilis to MHC class II molecules can be competed by peptides known to be presented in the antigen binding cleft (7).For protein-derived T-cell antigens, it is well established that their presence in the MHC class II binding groove leads to the recognition of their antigenic epitopes by the T-cell receptor (TCR), within the CDR3 antigen binding domain of the ␤-chain variable (BV) region, and to subsequent T-cell activation and oligoclonal T-cell proliferation. However, for ZPS, besides the requirement of engaging the ...

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“…Mice deficient in IL-12, but not in IL-4, signaling show fewer adhesions compared with wild-type mice (13), underscoring the Th1-type nature of the adhesion-forming process. Microbial zwitterionic polysaccharides can prevent adhesion formation, and this protective effect can be transferred through transfer of CD4 ϩ CD45RB low IL-10-producing T cells (118). Injections of IL-10 alone can also prevent adhesion formation in mice (46).…”

Section: Postoperative Fibrosismentioning

confidence: 99%

Animal models of intestinal fibrosis: new tools for the understanding of pathogenesis and therapy of human disease

Rieder

Kessler

Sans

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

121

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Fibrosis is a serious condition complicating chronic inflammatory processes affecting the intestinal tract. Advances in this field that rely on human studies have been slow and seriously restricted by practical and logistic reasons. As a consequence, well-characterized animal models of intestinal fibrosis have emerged as logical and essential systems to better define and understand the pathophysiology of fibrosis. In point of fact, animal models allow the execution of mechanistic studies as well as the implementation of clinical trials with novel, pathophysiology-based therapeutic approaches. This review provides an overview of the currently available animal models of intestinal fibrosis, taking into consideration the methods of induction, key characteristics of each model, and underlying mechanisms. Currently available models will be classified into seven categories: spontaneous, gene-targeted, chemical-, immune-, bacteria-, and radiation-induced as well as postoperative fibrosis. Each model will be discussed in regard to its potential to create research opportunities to gain insights into the mechanisms of intestinal fibrosis and stricture formation and assist in the development of effective and specific antifibrotic therapies.

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Modulation of surgical fibrosis by microbial zwitterionic polysaccharides

Cited by 38 publications

References 38 publications

Plasmacytoid Dendritic Cells Mediate Anti-inflammatory Responses to a Gut Commensal Molecule via Both Innate and Adaptive Mechanisms

Plasmacytoid Dendritic Cells Mediate Anti-inflammatory Responses to a Gut Commensal Molecule via Both Innate and Adaptive Mechanisms

Oligoclonal CD4⁺T Cells Promote Host Memory Immune Responses to Zwitterionic Polysaccharide ofStreptococcus pneumoniae

Animal models of intestinal fibrosis: new tools for the understanding of pathogenesis and therapy of human disease

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Modulation of surgical fibrosis by microbial zwitterionic polysaccharides

Cited by 38 publications

References 38 publications

Plasmacytoid Dendritic Cells Mediate Anti-inflammatory Responses to a Gut Commensal Molecule via Both Innate and Adaptive Mechanisms

Plasmacytoid Dendritic Cells Mediate Anti-inflammatory Responses to a Gut Commensal Molecule via Both Innate and Adaptive Mechanisms

Oligoclonal CD4+T Cells Promote Host Memory Immune Responses to Zwitterionic Polysaccharide ofStreptococcus pneumoniae

Animal models of intestinal fibrosis: new tools for the understanding of pathogenesis and therapy of human disease

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Oligoclonal CD4⁺T Cells Promote Host Memory Immune Responses to Zwitterionic Polysaccharide ofStreptococcus pneumoniae