1. |
- Enarsson, Karin, 1975, et al.
(författare)
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Differential mechanisms for T lymphocyte recruitment in normal and neoplastic human gastric mucosa
- 2006
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Ingår i: Clin Immunol. - : Elsevier BV. ; 118:1, s. 24-34
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Forskningsöversikt (refereegranskat)abstract
- Worldwide, gastric adenocarcinoma (GC) is the second most common cause of death from malignant disease. The reason why immune responses are unable to clear the tumour is not fully understood, although aberrant lymphocyte recruitment to the tumour site might be one factor. Therefore, we investigated the homing phenotype of mucosal T lymphocytes in GC, compared to tumour-free mucosa. We could detect significantly decreased frequencies of mucosal homing alpha4beta7+ T cells in the tumour tissues and increased frequencies of L-selectin+ T cells. This was probably due to the correlated decrease in MAdCAM-1 positive and increase in PNAd positive blood vessels in the tumour mucosa. There were also fewer CXCR3+ T lymphocytes in the tumour tissue. These findings provide evidence that endothelial cells within tumours arising at mucosal sites do not support extravasation of typical mucosa-infiltrating T cells. This may be of major relevance for future immunotherapeutic strategies for treatment of GC.
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2. |
- Lundgren, Anna, 1974, et al.
(författare)
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Mucosal FOXP3-expressing CD4+ CD25high regulatory T cells in Helicobacter pylori-infected patients
- 2005
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Ingår i: Infect Immun. ; 73:1, s. 523-31
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Tidskriftsartikel (refereegranskat)abstract
- Helicobacter pylori chronically colonizes the stomach and duodenum and causes peptic ulcers or gastric adenocarcinoma in 10 to 20% of infected individuals. We hypothesize that the inability of patients to clear H. pylori infections is a consequence of active suppression of the immune response. Here we show that H. pylori-infected individuals have increased frequencies of CD4(+) CD25(high) T cells in both the stomach and duodenal mucosa compared to uninfected controls. These cells have the phenotype of regulatory T cells, as they express FOXP3, a key gene for the development and function of regulatory T cells, as well as high levels of the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) protein. In contrast, mucosal CD4(+) CD25(low) and CD4(+) CD25(-) cells express little FOXP3 mRNA and low levels of the CTLA-4 protein. Mucosal CD4(+) CD25(high) T cells are present in individuals with asymptomatic H. pylori infections as well as in duodenal ulcer patients. The frequencies of CD4(+) CD25(high) cells are also increased in the stomachs of H. pylori-infected patients with gastric adenocarcinoma, particularly in cancer-affected tissues. These findings suggest that regulatory T cells may suppress mucosal immune responses and thereby contribute to the persistence of H. pylori infections.
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3. |
- Strömberg, Erika, 1974, et al.
(författare)
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Down-regulation of epithelial IL-8 responses in Helicobacter pylori-infected duodenal ulcer patients depends on host factors, rather than bacterial factors
- 2005
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Ingår i: Clin Exp Immunol. - : Oxford University Press (OUP). ; 140:1, s. 117-25
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Tidskriftsartikel (refereegranskat)abstract
- Helicobacter pylori infection is one of the most common gastrointestinal infections worldwide. Although the majority of the infected individuals remain asymptomatic carriers of the bacteria, approximately 15% develop peptic ulcers, which are most prevalent in the duodenum. H. pylori induce a vigorous immune response which, however, fails to clear the infection. Instead, the chronic inflammation that arises in the infected gastroduodenal mucosa may be involved in the development of H. pylori-associated peptic ulcers. We have previously shown that duodenal ulcer (DU) patients have a significantly lower epithelial cytokine, e.g. IL-8, response in the duodenum than asymptomatic (AS) carriers. In this study we have further investigated the mechanisms behind this finding, i.e. whether it can be explained by bacterial factors, down-regulation of epithelial cytokine production by regulatory T cells, or an impaired ability of the duodenal epithelium in DU patients to produce cytokines. Gastric AGS, and intestinal T84 epithelial cell lines were stimulated with H. pylori strains isolated from DU patients and AS carriers, respectively. All strains were found to induce comparable cytokine and cytokine receptor expression in epithelial cells. Regulatory T cells (CD4+ CD25(high)), isolated from human peripheral blood and cocultured with H. pylori stimulated AGS cells, were found to slightly suppress H. pylori-induced epithelial cytokine production. Furthermore, primary cultures of duodenal epithelial cells from DU patients were found to produce markedly lower amounts of cytokines than epithelial cells isolated from AS carriers. These results suggest that the lower epithelial cytokine responses in the duodenum of DU patients, which may be of importance for the pathogenesis of H. pylori-induced duodenal ulcers, most likely can be explained by host factors, i.e. mainly a decreased ability of the duodenal epithelium to produce cytokines, but possibly partly also down-regulation by regulatory T cells.
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4. |
- Strömberg, Erika, 1974
(författare)
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Mucosal T-cell and cytokine responses in Helicobacter pylori-infected duodenal ulcer patients
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Helicobacter pylori colonizes the human stomach and areas of gastric metaplasia in the duodenum. The bacterium is the major cause of chronic active gastritis and peptic ulcer disease and is a risk factor for the development of gastric adenocarcinoma and lymphoma. However, the majority of those infected remain asymptomatic (AS) carriers of the bacteria, and only 10-15% develop duodenal ulcers (DU). It is still unknown which factors determine whether an individual will develop duodenal ulcer disease or remain an AS carrier, but bacterial factors as well as host immune responses are believed to be important for the outcome of infection. To evaluate the role of the immune response in the development of duodenal ulcers, we compared the mucosal T-cell and cytokine responses in DU patients, AS carriers, and uninfected individuals. Immunohistochemical analysis of the duodenal cytokine responses showed similar cytokine staining in normal and metaplastic duodenal mucosa of H. pylori-infected individuals. However, decreased levels of several cytokines, i.e. IL-8, IL-6, IL-1b, IFN-g and TGF-b were observed in the epithelium of duodenal biopsies from DU patients, as compared to from AS carriers and uninfected subjects. Analysis of freshly isolated duodenal epithelial cells further confirmed this finding, i.e. significantly lower levels of IL-8 were produced by cells from DU patients than from AS carriers. This was found to be due to properties of the epithelial cells rather than apoptosis, down-regulation by other immune cells or differences in bacterial strains. In the lamina propria of the duodenum, the number of cytokine positive mononuclear cells (MNCs) was found to be up-regulated in H. pylori-infected, as compared to uninfected individuals, but with similar levels in DU patients and AS carriers. Analysis of the T-cell responses in the duodenum and the antrum of the stomach showed increased infiltration of primarily CD4+ T cells in the antrum, whereas no differences in the number of T cells were found in the duodenum of H. pylori-infected and uninfected individuals. The expression of the activation markers CD69 and CD25 was found to be significantly higher in the antrum, and slightly increased in the duodenum of both H. pylori-infected AS carriers and DU patients. Flow cytometric analysis of isolated mucosal T cells revealed increased numbers of CD4+CD25high cells, i.e. regulatory T cells (Treg) in the antrum and duodenum of H. pylori-infected individuals, as compared to uninfected subjects. CTLA-4, a marker of Treg, was found to be highly expressed in the majority of these cells. Interestingly, when comparing the numbers of down-regulating CTLA-4+ cells in the duodenum of H. pylori-infected DU patients and AS carriers by immunohistochemistry, we observed significantly increased frequencies of these cells in the duodenal mucosa of DU patients. We speculate that these cells, at least in part, are regulatory T cells that may down-regulate the specific T-cell responses in the duodenal mucosa of DU patients. In conclusion, our results show that the immune responses in the duodenum against H. pylori may be down-regulated or suppressed in DU patients and may hence not be efficient enough to clear the infection, which consequently becomes chronic and may lead to the development of duodenal ulcers.
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