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

Abstract

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...

Immune Modulation by Regulatory T Cells in Helicobacter pylori-Associated Diseases

“…Further studies have shown an accumulation of Treg in the stomach of H. pylori infected mice [179,180] and that depletion of Treg in C57BL/6 (H2 b ) mice using CD25 antibody in vivo followed by challenge with H. pylori bacteria results in enhanced inflammation and recruitment of T cells, macrophages, and B cells to the stomach compared to untreated infected WT mice [179]. These results are consistent with the role of Treg in suppressing H. pylori infection induced inflammation.…”

“…In the presence of TGF , IL-6 and IL-1 can polarize naïve T cells to a Th17 phenotype, while in the absence of the pro-inflammatory cytokines, TGF is important for the conversion of naïve T cells to iTreg as discussed above [172,173]. Thus, it can be envisaged that pro-and anti-inflammatory cytokines induced by H. pylori infection would lead to an accumulation of both Th17 cells and Treg in the stomach mucosa [142,[174][175][176][177][178][179][180][181]. Although most studies indicate that IL-17 is a pro-inflammatory cytokine, evidence suggests that IL-17 can be an effector cytokine in immunity to H. pylori infections [154,182,183].…”

A Double Mutant Heat-Labile Toxin from Escherichia coli, LT(R192G/L211A), Is an Effective Mucosal Adjuvant for Vaccination against Helicobacter pylori Infection

“…We and others have shown that, besides specific H. pylori antigens, an effective adjuvant is needed to induce protection against H. pylori infection after mucosal immunization (2,3). Thus, immunization with whole-cell or lysate preparations of H. pylori together with adjuvants such as cholera toxin (CT) or heat-labile toxin (LT) and in some cases also mutant forms of the toxins confers protection against H. pylori infection (2,4). CT, most often used in the preclinical evaluation of mucosal candidate vaccines, promotes strong T cell as well as B cell responses to vaccine components and is a golden standard for testing alternative mucosal adjuvants.…”

Helicobacter pylori Infection of the Gastric Mucosa

“…Functional studies in the H. pylori mouse model have also shown that Treg's may dampen effector T cell responses in the gastric mucosa and promote chronicity of the infection (Raghavan et al, 2003;Rad et al, 2006;Sayi et al, 2009;Becher et al, 2010). The mechanisms whereby Treg's mediate their suppressive effects during H. pylori infection could either be through cell contact dependent on CTLA-4 (Anderson et al, 2006) or secretion of the antiinflammatory cytokines (Matsumoto et al, 2005).…”