Mechanisms for Mucosal Immunogenicity and Adjuvancy of Escherichia coli Labile Enterotoxin

Takahashi, Ichiro; Marinaro, Mariarosaria; Kiyono, Hiroshi; Jackson, Raymond J.; Nakagawa, Ichirô; Fujihashi, Kohtaro; Hamada, Shigeyuki; Clements, John D.; Bost, Kenneth L.; McGhee, Jerry R.

doi:10.1093/infdis/173.3.627

Cited by 165 publications

(114 citation statements)

References 32 publications

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“…LTS63Y as well as wild-type LT induced antigen-specific IgG1, IgG2a and IgG2b responses by IN immunization, indicating that LTS63Y may promote both Th1-and Th2-type responses. This result is consistent with the general pattern of T-cell help induced by LT described by other workers who have studied the cytokines such as INF-γ and IL-5, released by T cells taken from mice following immunization with LT as a mucosal adjuvant (Takahashi et al, 1996). In contrast, LT∆110/112 as well as wild-type LT induced predominant IgG1 responses following IG immunization, which more closely resembled the Th2-type responses induced by CT (Snapper et al, 1993;Marinaro et al, 1995;Douce et al, 1997).…”

Section: Discussionsupporting

confidence: 92%

“…As shown in Figure 3B, LTS63Y induced IgG1, IgG2a and IgG2b subclass antibody responses to H. pylori urease, which is consistent with a previous report suggesting that antibody response profiles induced by LT are regulated by both CD4 + Th1 and Th2 cell types (Takahashi et al, 1996). These results were quite different from the IgG subclass response (predominantly IgG1) induced by LT∆110/112 via the IG route ( Figure 3A).…”

Section: Mucosal Adjuvanticity Of Mutant Lts In In Immunizationsupporting

confidence: 90%

“…Urease antibody responses enhanced by LT∆110/112 were largely restricted to IgG1 rather than IgG2a or IgG2b subclass in sera, and similar antibody patterns were observed using wild-type LT as an adjuvant ( Figure 3A). This pattern was not consistent with the immune responses induced by wild-type LT in previous reports, but rather resembled the responses induced by activation of CD4 + Th2-type cells by CT (Munoz et al, 1990;Marinaro et al, 1995;Takahashi et al, 1996;Yamamoto et al, 1997a).…”

Section: Mucosal Adjuvanticity Of Mutant Lts In Ig Immunizationcontrasting

confidence: 59%

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The mucosal adjuvanticity of two nontoxic mutants of Escherichia coli heat-labile enterotoxin varies with immunization routes

Park¹,

Chang²,

Kim³

et al. 2000

Exp Mol Med

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Escherichia coli heat-labile enterotoxin (LT), which causes a characteristic diarrhea in humans and animals, is a strong mucosal immunogen and has powerful mucosal adjuvant activity towards coadministered unrelated antigens. Here we report the different mucosal adjuvanticity of nontoxic LT derivatives, LTS63Y and LT∆110/112, generated by immunizing through two different mucosal routes. Intragastric (

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Section: Discussionsupporting

confidence: 92%

Section: Mucosal Adjuvanticity Of Mutant Lts In In Immunizationsupporting

confidence: 90%

Section: Mucosal Adjuvanticity Of Mutant Lts In Ig Immunizationcontrasting

confidence: 59%

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The mucosal adjuvanticity of two nontoxic mutants of Escherichia coli heat-labile enterotoxin varies with immunization routes

Park¹,

Chang²,

Kim³

et al. 2000

Exp Mol Med

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“…Both the cholera toxin (CT) from Vibrio cholerae and heat-labile enterotoxin (LT) from ETEC belong to the most potent mucosal adjuvants and immunogens known to date by oral and other mucosal routes, where most of antigens are unable to induce immune responses (Jackson et al, 1993;Takahashi et al, 1996). However, their toxi-cities have precluded usages in human (Douce et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Development of two novel nontoxic mutants of Escherichia coli heat-labile enterotoxin

Park¹,

Chang²,

Kim³

et al. 1999

Exp Mol Med

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Abbreviations: ETEC, enterotoxigenic Escherichia coli; LT, Escherichia c o l i h e a t -l a b i l e enterotoxin; CT, cholera toxin; GM 1, monosialoganglioside; ELISA, enzyme-linked immunosorbent assay AbstractEscherichia coli heat-labile enterotoxin (LT) is composed of catalytic A and non-catalytic homo-pentameric B subunits and causes diarrheal disease in human and animals. In order to produce a nontoxic LT for vaccine and adjuvant development, two novel derivatives of LT were constructed by a site-directed mutagenesis of A subunit; Ser 6 3 to Ty r 6 3 in LTS63Y and Glu 11 0 , G l u 11 2 were deleted in LT 11 0 / 112. The purified mutant LTs (mLTs) showed a similar molecular structural complex as AB 5 to that of wild LT. In contrast to wild-type LT, mLTs failed to induce either elongation activity, ADP-ribosyltransferase activity, cAMP synthesis in CHO cells or fluid accumulation in mouse small intestine in vivo. Mice immunized with m LTs either intragastrically or intranasally elicited high titers of LT-specific serum and mucosal antibodies comparable to those induced by wild-type LT. These results indicate that substitution of Ser 63 to Ty r 6 3 or deletion of Glu 11 0 and Glu 11 2 eliminate the toxicity of LT without a change of AB 5 conformation, and both mutants are immunogenic to LT itself. Therefore, both mLTs may be used to develop novel anti-diarrheal vaccines against enterotoxigenic E. coli.

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“…Therefore, it was of interest to determine the adjuvanticity of a mutant form of Escherichia. coli labile toxin (LT), which should lack these detrimental qualities (23)(24)(25)(26)(27)(28). Accordingly, we examined the mutant LT (designated as LT(R192G); see Refs.…”

mentioning

confidence: 99%

Interplay of Cytokines and Adjuvants in the Regulation of Mucosal and Systemic HIV-Specific CTL

Belyakov

Ahlers

Clements

et al. 2000

The Journal of Immunology

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We examined the interplay between cytokines and adjuvants to optimize the induction of CTL by a mucosal HIV peptide vaccine. We show synergy between IL-12 and GM-CSF when administered together with the HIV peptide PCLUS3–18IIIB and cholera toxin (CT) in the induction of CTL activity and protection against mucosal viral transmission. Further, we examine the efficacy of mutant Escherichia coli labile toxin, LT(R192G), as a less toxic adjuvant than CT. LT(R192G) was as effective as or more effective than CT at inducing a mucosal CTL response. Moreover, LT(R192G) was as effective without IL-12 as CT was when combined with IL-12, and the response elicited by LT(R192G) with the vaccine was not further enhanced by the addition of IL-12. GM-CSF synergized with LT(R192G) without exogenous IL-12. Therefore, LT(R192G) may induce a more favorable cytokine response by not inhibiting IL-12 production. In particular, less IL-4 is made after LT(R192G) than CT immunization, and the response is less susceptible to anti-IL-12 inhibition. Thus, the choice of mucosal adjuvant affects the cytokine environment, and the mucosal response and protection can be enhanced by manipulating the cytokine environment with synergistic cytokine combinations incorporated in the vaccine.

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Mechanisms for Mucosal Immunogenicity and Adjuvancy of Escherichia coli Labile Enterotoxin

Cited by 165 publications

References 32 publications

The mucosal adjuvanticity of two nontoxic mutants of Escherichia coli heat-labile enterotoxin varies with immunization routes

The mucosal adjuvanticity of two nontoxic mutants of Escherichia coli heat-labile enterotoxin varies with immunization routes

Development of two novel nontoxic mutants of Escherichia coli heat-labile enterotoxin

Interplay of Cytokines and Adjuvants in the Regulation of Mucosal and Systemic HIV-Specific CTL

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