| 1. |
- Akter, S., et al.
(author)
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The frequency of circulating integrin alpha 4 beta 7(+) cells correlates with protection against Helicobacter pylori infection in immunized mice
- 2019
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In: Helicobacter. - : Wiley. - 1083-4389 .- 1523-5378. ; 24:6
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Journal article (peer-reviewed)abstract
- Background Chronic Helicobacter pylori infection is the cause of peptic ulcers in a subpopulation of individuals and a risk factor for the development of gastric cancer. A vaccine against H pylori infection can prevent the acquisition of the infection and protect against reinfections. Clinical trials to date evaluating the efficacy of H pylori vaccines in human challenge models have shown moderate to poor protection with difficulties in predicting efficacy. Thus, while further studies are needed to design an effective vaccine, we also need to find relevant correlates for vaccine efficacy. Objective To find immune correlates to vaccine efficacy, the frequencies of neutrophils, eosinophils and inflammatory monocytes and CD4(+) T-cell memory and mucosa homing integrin alpha 4 beta 7(+) cells were assessed by flow cytometry in the blood of mice after vaccination. Materials and Methods H pylori antigens and cholera toxin or the multiple mutant CT (mmCT) were administered via the sublingual (SL) and intragastric route (IG). The vaccinated mice were infected with H pylori strain SS1 bacteria, and colonization in the stomach and immune responses were evaluated. Results The H pylori vaccine was effective in reducing bacterial load in the stomach of mice and enhancing immune responses compared to unvaccinated infection controls. In the blood of mice after SL or IG route of vaccination, we observed changes in frequencies of innate and adaptive immune cell subsets compared to infection controls. Remarkably, the frequency of circulating mucosal homing alpha 4 beta 7(+)CD4(+) T cells after vaccination correlated with low bacterial load in the stomach of individual mice irrespective of the immunization route. Conclusions Our study shows that the innate and adaptive immune cell subsets can be measured in the blood after vaccination and that increased frequency of alpha 4 beta 7(+)CD4(+) in the blood after immunization could be used as a predictive marker for the efficacy of vaccine against H pylori infection.
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| 2. |
- Sjökvist Ottsjö, Louise, 1986, et al.
(author)
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Defining the Roles of IFN-gamma and IL-17A in Inflammation and Protection against Helicobacter pylori Infection
- 2015
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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:7
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Journal article (peer-reviewed)abstract
- CD4(+) T cells have been shown to be essential for vaccine-induced protection against Helicobacter pylori infection. However, the effector mechanisms leading to reductions in the gastric bacterial loads of vaccinated mice remain unclear. We have investigated the function of IFN-gamma and IL-17A for vaccine-induced protection and inflammation (gastritis) using IFN-gamma-gene-knockout (IFN-gamma(-/-)) mice, after sublingual or intragastric immunization with H. pylori lysate antigens and cholera toxin. Bacteria were enumerated in the stomachs of mice and related to the gastritis score and cellular immune responses. We report that sublingually and intragastrically immunized IFN-gamma(-/-) mice had significantly reduced bacterial loads similar to immunized wild-type mice compared to respective unimmunized infection controls. The reduction in bacterial loads in sublingually and intragastrically immunized IFN-gamma(-/-) mice was associated with significantly higher levels of IL-17A in stomach extracts and lower gastritis scores compared with immunized wild-type mice. To study the role of IL-17A for vaccine-induced protection in sublingually immunized IFN-gamma(-/-) mice, IL-17A was neutralized in vivo at the time of infection. Remarkably, the neutralization of IL-17A in sublingually immunized IFN-gamma(-/-) mice completely abolished protection against H. pylori infection and the mild gastritis. In summary, our results suggest that IFN-gamma responses in the stomach of sublingually immunized mice promote vaccine-induced gastritis, after infection with H. pylori but that IL-17A primarily functions to reduce the bacterial load.
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| 3. |
- Sjökvist Ottsjö, Louise, 1986, et al.
(author)
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Induction of mucosal immune responses against Helicobacter pylori infection after sublingual and intragastric route of immunization
- 2017
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In: Immunology. - : Wiley. - 0019-2805. ; 150:2, s. 172-183
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Journal article (peer-reviewed)abstract
- There is a current lack of effective mucosal vaccines against major gastroenteric pathogens and particularly against Helicobacter pylori, which causes a chronic infection that can lead to peptic ulcers and gastric cancer in a subpopulation of infected individuals. Mucosal CD4(+) T-cell responses have been shown to be essential for vaccine-induced protection against H. pylori infection. The current study addresses the influence of the adjuvant and site of mucosal immunization on early CD4(+) T-cell priming to H. pylori antigens. The vaccine formulation consisted of H. pylori lysate antigens and mucosal adjuvants, cholera toxin (CT) or a detoxified double-mutant heat-labile enterotoxin from Escherichia coli (dmLT), which were administered by either the sublingual or intragastric route. We report that in vitro, adjuvants CT and dmLT induce up-regulation of pro-inflammatory gene expression in purified dendritic cells and enhance the H. pylori-specific CD4(+) T-cell response including interleukin-17A (IL-17A), interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha) secretion. In vivo, sublingual immunization led to an increased frequency of IL-17A(+), IFN-gamma(+) and TNF-alpha(+) secreting CD4(+) T cells in the cervical lymph nodes compared with in the mesenteric lymph nodes after intragastric immunization. Subsequently, IL-17A(+) cells were visualized in the stomach of sublingually immunized and challenged mice. In summary, our results suggest that addition of an adjuvant to the vaccine clearly activated dendritic cells, which in turn, enhanced CD4(+) T-cell cytokines IL-17A, IFN-gamma and TNF-alpha responses, particularly in the cervical lymph nodes after sublingual vaccination.
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| 4. |
- Sjökvist Ottsjö, Louise, 1986, et al.
(author)
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The role of IL-17A and IFN gamma in vaccine-induced protection against Helicobacter pylori infection
- 2014
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In: Cytokine. - : Elsevier BV. - 1043-4666 .- 1096-0023. ; 70:1, s. 65-65
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Conference paper (peer-reviewed)abstract
- The aim of the project was to evaluate mechanisms of vaccine-induced protection against Helicobacter pylori infection in mice. In particular, to elucidate the role of cytokines induced by H. pylori infection in promoting the protective or pathogenic immune responses in the stomach. Our group has previously shown that sublingual (SL; under the tongue) vaccination with H. pylori antigens and cholera toxin as an adjuvant was efficient in reducing the bacterial load in the stomach of mice with enhanced IFNγ and IL-17A responses in the stomach compared to unvaccinated mice. Using gene knockout mice and neutralizing antibodies, the impact of cytokines IFNγ and IL-17A on the bacterial load, immune responses and gastric inflammation was addressed. We report that after SL vaccination, IFNγ gene knockout (IFNγ−/−) mice were protected against H. pylori infection and had elevated IL-17A production and lower inflammation scores in the stomach compared to vaccinated wild-type mice. Furthermore, in vivo neutralization of IL-17A in sublingually vaccinated IFNγ−/−mice totally abrogated protection against H. pylori infection. We next examined the mechanisms for induction and maintenance of IL −17A after SL vaccination by studying the role of cytokines IL−1β and IL-23 using gene knockout mice either lacking IL-1 signaling or IL-23 production respectively. Our results show that after SL vaccination with H. pylori antigens and cholera toxin, IL-23p19−/− mice, but not IL-1RI−/− mice were protected against H. pylori infection. Gastric IL-17A responses could not be induced after challenge in the absence of IL-1 signaling, but could be maintained in the absence of IL-23. In summary, we report that IL-17A is important in reducing the bacterial load on the stomach of vaccinated mice which is dependent on intact IL-1 signaling, while IFNγ may promote inflammation. Based on our results, mechanisms of vaccine-induced protection against H. pylori infection and the role of specific cytokines will be discussed.
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| 5. |
- Walduck, A., et al.
(author)
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Inflammation, Immunity, and Vaccines for Helicobacter pylori Infection
- 2015
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In: Helicobacter. - : Wiley. - 1083-4389. ; 20:Supplement: 1 Special Issue: SI, s. 17-25
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Research review (peer-reviewed)abstract
- During the last year, a variety of studies have been published that increases our understanding of the basic mechanisms of immunity and inflammation in Helicobacter pylori infection and progression to gastric cancer. Innate immune regulation and epithelial cell response were covered by several studies that contribute with new insights in the host response to H. pylori infection. Also, the adaptive immune response to H. pylori and particularly the role of IL-22 have been addressed in some studies. These advances may improve vaccine development where new strategies have been published. Two major studies analyzed H. pylori genomes of 39 worldwide strains and looked at the protein profiles. In addition, multi-epitope vaccines for therapeutic use have been investigated. Studies on different adjuvants and delivery systems have also given us new insights. This review presents articles from the last year that reveal detailed insight into immunity and regulation of inflammation, the contribution of immune cells to the development of gastric cancer, and understanding mechanisms of vaccine-induced protection.
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| 6. |
- Walduck, A. K., et al.
(author)
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Immunity and Vaccine Development Against Helicobacter pylori
- 2019
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In: Advances in experimental medicine and biology. - Cham : Springer. - 0065-2598. - 9783030219154 ; , s. 257-275
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Book chapter (other academic/artistic)abstract
- Helicobacter pylori is a highly-adapted gastrointestinal pathogen of humans and the immunology of this chronic infection is extremely complex. Despite the availability of antibiotic therapy, the global incidence of H. pylori infection remains high, particularly in low to middle-income nations. Failure of therapy and the spread of antibiotic resistance among the bacteria are significant problems and provide impetus for the development of new therapies and vaccines to treat or prevent gastric ulcer, and gastric carcinoma. The expansion of knowledge on gastric conventional and regulatory T cell responses, and the role of TH17 in chronic gastritis from studies in mouse models and patients have provided valuable insights into how gastritis is initiated and maintained. The development of human challenge models for testing candidate vaccines has meant a unique opportunity to study acute infection, but the field of vaccine development has not progressed as rapidly as anticipated. One clear lesson learned from previous studies is that we need a better understanding of the immune suppressive mechanisms in vivo to be able to design vaccine strategies. There is still an urgent need to identify practical surrogate markers of protection that could be deployed in future field vaccine trials. Important developments in our understanding of the chronic inflammatory response, progress and problems arising from human studies, and an outlook for the future of clinical vaccine trials will be discussed.
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