Mucosal adjuvant activity of cholera toxin requires Th17 cells and protects against inhalation anthrax (original) (raw)
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Journal of immunology (Baltimore, Md. : 1950), 1995
Despite pathophysiologic effects including diarrhea, cholera toxin (CT) is a potent mucosal immunogen and adjuvant. We investigated the influence of CT on T helper (Th)-type 1 (Th1) and Th2 cell-regulated Ag-specific B cell isotype and IgG subclass Ab responses elicited when the toxin was co-administered orally with different protein Ags. When mice were orally immunized with tetanus toxoid (TT) and CT as adjuvant, this regimen induced TT-specific secretory IgA responses in the gastrointestinal tract as well as serum IgG, including IgG1 and IgG2b subclasses, and IgA responses. This oral regimen also induced TT- and CT-B-specific IgE responses. In addition, CT also elicited adjuvant effects for Ag-specific IgG1, IgE, and IgA responses when two other protein Ags, OVA and hen egg white lysozyme, were given by the oral route. Quantitative reverse transcriptase-PCR was performed to assess levels of mRNA for Th1 (IFN-gamma) and Th2 (IL-4) cytokine expression in TT-stimulated CD4+ T cell cu...
Infection and Immunity, 2003
CT was shown to be a strong adjuvant when it was coadministered to DC with OVA and was even stronger when it was coadministered with OVA-CTB and primed for a mixed Th1-Th2 response. The antibody and T-cell responses were further enhanced if OVA was coupled to CT, implying that CT can utilize a combined carrier and adjuvant function vis-a-vis linked antigens for DC vaccination. The immunopotentiating capacity of CT-and CTB-linked antigen was associated with both upregulated secretion of interleukin-1 by the pulsed DC and increased expression of CD80 and CD86 on the DC surface. These results imply that CT and CTB can be used to both markedly increase and partially direct the DC vaccineinduced immune response with respect to Th1 and Th2 responses, which has obvious implications for DCbased vaccine development.
The Journal of Immunology, 2003
Topical application of cholera toxin (CT) onto mouse skin can induce a humoral immune response to CT as well as to coadministered Ags. In this study, we examined the nontoxic cell-binding B subunit of CT (CTB) as a potential adjuvant for cutaneous immune responses when coadministered with the prototype protein Ag, OVA. CTB applied onto skin induced serum Ab responses to itself with magnitudes comparable to those evoked by CT but was poorly efficient at promoting systemic Ab responses to coadministered OVA. However, transcutaneous immunization (TCI) with either CT or CTB and OVA led to vigorous OVAspecific T cell proliferative responses. Furthermore, CTB potentiated Th1-driven responses (IFN-␥ production) whereas CT induced both Th1 and Th2 cytokine production. Coadministration of the toxic subunit CTA, together with CTB and OVA Ag, led to enhanced Th1 and Th2 responses. Moreover, whereas TCI with CT enhanced serum IgE responses to coadministered OVA, CTB suppressed these responses. TCI with either CT or CTB led to an increased accumulation of dendritic cells in the exposed epidermis and the underlying dermis. Thus, in contrast to CT, CTB appears to behave very differently when given by the transcutaneous as opposed to a mucosal route and the results suggest that the adjuvanticity of CT on Th1-and Th2-dependent responses induced by TCI involves two distinct moieties, the B and the A subunits, respectively.
International Journal of Medical Microbiology, 2001
Cholera toxin (CT) is a potent mucosal adjuvant. When administered through the mucosal route CT amplifies B and T lymphocyte responses to co-administered antigens. Since the discovery of CT as a mucosal adjuvant, other bacterial enterotoxins have been found to have this property. These molecules or their detoxified derivatives are all important for the development of mucosal vaccines for human use, and it is thus necessary to understand their mechanism of action. CT has immunomodulatory effects on different cell types, however, the interaction of CT with dendritic cells (DCs), which have a primary role in the priming of immune responses, may be crucial for its adjuvant activity.
European Journal of Immunology, 1999
Adjuvants that can improve mucosal vaccine efficacy are much warranted. In this comparative study between cholera toxin (CT) and immune-stimulating complexes (ISCOM) we found that, contrary to CT, ovalbumin (OVA)-ISCOM were poor inducers of mucosal anti-OVA IgA responses, but induced similar or better systemic immunity following oral immunizations. The addition of CT to the oral OVA-ISCOM protocol did not stimulate local anti-OVA IgA immunity, nor did it change the quality or magnitude of the systemic responses. Both vectors recruited strong innate immunity, but only OVA-ISCOM could directly induce IL-12, demonstrable at the protein and mRNA levels. CT had no inhibitory effects on lipopolysaccharide/ IFN-+ -induced IL-12 mRNA expression or IL-12 production. Furthermore, adjuvanticity of CT was unaffected in IL-12-deficient mice, while OVA-ISCOM showed partly impaired adjuvant effects by the lack of IL-12. CT abrogated the induction of oral tolerance stimulated by antigen feeding in these mice. In addition, CT did not alter TGF-g levels, suggesting that the immunomodulating effect of CT was independent of IL-12 as well as TGF-g production. Taken together, these findings indicate that mucosal adjuvanticity of CT and ISCOM are differently dependent on IL-12, suggesting that separate and distinct antigen-processing pathways are involved.
Immunology and Cell Biology, 1998
The mucosal route of vaccination has attracted a great deal of attention recently. Not only is mucosal application of vaccines, for example, orally or intranasally, particularly convenient, it also oers the possibility to induce locally produced and secreted S-IgA antibodies in addition to systemic IgG antibodies. These IgA antibodies are known to play a key role in protection against pathogens that invade the host through mucosal surfaces. Induction of such responses is not readily achieved by currently used vaccination strategies, which generally involve intramuscular or subcutaneous injection with inactivated pathogens or antigens thereof. For the induction of a mucosal immune response, the vaccine needs to be applied locally. However, local vaccination with non-replicating antigens is usually ineective and may result in tolerance unless a mucosal immunoadjuvant is included. The most potent mucosal immunoadjuvants known to date are probably cholera toxin (CT) and the closely related Escherichia coli heat-labile enterotoxin (LT). Although CT and LT have become standard adjuvants for experimental mucosal vaccines, the intrinsic toxicity has thus far precluded their use as adjuvants for human vaccine formulations. In the present review, the mucosal immunogenic and adjuvant properties of LT and CT are described, with special emphasis on the functional role of the individual subunits on their immunestimulatory properties.