Contribution of the ADP-ribosylating and receptor-binding properties of cholera-like enterotoxins in modulating cytokine secretion by human intestinal epithelial cells

Soriani, Marco; Bailey, Lorna E.; Hirst, Timothy R.

doi:10.1099/00221287-148-3-667

Cited by 35 publications

(31 citation statements)

References 53 publications

(31 reference statements)

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“…Both CT and LT(R912G) treatments increased IL-1␣ levels ( Fig. 1C), as previously reported (5,62). All immunomodulator treatments significantly increased levels of the pleiotropic inflammatory cytokine IL-6, neutrophil attractant KC (mouse IL-8 homolog; also known as CXCL1), monocyte attractant and NK cell activator MCP-1 (monocyte chemotactic protein-1, or CCL2), and leukocyte attractant, monocyte attractant and NK cell activator RANTES (CCL5).…”

Section: Resultssupporting

confidence: 77%

Prophylactic Administration of Bacterially Derived Immunomodulators Improves the Outcome of Influenza Virus Infection in a Murine Model

Norton

Clements

Voss

et al. 2010

J Virol

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Prophylactic or therapeutic immunomodulation is an antigen-independent strategy that induces nonspecific immune system activation, thereby enhancing host defense to disease. In this study, we investigated the effect of prophylactic immunomodulation on the outcome of influenza virus infection using three bacterially derived immune-enhancing agents known for promoting distinct immunological profiles.

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Section: Resultssupporting

confidence: 77%

Prophylactic Administration of Bacterially Derived Immunomodulators Improves the Outcome of Influenza Virus Infection in a Murine Model

Norton

Clements

Voss

et al. 2010

J Virol

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“…Binding and endocytosis of CT holotoxin in intestinal epithelial cells results in a cascade of events that culminates in elevation of cyclic AMP (cAMP) and apical chloride secretion 20 as well as activation of NF-κB and expression of cytokines that have immunomodulatory effects. 21,25 Recently, CT was shown to induce a rapid, transient increase in immature subepithelial DCs in the connective tissue of intestinal villi, followed later by the appearance of increased numbers of mature DCs in mesenteric lymph nodes. 26 Although CT had no effect on DC numbers in PPs, 26 migration within the PP was not examined.…”

Section: Introductionmentioning

confidence: 99%

Cholera toxin, E. coli heat-labile toxin, and non-toxic derivatives induce dendritic cell migration into the follicle-associated epithelium of Peyer's patches

et al. 2008

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The follicle-associated epithelium (FAE) of Peyer's patches (PPs) transports antigens and microorganisms into mucosal lymphoid tissues where they are captured by subepithelial dendritic cells (DCs). Feeding of cholera toxin (CT) induced migration of subepithelial DCs to interfollicular T-cell areas within 24 h. This study investigated short-term effects of CT, Escherichia coli heat-labile toxin, and non-toxic derivatives on DC migration. CT or CTB injected into ligated intestinal loops induced significant increase in CD11c + DCs within the FAE within 90 min. In mice fed CT intragastrically, DC numbers in the FAE increased by 1 h, were maximal by 2 h, declined between 8 and 12 h, and were reversed by 24 h. Feeding of native LT, recombinant CTB, dibutyryl cyclic AMP, and to a lesser extent mutated CT(E29H) or mutated LT(R192G) had the same effect. Thus, both A and B subunits of enterotoxins, presumably acting through distinct signaling pathways, may promote capture of incoming antigens and pathogens by PP DCs.

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“…Although less toxic mutants of CT and LT have been engineered with substantial adjuvant function, we believe that such molecules still carry a significant risk of causing adverse reactions (13)(14)(15). Especially when considering that the adjuvanticity of CT and LT appears to be a combination of the ADP-ribosyltransferase activity of the A subunit and the ability to bind ganglioside receptors on the target cells (6,16,17). Thus, identifying a dose of mutant holotoxin that meets with the need for a desired immunoenhancing effect in the clinic without toxic side effects may prove a cumbersome and difficult task.…”

mentioning

confidence: 99%

The Cholera Toxin-Derived CTA1-DD Vaccine Adjuvant Administered Intranasally Does Not Cause Inflammation or Accumulate in the Nervous Tissues

Eriksson

Schön

Lycke

2004

The Journal of Immunology

106

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Although highly effective, the use of GM1-receptor binding holotoxins as nasal mucosal adjuvants has recently been cautioned due to the risk for their accumulation in the brain and other nervous tissues. Therefore we have explored the efficacy of the CTA1-DD adjuvant for its ability to enhance nasal immune responses in mice. We found that despite the lack of a mucosal binding element, the B cell-targeted CTA1-DD molecule was an equally strong adjuvant as cholera toxin (CT). The potency of CTA1-DD was not a result of endotoxin contamination because more than a 50-fold higher dose of LPS was needed to achieve a similar enhancement. Moreover, the adjuvant effect was TLR4-independent and absent in mutant CTA1-E112K-DD, lacking enzymatic activity. The CTA1-DD adjuvant augmented germinal center formations and T cell priming in the draining lymph nodes, and contrary to CT, promoted a balanced Th1/Th2 response with little effect on IgE Ab production. CTA1-DD did not induce inflammatory changes in the nasal mucosa, and most importantly did not bind to or accumulate in the nervous tissues of the olfactory bulb, whereas CT bound avidly to the nervous tissues. We believe that the nontoxic CTA1-DD adjuvant is an attractive solution to the current dilemma between efficacy and toxicity encountered in CT-holotoxin adjuvant or Escherichia coli heat-labile toxin-holotoxin adjuvant strategies and provides a safe and promising candidate to be included in future vaccines for intranasal administration.

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Contribution of the ADP-ribosylating and receptor-binding properties of cholera-like enterotoxins in modulating cytokine secretion by human intestinal epithelial cells

Cited by 35 publications

References 53 publications

Prophylactic Administration of Bacterially Derived Immunomodulators Improves the Outcome of Influenza Virus Infection in a Murine Model

Prophylactic Administration of Bacterially Derived Immunomodulators Improves the Outcome of Influenza Virus Infection in a Murine Model

Cholera toxin, E. coli heat-labile toxin, and non-toxic derivatives induce dendritic cell migration into the follicle-associated epithelium of Peyer's patches

The Cholera Toxin-Derived CTA1-DD Vaccine Adjuvant Administered Intranasally Does Not Cause Inflammation or Accumulate in the Nervous Tissues

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