Absence of CD4+CD25+ regulatory T cells is associated with a loss of regulation leading to increased pathology in <i>Helicobacter pylori</i>-infected mice

Raghavan, Sukanya; Fredriksson, M.; Svennerholm, Ann Mari; Holmgren, Jan; Suri‐Payer, Elisabeth

doi:10.1046/j.1365-2249.2003.02177.x

Cited by 157 publications

(134 citation statements)

References 31 publications

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“…Kandulski et al reported that H. pylori-induced gastritis is associated with a recruitment of naturally occurring FOxP3(+) Treg cells that correlate with higher bacterial colonization and increased mucosal TGFβ1 expression, suggesting that H. pylori infection suppresses the maintenance and aggravation of gastric inflammation by activating the TGFβ1-FoxP-CD4 + CD25 high Treg pathway (16). A similar phenomenon was observed in other animal studies (17,18). Based on the above studies, we inferred that TGFβ1 plays an important role in the inhibition of H. pylori-induced gastritis.…”

Section: Discussionsupporting

confidence: 56%

Association between the TGFB1 -509C/T and TGFBR2 -875A/G polymorphisms and gastric cancer: a case-control study

Zeng

Chen

et al. 2011

Oncology Letters

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Abstract.The transforming growth factor-β (TGFβ) pathway plays an important role in various types of human cancer. However, the role of TGFB1 -509C/T and TGFBR2 -875A/G polymorphisms in gastric cancer is controversial. We aimed to investigate the associations between these polymorphisms and gastric cancer susceptibility, clinicopathological parameters and survival. A case-control study was conducted in 1,010 gastric cancer patients and 1,500 healthy controls. Genotypes were determined by PCR-restriction fragment length polymorphism and DNA sequencing. Compared with the TT genotype, the TGFB1 -509 C allele (CT/CC) was significantly associated with a reduced risk of gastric cancer (OR, 0.71; 95% CI, 0.58-0.87; P=0.001) and certain subtypes of gastric cancer including intestinal type (OR, 0.70; 95% CI, 0.57-0.87; P=0.001), poorly differentiated (OR, 0.67; 95% CI, 0.54-0.85; P=0.001) and stage TNM III+IV (OR, 0.73; 95% CI, 0.58-0.92; P=0.008). Compared with the TGFBR2 -875 GG genotype, carriers of the A allele (AA/AG) had a significantly decreased gastric cancer risk (OR, 0.58; 95% CI, P<0.001). A combination of the TGFB1 -509 C and TGFBR2 -875 A alleles was associated with a further decreased risk of gastric cancer (OR, 0.42; 95% CI, 0.32-0.57, P<0.001). No significant correlation was observed between polymorphisms and survival of gastric cancer patients. Our results suggest that both the TGFB1 -509 and TGFBR2 -875 polymorphisms contribute to a decreased gastric cancer risk. The TGFB1 -509 polymorphism affects certain subtypes of gastric cancer according to clinicopathological parameters. A combination of the TGFB1 -509 C and TGFBR2 -875 A alleles conferred a further decreased gastric cancer risk. These findings provide clues to the biological mechanisms that underline tumor heterogeneity.

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Section: Discussionsupporting

confidence: 56%

Association between the TGFB1 -509C/T and TGFBR2 -875A/G polymorphisms and gastric cancer: a case-control study

Zeng

Chen

et al. 2011

Oncology Letters

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“…Treg appear to induce anergy of gastric CD4 1 T cells by interfering with the costimulation of TCR in a mechanism that depends on CTLA-4 expression by Treg [51]. In mice, adoptive transfer of CD4 1 T cells depleted of the Treg subset in athymic nu/nu mice leads to decreased H. pylori numbers after challenge, and increased inflammation compared with transfer of both CD4 1 T cells and Treg [52]. Depletion of Treg in C57BL/6 mice infected with H. pylori resulted in increased gastritis and reduced bacterial numbers and a strong Th1 response [19].…”

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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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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“…This might be related to suppression of immune responses by regulatory T (Treg) cells. Recent studies have shown that Treg cells can restrict memory CD8+ T cell responses and suppress inflammation [41,42]. Furthermore, it has been shown that Treg cells express toll-like receptor 4 (TLR-4) and are activated by LPS [43].…”

Section: Discussionmentioning

confidence: 99%

Effects of a Th1- versus a Th2-biased immune response in protection against Helicobacter pylori challenge in mice

Taylor

Ziman

Canfield

et al. 2008

Microbial Pathogenesis

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The roles that T helper type 1 (Th1) and T helper type 2 (Th2) H. pylori specific immune responses play in protection from H. pylori challenge are poorly understood. It is expected that Th2 immune responses are required for protection against extracellular bacteria, such as H. pylori. However, recent studies have suggested that Th1 immunity is required for protection. The mechanisms by which this might occur are unknown. Our goal in this study was to more clearly define the effects of a Th1 vs. a Th2 promoting H. pylori vaccine on immunity and protection. Therefore, we tested a Th1 vaccine consisting of an H. pylori sonicate and CpG oligonucleotides (CpG) and a Th2 vaccine consisting of a lipopolysaccharide (LPS) depleted H. pylori sonicate combined with cholera toxin (CT). We demonstrate that although the Th2 promoting vaccine induced stronger systemic and local immune responses, only the Th1 promoting vaccine was protective.

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Absence of CD4+CD25+ regulatory T cells is associated with a loss of regulation leading to increased pathology in Helicobacter pylori-infected mice

Cited by 157 publications

References 31 publications

Association between the TGFB1 -509C/T and TGFBR2 -875A/G polymorphisms and gastric cancer: a case-control study

Association between the TGFB1 -509C/T and TGFBR2 -875A/G polymorphisms and gastric cancer: a case-control study

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

Effects of a Th1- versus a Th2-biased immune response in protection against Helicobacter pylori challenge in mice

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