A nontoxic mutant of cholera toxin elicits Th2-type responses for enhanced mucosal immunity

Yamamoto, Shingo; Kiyono, Hiroshi; Yamamoto, Masafumi; Imaoka, Koichi; Yamamoto, Miho; Fujihashi, Kohtaro; Ginkel, Frederik W. van; Noda, Masatoshi; Takeda, Yoshifumi; McGhee, Jerry R.

doi:10.1073/pnas.94.10.5267

Cited by 290 publications

(292 citation statements)

References 37 publications

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“…Our results show robust expression of IFN-g, IL-2 and TNF-a in CD4 1 T cells after immunization with HEL and CT, whereas IL-4 and IL-5 were not detectable, which is in contrast with previous reports that indicated a Th2 cytokine response after ear immunization [10,11]; this also argues against the occurrence of dominant Th2 responses toward antigens that are coadministered with CT in mucosae [16,17]. In the skin, both Th1 and Th2 cytokines have been reported following immunization with OVA and CT [24].…”

Section: Discussioncontrasting

confidence: 99%

“…It has been reported that LCs remain in the epidermis for 48 h, even in the presence of Th1-polarizing adjuvants [7]. In our experiments, 24 h after CT or CTB inoculation in the ear, the number of LCs in the epidermis was reduced, suggesting that LCs could be mobilized from the dermis at this time point in the presence of strong adjuvants such as CT.Our results show robust expression of IFN-g, IL-2 and TNF-a in CD4 1 T cells after immunization with HEL and CT, whereas IL-4 and IL-5 were not detectable, which is in contrast with previous reports that indicated a Th2 cytokine response after ear immunization [10,11]; this also argues against the occurrence of dominant Th2 responses toward antigens that are coadministered with CT in mucosae [16,17]. In the skin, both Th1 and Th2 cytokines have been reported following immunization with OVA and CT [24].…”

contrasting

confidence: 89%

“…When administered in the mucosa, CT can elicit a Th2-type response that is based on the production of IL-4, IL-5 and IL-10 but virtually no IFN-g [16,17]. However, a mixed Th1/Th2 response that produces both IFN-g and IL-4 has also been observed [18], and the administration of ovalbumin (OVA) in combination with CT elicits a dominant Th17 response following intranasal immunization [19].…”

Section: Introductionmentioning

confidence: 99%

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Intradermal immunization in the ear with cholera toxin and its non‐toxic β subunit promotes efficient Th1 and Th17 differentiation dependent on migrating DCs

et al. 2011

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The nature of CD4 1 T-cell responses after skin immunization and the role of migrating DCs in the presence of adjuvants in the elicited response are interesting issues to be investigated. Here, we evaluated the priming of CD4 1 T cells following ear immunization with low doses of model antigens in combination with either cholera toxin (CT) or the non-toxic b CT subunit (CTB) as an adjuvant. Following immunization with CT, we found efficient antigen presentation that is reflected in the production of IFN-c and IL-17 by CD4 1 T cells over IL-4 or IL-5 production. The CTB-induced activation of DCs in the ear occurred without visible inflammation, which reflects a similar type of CD4 1 T-cell differentiation. In both cases, the elicited response was dependent on the presence of migrating skin cells. Remarkably, immunization with CT or with CTB led to the induction of a delayed-type hypersensitivity (DTH) response in the ear. The DTH response that was induced by CT immunization was dependent on IL-17 and partially dependent on IFN-c activity. These results indicate that both CT and CTB induce an efficient CD4 1 T-cell response to a co-administered antigen following ear immunization that is dependent on migrating DCs.Key words: DCs . Migrating DCs . Skin immunization Supporting Information available online IntroductionThe skin is the first line of defense against microbial pathogens. There is supporting evidence that DCs are crucial for the initiation, polarization and control of the adaptive immune response [1,2]. Efficient immunosurveillance in the skin is based upon the continuous traffic of cells from the skin to the draining lymph nodes. Although Langerhans cells (LCs) have been shown to be potent APCs in vitro [3], in vivo approaches have produced conflicting data regarding their role in T-cell priming [4,5]. Dermal DCs are also migrating DCs that colonize lymph nodes more rapidly than LCs [6,7], and different roles for skin DC subsets in T-cell priming have been reported [7][8][9]. Skin immunization has yielded controversial data, with some reports supporting a Th2-type response [10,11] and others a Th1-type response [12,13]. IL-17-producing CD4 1 T cells (Th17) have also been found after skin immunization [13,14]. 2894Cholera toxin (CT) has a strong adjuvant effect [15]. When administered in the mucosa, CT can elicit a Th2-type response that is based on the production of IL-4, IL-5 and IL-10 but virtually no 17]. However, a mixed Th1/Th2 response that produces both IFN-g and IL-4 has also been observed [18], and the administration of ovalbumin (OVA) in combination with CT elicits a dominant Th17 response following intranasal immunization [19]. This dominance of IL-17 was also observed in response to the CT b subunit (CTB). Although the precise mechanism for the adjuvant effect of CT is not completely understood, it appears that CTB targets DCs in vivo by binding to the cell membrane ganglioside GM1 [20]; moreover, the CT a subunit (CTA) triggers the PKA-mediated induction of cAMP, which plays a critical role ...

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Section: Discussioncontrasting

confidence: 99%

contrasting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

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Intradermal immunization in the ear with cholera toxin and its non‐toxic β subunit promotes efficient Th1 and Th17 differentiation dependent on migrating DCs

et al. 2011

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“…An alternative approach to circumvent this problem is the use of genetically detoxified heat labile enterotoxins of E. coli LTK63 or non-toxic mutant cholera toxin CT S61F. 125,134,135 The challenge currently faced by several laboratories is to discover whether or not the promising results obtained in the animal model can be reproduced in humans.…”

Section: Vaccination Development For Clinical Use and Future Of The Hmentioning

confidence: 99%

“…137 Additionally, the use of non-toxic LTK63 or CT S61F for oral vaccination induces a relatively greater Th2 cell response that can cure and prevent infection in H. felis/ mice models. 128,129,135,139 Thus, with the discovery of the appropriate formulation and routes of administration, it is possible that vaccination could trigger an immune response that differs substantially from that induced by natural infection with H. pylori. Undoubtedly, the continuous efforts of laboratories around the world to develop a vaccine and therapeutic approaches may soon bring an end to the long evolutionary relationship between humankind and Helicobacter pylori.…”

Section: Vaccination Development For Clinical Use and Future Of The Hmentioning

confidence: 99%

Helicobacter pylori: recent advances in the study of its pathogenicity and prevention

Aguilar¹,

Ayala²,

Fierros-Zarate³

2001

Salud pública Méx

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Helicobacter pylori has acquired great importance during the last two decades, after being recognized as an important pathogen that infects a great portion of the human population. This microorganism is recognized as the main causal agent of chronic gastritis and duodenal ulcers, and it is associated with the subsequent development of gastric carcinoma. The pathogenic mechanisms of H. pylori and their relation to gastric ailments have not been clearly defined. However, at present it is well established that urease, vacuolating cytotoxin VacA, and the pathogenicity island (cag PAI) gene products, are the main factors of virulence of this organism. Thus, individuals infected with strains that express these virulence factors probably develop a severe local inflammation that may induce the development of peptic ulcer and gastric cancer. The way the infection spreads throughout the world suggests the possibility that there are multiple pathways of transmission. Due to the importance that H. pylori has acquired as a human pathogen, laboratories worldwide are attempting to develop a vaccine that confers long-term immunological protection against infection by this microorganism. Hence, the objective of this review is to present the most relevant findings of the biology of H. Pylori and its interaction with the human host. The full version of this paper is available too at: http:// www.insp.mx/salud/index.html ResumenHelicobacter pylori ha adquirido gran importancia durante las últimas dos décadas, al ser reconocido como un importante patógeno que infecta una gran porción de la población humana. Este microrganismo es reconocido como el principal agente que causa la gastritis crónica y la úlcera duodenal, además de que se ha asociado con el subsecuente desarrollo del carcinoma gástrico. Los mecanismos patogé-nicos de H. pylori y su relación con los padecimientos gás-tricos no se han definido en forma clara. Sin embargo, actualmente está bien establecido que la ureasa, la citotoxina vacuolizante VacA y los productos de los genes de la isla de patogenicidad (cag PAI) son los principales factores de virulencia de este organismo. Así, los individuos infectados con cepas que expresan dichos factores de virulencia, probablemente manifiesten una marcada inflamación local que podría inducir el desarrollo de úlcera péptica y cáncer gástri-co. La manera como la infección se propaga a nivel mundial sugiere la posibilidad de múltiples vías de transmisión. A consecuencia de la importancia que H. pylori ha adquirido como patógeno humano, los laboratorios del mundo se esfuerzan para desarrollar una vacuna que confiera protección inmunológica de larga duración contra la infección por este microorganismo. El objetivo de esta revisión es presentar los hallazgos más relevantes sobre la biología de H. pylori y su interacción con su huésped humano. El texto completo de este artículo también está disponible en:

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Fibronectin-binding protein I ofStreptococcus pyogenes is a promising adjuvant for antigens delivered by mucosal route

et al. 1998

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A common problem in human vaccinology is the limited availability of efficient and non-toxic adjuvants capable of promoting mucosal responses. The potential usefulness of fibronectin-binding protein I (Sfbl) of Streptococcus pyogenes as immunological adjuvant was assessed using ovalbumin (OVA) as a model antigen. Mice were immunized by intranasal route, either with soluble OVA or OVA covalently coupled to Sfbl. Immunization with OVA-Sfbl resulted in the elicitation of about 100-fold higher titers of anti-OVA serum IgG than using OVA alone. The anti-OVA IgG subclass pattern was dominated in both groups of mice by IgG1, followed by IgG2b, IgG2a, and IgG3. Immunization with OVA-Sfbl also resulted in the elicitation of OVA-specific IgA in lung washes (24% of the total IgA), which was absent in mice immunized with OVA alone. Spleen cells from OVA-Sfbl-immunized mice also gave a much stronger proliferative response to restimulation with soluble OVA in vitro. Phenotypic analysis of proliferating cells showed an enrichment in CD4+ T cells, producing a pattern of cytokines (IL-4, IL-5, IL-6 and IL-10) characteristic of Th2-type cells. In contrast to immunization with soluble OVA alone, OVA-Sfbl induced the generation of CD8+ OVA-specific cytotoxic cells. These results demonstrate that Sfbl represents a promising mucosal adjuvant able to substantially improve cellular, humoral and mucosal responses when coupled to an antigen administered by intranasal route.

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A nontoxic mutant of cholera toxin elicits Th2-type responses for enhanced mucosal immunity

Abstract: We have characterized a nontoxic mutant of cholera toxin (

Cited by 290 publications

References 37 publications

Intradermal immunization in the ear with cholera toxin and its non‐toxic β subunit promotes efficient Th1 and Th17 differentiation dependent on migrating DCs

Intradermal immunization in the ear with cholera toxin and its non‐toxic β subunit promotes efficient Th1 and Th17 differentiation dependent on migrating DCs

Helicobacter pylori: recent advances in the study of its pathogenicity and prevention

Fibronectin-binding protein I ofStreptococcus pyogenes is a promising adjuvant for antigens delivered by mucosal route

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