| 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. |
- Brisslert, Mikael, 1974, et al.
(författare)
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Helicobacter pylori induce neutrophil transendothelial migration: role of the bacterial HP-NAP
- 2005
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Ingår i: FEMS Microbiol Lett. ; 249:1, s. 95-103
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Tidskriftsartikel (refereegranskat)abstract
- Continuous recruitment of neutrophils into the inflamed gastric mucosal tissue is a hallmark of Helicobacter pylori infection in humans. In this study, we examined the ability of H. pylori to induce transendothelial migration of neutrophils using a transwell system consisting of a cultured monolayer of human endothelial cells as barrier between two chambers. We showed for the first time that live H. pylori, but not formalin-killed bacteria, induced a significantly increased transendothelial migration of neutrophils. H. pylori conditioned culture medium also induced significantly increased transendothelial migration, whereas heat-inactivated culture filtrates had no effect, suggesting that the chemotactic factor was proteinaceous. Depletion of H. pylori-neutrophil activating protein (HP-NAP) from the culture filtrates resulted in significant reduction of the transmigration. Culture filtrates from isogenic HP-NAP deficient mutant bacteria also induced significantly less neutrophil migration than culture filtrates obtained from wild-type bacteria. HP-NAP did not induce endothelial cell activation, suggesting that HP-NAP acts directly on the neutrophils. In conclusion, our results demonstrate that secreted HP-NAP is one of the factors resulting in H. pylori induced neutrophil transendothelial migration. We propose that HP-NAP contributes to the continuous recruitment of neutrophils to the gastric mucosa of H. pylori infected individuals.
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| 3. |
- Enarsson, Karin, 1975, et al.
(författare)
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CD4+ CD25high regulatory T cells reduce T cell transendothelial migration in cancer patients.
- 2007
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Ingår i: European journal of immunology. - : Wiley. - 0014-2980 .- 1521-4141. ; 37:1, s. 282-91
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Tidskriftsartikel (refereegranskat)abstract
- Cell-mediated immunity is thought to be the main mechanism of anti-tumour responses of the host, but it is not known if cancer disease affects T cell recruitment from blood to tissues. Therefore, we compared Heliobacter pylori-induced T cell transendothelial migration (TEM) in H. pylori-infected gastric carcinoma patients, colon and lung carcinoma patients and healthy volunteers. H. pylori induced significant T cell migration from all groups. However, there was a dramatic reduction of T cell TEM in gastric carcinoma patients (80%) compared to healthy individuals. A similarly reduced transmigration was also seen in colon and lung carcinoma patients. We found significantly increased frequencies of T(reg) cells in the blood of gastric carcinoma patients compared to healthy individuals, and depletion of T(reg) cells from the blood of these patients prior to TEM restored T cell migration. The effect of T(reg) cells was largely dependent on cell-cell contact, but not on IL-10 or TGF-beta. In addition, the presence of T(reg) cells led to reduced T cell attachment to endothelium and decreased production of T cell-recruiting chemokines during TEM. In conclusion, T(reg) cell-mediated reduction of T cell TEM may reduce T cell recruitment in patients with epithelial malignancies, thereby hampering anti-tumour responses.
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| 4. |
- Enarsson, Karin, 1975, et al.
(författare)
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Function and recruitment of mucosal regulatory T cells in human chronic Helicobacter pylori infection and gastric adenocarcinoma.
- 2006
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Ingår i: Clinical immunology (Orlando, Fla.). - : Elsevier BV. - 1521-6616. ; 121:3, s. 358-68
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Tidskriftsartikel (refereegranskat)abstract
- CD4(+)CD25(high) FOXP3-expressing regulatory T cells (Treg) can suppress immune responses to infections and tumors, thereby promoting microbial persistence and tumor progression. However, little is known about the phenotype and function of human mucosal Treg. Therefore, we analyzed the suppressive activity and homing phenotype of Treg in gastric mucosa of Helicobacter pylori-infected gastric adenocarcinoma patients. We found increased numbers of CD4(+)FOXP3(+) Treg in the tumor compared to tumor-free gastric mucosa. Gastric Treg cells were able to suppress H. pylori-induced T cell proliferation and IFN-gamma production. Furthermore, gastric Treg expressed increased levels of l-selectin and CCR4, compared to non-Treg cells, suggesting that these receptors contribute to Treg recruitment. The presence of functional antigen-specific Treg in H. pylori-infected gastric mucosa supports an important role for these cells in suppression of mucosal effector T cell responses, which probably contribute to bacterial persistence and possibly also to gastric tumor progression.
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| 5. |
- Enarsson, Karin, 1975, et al.
(författare)
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Helicobacter pylori induces transendothelial migration of activated memory T cells.
- 2005
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Ingår i: Infection and immunity. - 0019-9567. ; 73:2, s. 761-9
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Forskningsöversikt (refereegranskat)abstract
- Helicobacter pylori infection is associated with pronounced infiltration of granulocytes and lymphocytes into the gastric mucosa, resulting in active chronic gastritis that may develop into duodenal ulcer disease or gastric adenocarcinoma. Infiltrating T cells play a major role in the pathology of these diseases, but the signals involved in recruitment of T cells from blood to H. pylori-infected tissues are not well understood. We therefore examined H. pylori-induced T-cell transendothelial migration (TEM). The Transwell system, employing a monolayer of human umbilical vein endothelial cells, was used as a model to study TEM. H. pylori induced a significant T-cell migration, compared to spontaneous migration. CD4+ and CD8+ T cells migrated to the same extent in response to H. pylori, whereas there was significantly larger transmigration of memory T cells compared to naive T cells. Both H. pylori culture filtrate and urease induced migration, and the presence of the H. pylori cag pathogenicity island increased TEM. T-cell TEM was mediated by LFA-1-ICAM-1 interactions in accordance with an increased ICAM-1 expression on the endothelial cells after contact with H. pylori. Migrating T cells had increased expression of activation marker CD69 and chemokine receptors CXCR3, CCR4, and CCR9. Furthermore, T cells migrating in response to H. pylori secreted Th1 but not Th2 cytokines upon stimulation. In conclusion, our data indicate that live H. pylori and its secreted products contribute to T-cell recruitment to the gastric mucosa and that the responding T cells have an activated memory Th1 phenotype.
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| 6. |
- Enarsson, Karin, 1975
(författare)
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T Cell recruitment in human Helicobacter pylori associated diseases
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Helicobacter pylori (Hp) infection is associated with pronounced infiltration of granulocytes and lymphocytes into the gastric mucosa, resulting in active chronic gastritis that may develop into duodenal ulcer disease or gastric adenocarcinoma (GC). Infiltrating T cells play a major role in the pathology of these diseases, but the signals involved in recruitment of T cells from blood to H. pylori-infected tumour-free and tumour tissues are not well understood. In addition, CD4+CD25high regulatory T cells (Treg) may limit effector responses of infiltrating T cells, thereby affecting immunity to both Hp infection and GC. The overall aim of this thesis was to investigate the mechanisms of Hp-induced T cell transendothelial migration (TEM) in healthy volunteers and Hp-infected GC patients. We wanted to determine the homing mechanisms used by both ordinary mucosal T cells and Treg in both Hp-induced gastritis and tumour mucosa, and to investigate the potential suppressive function of mucosal Treg in Hp infection and in GC.In the transwell system, employing a monolayer of human umbilical vein endothelial cells to mimick TEM, H. pylori induced recruitment of activated memory CD4+ and CD8+ T cells with a Th1 phenotype. Both live H. pylori as well as secreted components, such as urease, induced T cell recruitment. H. pylori-induced T cell TEM was dependent on LFA-1-ICAM-1 interactions and H. pylori readily up-regulated ICAM-1 on the endothelium, as well as increased the production of T cell recruiting chemokines during TEM. However, in Hp-infected individuals and in GC patients T cell TEM towards H. pylori was dramatically decreased. There was a corresponding decrease in attachment of T cells to the endothelial monolayer during TEM and also a decreased production of the T cell recruiting chemokines IP-10, MDC and RANTES. Furthermore, we could also detect increased frequencies of Treg in blood from the GC patients compared to healthy individuals, suggesting that these cells might play a role in the decreased T cell TEM. Indeed, depletion of Treg from blood lymphocytes increased T cell TEM towards H. pylori in GC patients, but not in healthy volunteers. When investigating the homing receptors on T cells present in the tumor-free and tumour mucosa of GC patients, we found that there were decreased frequencies of T cells expressing the typical mucosal homing receptor alpha4beta7 and increased frequencies of T cells expressing the lymph node homing receptor L-selectin. This was probably caused by decreased levels of MAdCAM-1+ blood vessels and increased levels of PNAd+ blood vessels in the tumour, suggesting that endothelial cells within tumours arising at mucosal sites do not support extravasation of typical mucosa-infiltrating T cells. Furthermore, investigation of mucosal Treg function revealed that these cells were increased in frequency in the tumour compared to tumour-free mucosa and that they were able to suppress H. pylori-specific T cell responses in both tissue types. Furthermore, Treg expressed high levels of L-selectin and chemokine receptor CCR4, suggesting that these molecules are involved in recruitment of Treg to both tissue types. Our results suggest that live H. pylori and its secreted products contribute to T cell recruitment to the gastric mucosa and that the presence of Treg in blood or mucosa of GC patients may hamper anti-tumour immunity by reducing T cell TEM and by suppressing H. pylori-induced T cells responses in the tumour mucosa.
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| 7. |
- Enarsson, Karin, 1975
(författare)
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T lymphocyte recruitment in Helicobacter pylori-associated diseases
- 2005
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Helicobacter pylori (Hp) infection is associated with pronounced infiltration of granulocytes and lymphocytes into the gastric mucosa, resulting in active chronic gastritis that may develop into duodenal ulcer disease or gastric adenocarcinoma (GC). Infiltrating T cells play a major role in the pathology of these diseases, but the signals involved in recruitment of T cells from blood to H. pylori-infected tumour-free and tumour tissues are not well understood. In addition, CD4+CD25high regulatory T cells (Treg) may limit effector responses of infiltrating T cells, thereby affecting immunity to both Hp infection and GC. The overall aim of this thesis was to investigate the mechanisms of Hp-induced T cell transendothelial migration (TEM) in healthy volunteers and Hp-infected GC patients. We wanted to determine the homing mechanisms used by both ordinary mucosal T cells and Treg in both Hp-induced gastritis and tumour mucosa, and to investigate the potential suppressive function of mucosal Treg in Hp infection and in GC.In the transwell system, employing a monolayer of human umbilical vein endothelial cells to mimick TEM, H. pylori induced recruitment of activated memory CD4+ and CD8+ T cells with a Th1 phenotype. Both live H. pylori as well as secreted components, such as urease, induced T cell recruitment. H. pylori-induced T cell TEM was dependent on LFA-1-ICAM-1 interactions and H. pylori readily up-regulated ICAM-1 on the endothelium, as well as increased the production of T cell recruiting chemokines during TEM. However, in Hp-infected individuals and in GC patients T cell TEM towards H. pylori was dramatically decreased. There was a corresponding decrease in attachment of T cells to the endothelial monolayer during TEM and also a decreased production of the T cell recruiting chemokines IP-10, MDC and RANTES. Furthermore, we could also detect increased frequencies of Treg in blood from the GC patients compared to healthy individuals, suggesting that these cells might play a role in the decreased T cell TEM. Indeed, depletion of Treg from blood lymphocytes increased T cell TEM towards H. pylori in GC patients, but not in healthy volunteers. When investigating the homing receptors on T cells present in the tumor-free and tumour mucosa of GC patients, we found that there were decreased frequencies of T cells expressing the typical mucosal homing receptor alpha4beta7 and increased frequencies of T cells expressing the lymph node homing receptor L-selectin. This was probably caused by decreased levels of MAdCAM-1+ blood vessels and increased levels of PNAd+ blood vessels in the tumour, suggesting that endothelial cells within tumours arising at mucosal sites do not support extravasation of typical mucosa-infiltrating T cells. Furthermore, investigation of mucosal Treg function revealed that these cells were increased in frequency in the tumour compared to tumour-free mucosa and that they were able to suppress H. pylori-specific T cell responses in both tissue types. Furthermore, Treg expressed high levels of L-selectin and chemokine receptor CCR4, suggesting that these molecules are involved in recruitment of Treg to both tissue types. Our results suggest that live H. pylori and its secreted products contribute to T cell recruitment to the gastric mucosa and that the presence of Treg in blood or mucosa of GC patients may hamper anti-tumour immunity by reducing T cell TEM and by suppressing H. pylori-induced T cells responses in the tumour mucosa.
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| 8. |
- 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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| 9. |
- Lundin, Samuel B, 1970, et al.
(författare)
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The local and systemic T-cell response to Helicobacter pylori in gastric cancer patients is characterised by production of interleukin-10.
- 2007
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Ingår i: Clinical immunology (Orlando, Fla.). - : Elsevier BV. - 1521-6616. ; 125:2, s. 205-13
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Tidskriftsartikel (refereegranskat)abstract
- Helicobacter pylori causes a life-long infection that may lead to development of gastric adenocarcinoma (GC) and thereby cause major worldwide health problems. The present study was designed to study whether those that develop GC have an altered immune response to H. pylori compared to individuals that remain asymptomatic. When stimulated with H. pylori antigens, T cells from both peripheral blood and gastric mucosa of H. pylori-infected GC patients produced high amounts of IL-10, while the IL-10 production from blood T cells of H. pylori-infected asymptomatic subjects was low. Furthermore, mRNA levels of IL-10 were increased in the gastric mucosa of GC patients. In addition, the frequency of activated CD8(+) T cells was markedly reduced in stomach mucosa of patients with GC compared to asymptomatic individuals. We propose that the increased production of the suppressive cytokine IL-10 in H. pylori-infected GC patients leads to a diminished cytotoxic anti-tumour T-cell response in the stomach, which may contribute to tumour progression in subjects suffering from GC.
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| 10. |
- Quiding-Järbrink, Marianne, 1964, et al.
(författare)
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Decreased IgA antibody production in the stomach of gastric adenocarcinoma patients.
- 2009
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Ingår i: Clinical immunology. - : Elsevier BV. - 1521-7035 .- 1521-6616. ; 131:3, s. 463-71
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Tidskriftsartikel (refereegranskat)abstract
- Gastric adenocarcinoma is closely associated with Helicobacter pylori infection. It is also much more frequent in patients with common variable immunodeficiency or selective IgA-deficiency than in the general population. To investigate a possible link between local antibody production and gastric tumors, we studied gastric B cell infiltration and local IgA production in patients with H. pylori induced gastric adenocarcinomas. These studies showed that total and H. pylori-specific IgA antibody levels were substantially lower in gastric tissue from the cancer patients compared to those from asymptomatic H. pylori carriers. However, serum IgA levels were similar in the cancer patients and asymptomatic carriers. As could be expected, H. pylori infected asymptomatic carriers had considerably increased IgA antibody levels compared to uninfected subjects. We conclude that patients suffering from gastric adenocarcinoma have a dramatically decreased local IgA production in the stomach compared to asymptomatic H. pylori infected individuals.
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