Recombinant cholera toxin B subunit acts as an adjuvant for the mucosal and systemic responses of mice to mucosally co-administered bovine serum albumin

Tochikubo, Kunio; Isaka, Masanori; Yasuda, Yoko; Kozuka, Satoshi; Matano, Keiko; Miura, Yataka; Taniguchi, Tooru

doi:10.1016/s0264-410x(97)00194-1

Cited by 75 publications

(57 citation statements)

References 26 publications

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“…The rCTB preparation contained predominantly stable pentameric form and its GMI binding ability was similar to that of the native CTB (43). It contained little or no leucocytosis-promoting factor, as described previously (34), and it elicited no in vitro cytotoxicities, local histopathological or vascular permeability-increasing reactions in the experimental animals (10).…”

Section: Methodsmentioning

confidence: 62%

“…1). Nevertheless, rCTB displays strong mucosal adjuvant properties (15,16,34,43); it has been reported that mutant CTs which have no or little enzyme activity of A subunit also retain mucosal adjuvanticity (41,42). Furthermore, rCTB induces no in vitro cytotoxicity and no local histopathological or vascular permeability-increasing reactions in the experimental animals (10).…”

Section: Cytokine Production By Mouse Spleen Cells Restimulated With mentioning

confidence: 99%

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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: Methodsmentioning

confidence: 62%

Section: Cytokine Production By Mouse Spleen Cells Restimulated With mentioning

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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“…Moreover, non-toxic B subunits of these toxins (CTB, LTB), which have strong binding capacity to GM 1 gangliosides, have been investigated about their adjuvanticity in these years and have been shown to induce both systemic and mucosal immune response in all mucosal tissues to some mucosally co-administered antigens (20,27,30). However, oral administration of CTB chemically coupled to antigens is known to induce tolerance, such as inhibition of acute GVHD and prevention of autoimmune diabetes (26,31).…”

Section: Discussionmentioning

confidence: 99%

Recombinant Cholera Toxin B Subunit Activates Dendritic Cells and Enhances Antitumor Immunity

Isomura

Yasuda

Tsujimura

et al. 2005

Microbiology and Immunology

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Activation of dendritic cells (DC) is crucial for priming of cytotoxic T lymphocytes (CTL), which have a critical role in tumor immunity, and it is considered that adjuvants are necessary for activation of DC and for enhancement of cellular immunity. In this study, we examined an adjuvant capacity of recombinant cholera toxin B subunit (rCTB), which is non‐toxic subunit of cholera toxin, on maturation of murine splenic DC. After the in vitro incubation of DC with rCTB, the expression of MHC class II and B7–2 on DC was upregulated and the secretion of IL‐12 from DC was enhanced. In addition, larger DC with longer dendrites were observed. These data suggest that rCTB induced DC maturation. Subsequently, we examined the induction of tumor immunity by rCTB‐treated DC by employing Meth A tumor cells in mice. Pretreatment with subcutaneous injection of rCTB‐treated DC pulsed with Meth A tumor lysate inhibited the growth of the tumor cells depending on the number of DC. Moreover, intratumoral injection of rCTB‐treated DC pulsed with tumor lysate had therapeutic effect against established Meth A tumor. Immunization with DC activated by rCTB and the tumor lysate increased number of CTL precursor recognizing Meth A tumor. The antitumor immune response was significantly inhibited in CD8+ T cell‐depleted mice, although substantial antitumor effect was observed in CD4+ T cell‐depleted mice. These results indicated that rCTB acts as an adjuvant to enhance antitumor immunity through DC maturation and that CD8+ T cells play a dominant role in the tumor immunity. Being considered to be safe, rCTB may be useful as an effective adjuvant to raise immunity for a tumor in clinical application.

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“…Recent studies of the adjuvant activity of recombinant B subunit have provided evidence that coadministration of CT-B or LT-B with Ag usually (but not always) enhances immune responses, especially when the two are given by an intranasal route (10,11,35). However, this adjuvant activity was considerably less than that of the holotoxin or, indeed, detoxified holotoxin in the few studies in which this comparison was made (33,36).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, even studies with recombinant CT-B (rCT-B) provide seemingly contradictory data. On the one hand, there seems to be little question that rCT-B can act as a mucosal adjuvant in that it enhances humoral (Ab) responses to Ag when both are administered by an intranasal route (10,11). On the other hand, there is also good evidence that rCT-B acts as an immunosuppressant: when conjugated to Ag, it enhances oral tolerance induced by the Ag (12)(13)(14); in addition, administration of nonrecombinant CT-B to nonobese diabetic mice delays the onset of diabetes in such mice and administration of rLT-B, a molecule structurally and functionally related to CT-B, prevents collageninduced arthritis (15,16).…”

Section: Holera Toxin (Ct)mentioning

confidence: 99%

Oral Administration of Recombinant Cholera Toxin Subunit B Inhibits IL-12-Mediated Murine Experimental (Trinitrobenzene Sulfonic Acid) Colitis

Boirivant

Fuss

Ferroni

et al. 2001

The Journal of Immunology

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Trinitrobenzene sulfonic acid (TNBS)-induced colitis is an IL-12-driven, Th1 T cell-mediated colitis that resembles human Crohn’s disease. In the present study, we showed initially that the oral administration of recombinant subunit B of cholera toxin (rCT-B) at the time of TNBS-induced colitis by intrarectal TNBS instillation inhibits the development of colitis or, at later time when TNBS-induced colitis is well established, brings about resolution of the colitis. Dose-response studies showed that a majority of mice (68%) treated with rCT-B at a dose of 100 μg (times four daily doses) exhibited complete inhibition of the development of colitis, whereas a minority (30%) treated with rCT-B at a dose of 10 μg (times four daily doses) exhibited complete inhibition; in both cases, however, the remaining mice exhibited some reduction in the severity of inflammation. In further studies, we showed that rCT-B administration is accompanied by prevention/reversal of increased IFN-γ secretion (the hallmark of a Th1 response) without at the same time causing an increase in IL-4 secretion. This decreased IFN-γ secretion was not associated with the up-regulation of the secretion of counterregulatory cytokines (IL-10 or TGF-β), but was associated with a marked inhibition of IL-12 secretion, i.e., the secretion of the cytokine driving the Th1 response. Finally, we showed that rCT-B administration results in increased apoptosis of lamina propria cells, an effect previously shown to be indicative of IL-12 deprivation. From these studies, rCT-B emerges as a powerful inhibitor of Th1 T cell-driven inflammation that can conceivably be applied to the treatment of Crohn’s disease.

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Recombinant cholera toxin B subunit acts as an adjuvant for the mucosal and systemic responses of mice to mucosally co-administered bovine serum albumin

Cited by 75 publications

References 26 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

Recombinant Cholera Toxin B Subunit Activates Dendritic Cells and Enhances Antitumor Immunity

Oral Administration of Recombinant Cholera Toxin Subunit B Inhibits IL-12-Mediated Murine Experimental (Trinitrobenzene Sulfonic Acid) Colitis

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