Immunization of Mice with Urease Vaccine Affords Protection against <i>Helicobacter pylori</i> Infection in the Absence of Antibodies and Is Mediated by MHC Class II–restricted Responses

Ermak, Thomas H.; Giannasca, Paul J.; Nichols, Richard A.; Myers, Gene; Nedrud, John G.; Weltzin, Richard; Lee, Cynthia; Kleanthous, Harold; Monath, Thomas P.

doi:10.1084/jem.188.12.2277

Cited by 366 publications

(351 citation statements)

References 46 publications

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“…Other workers have reported increased gastric neutrophil infiltration in vaccinated mice [28,38]and it has not been clarified whether this represents a mechanism or a byproduct of the inflammatory response. Velin et al reported that depletion of neutrophils had no effect on protection in vaccinated mice challenged with H. felis [43].…”

Section: Discussionmentioning

confidence: 99%

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Local recall responses in the stomach involving reduced regulation and expanded help mediate vaccine‐induced protection against Helicobacter pylori in mice

Becher¹,

Deutscher²,

Simpfendorfer³

et al. 2010

Eur J Immunol

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Helicobacter pylori is recognised as the chief cause of chronic gastritis, ulcers and gastric cancer in humans. With increased incidence of treatment failure and antibiotic resistance, development of prophylactic or therapeutic vaccination is a desirable alternative. Although the results of vaccination studies in animal models have been promising, studies in human volunteers have revealed problems such as 'post-immunisation gastritis' and comparatively poor responses to vaccine antigens. The focus of this study was to compare the gastric and systemic cellular immune responses induced by recombinant attenuated Salmonella Typhimurium-based vaccination in the C57BL/6 model of H. pylori infection. Analysis of lymphocyte populations in the gastric mucosa, blood, spleen, paragastric LN and MLN revealed that the effects of vaccination were largely confined to the parenchymal stomach rather than lymphoid organs. Vaccine-induced protection was correlated with an augmented local recall response in the gastric mucosa, with increased proportions of CD4 1 T cells, neutrophils and reduced proportions of CD4 1 Treg. CD4 1 T cells isolated from the stomachs of vaccinated mice proliferated ex vivo in response to H. pylori antigen, and secreted Th1 cytokines, particularly IFN-c. This detailed analysis of local gastric immune responses provides insight into the mechanism of vaccine-induced protection.Key words: Helicobacter pylori . Stomach . Treg cells . Vaccine IntroductionHelicobacter pylori is a Gram-negative spiral bacterium that infects the mucous gel layer of the human stomach. Infection is chronic and causes a range of diseases ranging from acute to chronic gastritis, ulcers and, in a small proportion of patients, gastric adenocarcinoma [1].The treatment of H. pylori disease is not straightforward. The most commonly used combination antibiotic therapy, amoxicillin plus clathromycin and a proton pump inhibitor, now only achieve a cure in o80% of cases [2]. This efficacy rate is substantially less than the 495% rate that is deemed acceptable for most other infectious diseases. A prophylactic or therapeutic vaccine would be a cost-effective way to control H. pylori-induced disease.Vaccination is effective in animal models, with 10-to 100-fold reductions (but not sterile immunity) in bacterial colonisation reported in a variety of experimental animals, following immunisation by either oral or parenteral routes (reviewed in [3][4][5]). Oral (mucosal route) vaccination is desirable for a human H. pylori vaccine because of the ease of delivery and, for a live vaccine, the necessity of a single dose is also attractive. 2778with issues such as poor immunogenicity [6], and adverse reactions [7], presenting serious obstacles to further progression of a human vaccine [8]. The reasons for this failure probably result from apparently opposing aspects of the immune response to vaccination. On the one hand vaccination causes 'post-immunisation gastritis' a local inflammatory responses in the stomach in many animal and human recipients, a...

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Section: Discussionmentioning

confidence: 99%

“…However, the key role of Th1 cells in inducing the secretion of IgG by activated plasma cells or the activation of macrophage killing appear to be dispensable for protection [37][38][39]. Immunity might be facilitated by as yet unknown effector mechanisms and it is important to explore novel cell types or molecules in immunity to this end.…”

Section: Discussionmentioning

confidence: 99%

Local recall responses in the stomach involving reduced regulation and expanded help mediate vaccine‐induced protection against Helicobacter pylori in mice

Becher¹,

Deutscher²,

Simpfendorfer³

et al. 2010

Eur J Immunol

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“…In the present study IL-18 Ϫ/Ϫ mice exhibited a reduction in splenic as well as gastric IFN-␥ production. We and others have documented that well-protected WT mice have increased numbers of CD4 ϩ T cells infiltrating the gastric mucosa (6,8,18,47,48). Therefore, one would hypothesize that local production of IFN-␥ is a key element in T cell-mediated protection against H. pylori infection.…”

Section: Discussionmentioning

confidence: 99%

Vaccine-Induced Immunity againstHelicobacter pyloriInfection Is Impaired in IL-18-Deficient Mice

Akhiani

Schön

Lycke

2004

The Journal of Immunology

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Protective immunity against Helicobacter pylori infection in mice has been associated with a strong Th1 response, involving IL-12 as well as IFN-γ, but recent studies have also demonstrated prominent eosinophilic infiltration, possibly linked to local Th2 activity in the gastric mucosa. In this study we investigated the role of IL-18, because this cytokine has been found to be a coregulator of Th1 development as well as involved in Th2-type responses with local eotaxin production that could influence gastric eosinophilia and resistance to infection. We found that IL-18−/− mice failed to develop protection after oral immunization with H. pylori lysate and cholera toxin adjuvant, indicating an important role of IL-18 in protection. Well-protected C57BL/6 wild-type (WT) mice demonstrated substantial influx of CD4+ T cells and eosinophilic cells in the gastric mucosa, whereas IL-18−/− mice had less gastritis, few CD4+ T cells, and significantly reduced numbers of eosinophilic cells. T cells in well-protected WT mice produced increased levels of IFN-γ and IL-18 to recall Ag. By contrast, unprotected IL-18−/− mice exhibited significantly reduced gastric IFN-γ and specific IgG2a Ab levels. Despite differences in gastric eosinophilic cell infiltration, protected WT and unprotected IL-18−/− mice had comparable levels of local eotaxin, suggesting that IL-18 influences protection via Th1 development and IFN-γ production rather than through promoting local production of eotaxin and eosinophilic cell infiltration.

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“…Also, the fact that post-immunization gastritis, seen in well-protected mice, is usually correlated with a strong local IgG response in the gastric mucosa (24) reveals the unfavorable effect of humoral immunity against H. pylori. In addition, it has been shown that H. pylori-specifi c circulating antibodies failed to protect against H. pylori infection (9). Moreover, B-cell defi cient mice were fully protected by challenging with H. pylori (3).…”

Section: Methodsmentioning

confidence: 99%

Augmentation of Helicobacter pylori urease activity by its specific IgG antibody: implications for bacterial colonization enhancement

et al. 2005

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Gastric colonization of Helicobacter pylori (H. pylori) occurs in a very early age via infected mothers having H. pylori-specifi c IgG antibodies that would be transplacentally transferred to infants. In addition, H. pylori urease-specifi c IgG was associated with chronic gastric atrophy and post-immunization gastritis is usually correlated with a strong local IgG response. These fi ndings indicate that H. pylori-specifi c IgG antibodies, in particular its urease-specifi c IgG, may induce unfavorable infl uence on host resistance against H. pylori. Here, we show that we have found a unique H. pylori urease-specifi c IgG monoclonal antibody (MAb), termed S3, recognizing the conformational structure of the small subunit Ure-A, which enhanced the urease enzymatic activity.

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Immunization of Mice with Urease Vaccine Affords Protection against Helicobacter pylori Infection in the Absence of Antibodies and Is Mediated by MHC Class II–restricted Responses

Cited by 366 publications

References 46 publications

Local recall responses in the stomach involving reduced regulation and expanded help mediate vaccine‐induced protection against Helicobacter pylori in mice

Local recall responses in the stomach involving reduced regulation and expanded help mediate vaccine‐induced protection against Helicobacter pylori in mice

Vaccine-Induced Immunity againstHelicobacter pyloriInfection Is Impaired in IL-18-Deficient Mice

Augmentation of Helicobacter pylori urease activity by its specific IgG antibody: implications for bacterial colonization enhancement

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