Bacterial Toxins as Mucosal Adjuvants

Freytag, Lucy C.; Clements, John D.

doi:10.1007/978-3-642-59951-4_11

Cited by 61 publications

(54 citation statements)

References 51 publications

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“…Several mucosal adjuvants have been developed recently in an attempt to enhance the immunogenicity of nonreplicating antigens. While currently no effective adjuvants are approved for oral use in humans, CT and LT are adjuvants tested widely in preclinical studies (9,35), and mutant toxins are being developed (6,12,14,15,18). We evaluated one mutant LT, LT(R192G), that has a single amino acid substitution in position 192 that decreases toxicity while still retaining the adjuvant properties.…”

Section: Discussionmentioning

confidence: 99%

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Recombinant Norwalk Virus-Like Particles Administered Intranasally to Mice Induce Systemic and Mucosal (Fecal and Vaginal) Immune Responses

Guerrero

Ball²,

Krater³

et al. 2001

J Virol

109

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Section: Discussionmentioning

confidence: 99%

“…Only a few natural antigens, including bacterial toxins such as cholera toxin (CT) or Escherichia coli labile toxin (LT), consistently stimulate strong mucosal responses (18). These antigens are also useful as mucosal adjuvants to stimulate mucosal responses to unrelated coadministered antigens.…”

mentioning

confidence: 99%

Recombinant Norwalk Virus-Like Particles Administered Intranasally to Mice Induce Systemic and Mucosal (Fecal and Vaginal) Immune Responses

Guerrero

Ball²,

Krater³

et al. 2001

J Virol

109

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show abstract

“…Other groups have taken a different approach to separate toxicity from adjuvanticity in CT and the related Escherichia coli heatlabile toxin (LT), by introducing, by site-directed mutagenesis, single amino acid replacements in the enzymatically active cleft of the A1 subunit (11)(12)(13). These groups are now reporting successful nontoxic constructions with retained adjuvant function where the enzyme is partly or even completely inactive (14 -17).…”

mentioning

confidence: 99%

The ADP-Ribosylating CTA1-DD Adjuvant Enhances T Cell-Dependent and Independent Responses by Direct Action on B Cells Involving Anti-Apoptotic Bcl-2- and Germinal Center-Promoting Effects

Ågren

Sverremark

Ekman

et al. 2000

The Journal of Immunology

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We recently developed a novel immunomodulating gene fusion protein, CTA1-DD, that combines the ADP-ribosylating ability of cholera toxin (CT) with a dimer of an Ig-binding fragment, D, of Staphylococcus aureus protein A. The CTA1-DD adjuvant was found to be nontoxic and greatly augmented T cell-dependent responses to soluble protein Ags after systemic as well as mucosal immunizations. Here we show that CTA1-DD does not appear to form immune complexes or bind to soluble Ig following injections, but, rather, it binds directly to B cells of all isotypes, including naive IgD+ cells. No binding was observed to macrophages or dendritic cells. Immunizations in FcεR (common FcRγ-chain)- and FcγRII-deficient mice demonstrated that CTA1-DD exerted unaltered enhancing effects, indicating that FcγR-expressing cells are not required for the adjuvant function. Whereas CT failed to augment Ab responses to high m.w. dextran B512 in athymic mice, CTA1-DD was highly efficient, demonstrating that T cell-independent responses were also enhanced by this adjuvant. In normal mice both CT and CTA1-DD, but not the enzymatically inactive CTA1-R7K-DD mutant, were efficient enhancers of T cell-dependent as well as T cell-independent responses, and both promoted germinal center formation following immunizations. Although CT augmented apoptosis in Ag receptor-activated B cells, CTA1-DD strongly counteracted apoptosis by inducing Bcl-2 in a dose-dependent manner, a mechanism that was independent of the CD19 coreceptor. However, in the presence of CD40 stimulation, apoptosis was low and unaffected by CT, suggesting that the adjuvant effect of CT is dependent on the presence of activated CD40 ligand-expressing T cells.

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“…The toxic A subunit is then translocated into the cell, where this enzymatically active peptide transfers the ADP ribose group of NAD to a GTP-binding protein, initiating the toxic effects by increasing intracellular levels of cAMP. The adjuvant effects of CT (reviewed in Freytag and Clements, 1999) are broad-based and can include increased mucosal epithelial cell and macrophage production of pro-inflammatory cytokines, up-regulation of B7-2 co-stimulatory factors on APCs, and increased antigen transfer from the mucosal to the systemic compartment. These effects may be, at least in part, locally manifest and may involve dendritic cells as the predominating antigen-presenting cell (APC) population (Porgador et al, 1997).…”

Section: Heat-labile Enterotoxinsmentioning

confidence: 99%

Dental Caries Vaccines: Prospects and Concerns

Smith¹

2002

Critical Reviews in Oral Biology & Medicine

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Dental caries remains one of the most common infectious diseases of mankind. Cariogenic micro-organisms enter the dental biofilm early in life and can subsequently emerge, under favorable environmental conditions, to cause disease. In oral fluids, adaptive host defenses aroused by these infections are expressed in the saliva and gingival crevicular fluid. This review will focus on methods by which mucosal host defenses can be induced by immunization to interfere with dental caries caused by mutans streptococci. The natural history of mutans streptococcal colonization is described in the context of the ontogeny of mucosal immunity to these and other indigenous oral streptococci. Molecular targets for dental caries vaccines are explored for their effectiveness in intact protein and subunit (synthetic peptide, recombinant and conjugate) vaccines in pre-clinical studies. Recent progress in the development of mucosal adjuvants and viable and non-viable delivery systems for dental caries vaccines is described. Finally, the results of clinical trials are reviewed, followed by a discussion of the prospects and concerns of human application of the principles presented.

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Bacterial Toxins as Mucosal Adjuvants

Cited by 61 publications

References 51 publications

Recombinant Norwalk Virus-Like Particles Administered Intranasally to Mice Induce Systemic and Mucosal (Fecal and Vaginal) Immune Responses

Recombinant Norwalk Virus-Like Particles Administered Intranasally to Mice Induce Systemic and Mucosal (Fecal and Vaginal) Immune Responses

The ADP-Ribosylating CTA1-DD Adjuvant Enhances T Cell-Dependent and Independent Responses by Direct Action on B Cells Involving Anti-Apoptotic Bcl-2- and Germinal Center-Promoting Effects

Dental Caries Vaccines: Prospects and Concerns

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