Synergistic action of cholera toxin B subunit (and Escherichia coli heat-labile toxin B subunit) and a trace amount of cholera whole toxin as an adjuvant for nasal influenza vaccine

Tamura, Shinichi; Yamanaka, Aya; Shimohara, Miyuki; Tomita, Toshio; Komase, Katsuhiro; Tsuda, Yusuke; Suzuki, Yujiro; Nakagawa, Takashi; Kawahara, Kazuyoshi; Danbara, Hirofumi; Aizawa, Chikara; Oya, Akira; Kurata, Takeshi

doi:10.1016/0264-410x(94)90118-x

Cited by 138 publications

(56 citation statements)

References 27 publications

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“…4). The effect of rCTB on induction of IL-I and IL-6 by Mq> is different from that of CT. CT (50) CT (10) CT (1) rCTB (10)+LPS (1) rCTB ( 1)+LPS ( 1) CT ( CTB have reported that ADP-ribosyltransferase activity is indispensable for the adjuvant effect of CT (23), CTB possesses no mucosal adjuvanticity (20,22,23) and trace amounts of contaminated holotoxin are essential for the mucosal adjuvanticity of CTB purified from natural CT (6,33). rCTB is devoid of A subunit and has no ADP-ribosyltransferase activity, which is closely related to the enterotoxicity of CT. Actually, it was shown in this study that rCTB did not elicit accumulation of intracellular cAMP, unlike natural or commercial CTB containing trace amounts of holotoxin (Fig.…”

Section: Cytokine Production By Mouse Spleen Cells Restimulated With mentioning

confidence: 99%

“…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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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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Section: Cytokine Production By Mouse Spleen Cells Restimulated With mentioning

confidence: 99%

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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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“…11 However, as the adjuvant effect of CTB is due to the presence of contaminating holotoxin, 12 its potential toxicity makes it unsuitable for human use.…”

Section: Introductionmentioning

confidence: 99%

The adjuvant effect of a non‐toxic mutant of heat‐labile enterotoxin of Escherichia coli for the induction of measles virus‐specific CTL responses after intranasal co‐immunization with a synthetic peptide

et al. 1996

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SUMMARYThe intranasal route has been shown to be effective for immunization. However, immunization via this route may require the use of potent and safe adjuvant. The construction of non-toxic mutants of heat labile enterotoxin of Escherichia coli (LT), which is a potent mucosal adjuvant, is a major breakthrough for the development of mucosal vaccines. In this study we have assessed the ability of an LT mutant (LTK63) to act as an adjuvant following intranasal co-immunization with a peptide corresponding to a measles virus cytotoxic T lymphocyte (CTL) epitope. LTK63 was more effective at potentiating the in vivo induction of peptide-specific and measles virus-specific CTL responses than was administration of the peptide in saline. A concentration of 10 g/dose of LTK63 was found to be the most effective in potentiating the in vivo priming of peptide-specific and measles virus-specific CTL responses. These findings highlight the potential of the non-toxic mutant of LT as a safe mucosal adjuvant for use in humans.

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“…To reduce toxicity, modified exotoxins are described in which the A subunit is mutated or deleted to reduce or eliminate ribosylation activity (20,21). However, these formulations may still retain toxicity due to residual ribosylation activity, or there is an undesirable loss of adjuvanticity (15,22). Exotoxins with B subunit modifications that interfere with cellular binding are not considered potent adjuvants.…”

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confidence: 99%

GM1 Binding-Deficient Exotoxin Is a Potent Noninflammatory Broad Spectrum Intradermal Immunoadjuvant

Zoeteweij

Epperson

Porter

et al. 2006

The Journal of Immunology

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Intradermal (i.d.) immunization is a promising route of vaccine administration. Suitable i.d. adjuvants are important to increase vaccine efficacy in poorly responding populations such as the elderly or for dose-sparing strategies in the face of vaccine shortages. Bacterial exotoxins, such as Escherichia coli heat-labile enterotoxin (LT), exert strong immunostimulatory effects through binding to monosialoganglioside (GM1) cell surface receptors; however, injection is hampered by local inflammation. We demonstrate that the injection of LT formulations deficient in GM1 binding by mutation (LT(G33D)) or in vitro ligand coupling does not cause localized edema and inflammation in mice, yet these formulations retain potent adjuvant activity by enhancing functional Ab and cellular immune responses to coadministered Ags. Complete protection against in vivo lethal tetanus toxin challenge and the induction of Ag-specific CTL responses capable of killing target cells in vivo indicated in vivo efficacy of the induced immune responses. LT(G33D) proved superior to standard alum adjuvant regarding the magnitude and breadth of the induced immune responses. Immunizations in complex ganglioside knockout mice revealed a GM1-independent pathway of LT adjuvanticity. Immunostimulation by i.d. LT(G33D) is explained by its ability to induce migration of activated APCs to the proximal draining lymph nodes. LT(G33D) is a promising candidate adjuvant for human trials of parenteral vaccines in general and for current i.d. vaccine development in particular.

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Synergistic action of cholera toxin B subunit (and Escherichia coli heat-labile toxin B subunit) and a trace amount of cholera whole toxin as an adjuvant for nasal influenza vaccine

Cited by 138 publications

References 27 publications

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

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

The adjuvant effect of a non‐toxic mutant of heat‐labile enterotoxin of Escherichia coli for the induction of measles virus‐specific CTL responses after intranasal co‐immunization with a synthetic peptide

GM1 Binding-Deficient Exotoxin Is a Potent Noninflammatory Broad Spectrum Intradermal Immunoadjuvant

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