Whole Cholera Toxin and B Subunit Act Synergistically as an Adjuvant for the Mucosal Immune Response of Mice to Keyhole Limpet Haemocyanin

Wilson, A D; Clarke, Charlene; Stokes, C.R.

doi:10.1111/j.1365-3083.1990.tb02791.x

Cited by 82 publications

(35 citation statements)

References 22 publications

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“…Previous studies demonstrated that it is advantageous to increase the immunogenicity of vaccine antigens by coadministration of an appropriate adjuvant. Cholera toxin (CT) is a well-known mucosal adjuvant, stimulating antigenspecific secretory IgA and systemic IgG antibody responses to unrelated antigens when coadministered via the oral, nasal, or genital route (14,32,47). The CT holotoxin consists of two subunits: a toxigenic A subunit (CTA), which activates the adenylate cyclase system, and a pentameric B subunit (CTB), which is responsible for CT binding to GM1 gangliosides on the cell membrane.…”

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confidence: 99%

Mucosal Immunization with Virus-Like Particles of Simian Immunodeficiency Virus Conjugated with Cholera Toxin Subunit B

Kang

Yao

Guo

et al. 2003

J Virol

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To enhance the efficiency of antigen uptake at mucosal surfaces, CTB was conjugated to simian immunodeficiency virus (SIV) virus-like particles (VLPs). We characterized the immune responses to the Env and Gag proteins after intranasal administration. Intranasal immunization with a mixture of VLPs and CTB as an adjuvant elicited higher levels of SIV gp160-specific immunoglobulin G (IgG) in sera and IgA in mucosae, including saliva, vaginal-wash samples, lung, and intestine, as well as a higher level of neutralization activities than immunization with VLPs alone. Conjugation of CTB to VLPs also enhanced the SIV VLP-specific antibodies in sera and in mucosae to similar levels. Interestingly, CTB-conjugated VLPs showed higher levels of cytokine (gamma interferon)-producing splenocytes and cytotoxic-T-lymphocyte activities of immune cells than VLPs plus CTB, as well as an increased level of both IgG1 and IgG2a serum antibodies, which indicates enhancement of both Th1-and Th2-type cellular immune responses. These results demonstrate that CTB can be an effective mucosal adjuvant in the context of VLPs to induce enhanced humoral, as well as cellular, immune responses.

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confidence: 99%

Mucosal Immunization with Virus-Like Particles of Simian Immunodeficiency Virus Conjugated with Cholera Toxin Subunit B

Kang

Yao

Guo

et al. 2003

J Virol

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“…epithelial layer that may produce inhibitory cytokines (9). Some investigators have suggested that the adjuvant mechanism of CT is linked to the ability to ADP-ribosylate and to stimulate cyclic AMP (cAMP) formation (23), and that the adjuvant activity of natural CTB may be due to the presence of the trace amounts of CTA that are frequently present in CTB preparations obtained from CT holotoxin (6,20,33,38). We purified a large amount of recombinant cholera toxin B subunit (rCTB) secreted by Bacillus brevis carrying pNU212-CTB (14,43), and it showed powerful adjuvant properties for biologicals without the holotoxin (15,16).…”

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confidence: 99%

Cytokine Responses to Recombinant Cholera Toxin B Subunit Produced by Bacillus brevis as a Mucosal Adjuvant

Maeyama

Isaka

Yasuda

et al. 2001

Microbiology and Immunology

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We attempted to clarify the mechanism of the mucosal adjuvanticity of recombinant cholera toxin B subunit (rCTB), which is inherently uncontaminated with the holotoxin produced by Bacillus brevis and has a powerful mucosal adjuvant activity, on cytokine responses compared with that of cholera toxin (CT). rCTB had no ability to stimulate cyclic AMP formation in mouse peritoneal macrophages (M«/»). Cytokine production by non-immunized M«/» cultured with rCTB or CT and by the spleen cells of mice co-immunized intranasally with ovalbumin (OVA) and rCTB or CT was examined. rCTB alone did not induce interleukin (IL)-lalll or IL-6 production by M«/», but combination ofrCTB with lipopolysaccharide (LPS) enhanced both IL-lalll production. Conversely, CT plus LPS suppressed IL-lalll production more than LPS alone. Both rCTB and CT suppressed IL-12 secretion induced by interferon -y (IFN -y) plus LPS. IL-2, IL-4, IL-S, and IL-IO were secreted by mouse spleen cells restimulated with OVA after intranasal co-administration of OVA together with rCTB, and in response to CT, the same cytokines were secreted. The different effect of rCTB on M«/» from that of CT may mean a difference between the mechanisms of rCTB and CT during the early stage of an immune response. Key words: Recombinant cholera toxin B subunit (rCTB), Mucosal adjuvant, InterleukinOral and nasal mucosal immunizations have received a great deal of attention in recent years, because they stimulate both mucosal and systemic immunities, and antigen-specific mucosal immune responses can be expressed at all mucosal sites (26). In addition, the inoculation procedure is simple, reliable, and cheap, and injection needles are unnecessary. However, mucosal immune responses to protein antigen alone usually could not be demonstrated, or could only be weakly demonstrated, and therefore, mucosal adjuvants that can sufficiently enhance mucosal antigen-specific IgA antibody response levels are required for immunization. Cholera toxin (CT), Escherichia coli-derived heat-labile toxin, and their mutated modified proteins are generally well-known as mucosal adjuvants (4,8,22,41,42). CT is composed of two subunits, a toxigenic A subunit (CTA), which is involved in ADP-ribosylation and a pentameric B subunit (CTB) which binds with GMI ganglioside present in most mammalian cells. Possible mechanisms of action of CT as a mucosal adjuvant include (a) enhancement of uptake of co-administered antigen across either the follicular or surface epithelial layer, (b) enhancement of antigen presentationby increasing the expression of costimulatorysurface moleculesand cytokines such as IL-l and IL-6 of antigen presenting cells, (c) induction of both antigen-and CT-specific CD4+ T cells, (d) enhancement of the IgGl and IgA isotype production of B cells by IL-4 produced by primed T cells, and (e) inhibition of CD8 + T cells in the

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“…A possibility exists that CT exerts a bidirectional influence on the antigen presentation. One action is an inhibition by CTA through an increase in cAMP, and the other is an enhancement by CTB alone or with a trace amount of CT [6,7,[31][32][33]. In some cases, CTB alone might act as a co-stimulator on the surface of APC [16].…”

Section: Discussionmentioning

confidence: 99%

Cholera toxin increases intracellular pH in B lymphoma cells and decreases their antigen-presenting ability

et al. 1999

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Cholera toxin (CT) can function as a potent adjuvant in the mucosal immune response. However, we have found that treatment of A20-HL murine B lymphoma cells with CT severely inhibits the presentation of ovalbumin (OVA) to cells of the T cell clone 42-6A specific for OVA 323-339 /I-A d , whereas it does not affect the presentation of OVA 323-339 peptide. CT treatment did not affect the expression of B7-1, B7-2, ICAM-1, LFA-1 or MHC class II on, or the internalization of OVA into A20-HL cells. In CT-treated A20-HL cells, degradation of OVA was decreased, and intracellular pH was raised to a level approximately equivalent to that in CH 3 NH 2 -treated cells. Treatment with CH 3 NH 2 is known to raise the pH in endocytic structures and thus inhibits antigen processing. Treatment of A20-HL cells with dibutyryl-cAMP similarly increased intracellular pH. The increase in intracellular pH following CT treatment was inhibited by a cAMP inhibitor, 2',3'-dideoxyadenosine. These results strongly suggest that CT treatment of A20-HL cells inhibits their antigen-presenting cell function by triggering the cAMP cascade, increasing intracellular pH, and reducing the degradation of OVA.

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Whole Cholera Toxin and B Subunit Act Synergistically as an Adjuvant for the Mucosal Immune Response of Mice to Keyhole Limpet Haemocyanin

Cited by 82 publications

References 22 publications

Mucosal Immunization with Virus-Like Particles of Simian Immunodeficiency Virus Conjugated with Cholera Toxin Subunit B

Mucosal Immunization with Virus-Like Particles of Simian Immunodeficiency Virus Conjugated with Cholera Toxin Subunit B

Cytokine Responses to Recombinant Cholera Toxin B Subunit Produced by Bacillus brevis as a Mucosal Adjuvant

Cholera toxin increases intracellular pH in B lymphoma cells and decreases their antigen-presenting ability

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