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Träfflista för sökning "WFRF:(Quiding Järbrink Marianne 1964) "

Sökning: WFRF:(Quiding Järbrink Marianne 1964)

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1.
  • Lingblom, Christine, 1984, et al. (författare)
  • Topical Corticosteroids Do Not Revert the Activated Phenotype of Eosinophils in Eosinophilic Esophagitis but Decrease Surface Levels of CD18 Resulting in Diminished Adherence to ICAM-1, ICAM-2, and Endothelial Cells.
  • 2014
  • Ingår i: Inflammation. - : Springer Science and Business Media LLC. - 1573-2576 .- 0360-3997. ; 37:6, s. 1932-1944
  • Tidskriftsartikel (refereegranskat)abstract
    • Swallowed topical corticosteroids are the standard therapy for eosinophilic esophagitis (EoE) in adults. Eosinophils in the blood of untreated EoE patients have an activated phenotype. Our aim was to determine if corticosteroids restore the phenotype of eosinophils to a healthy phenotype and if certain cell-surface molecules on blood eosinophils correlate with eosinophilic infiltration of the esophagus. Levels of eight surface markers on eosinophils from treated and untreated EoE patients were determined by flow cytometry and analyzed using multivariate methods of pattern recognition. Corticosteroid-treated EoE patients' eosinophils had decreased levels of CD18 compared to both untreated patients and healthy controls, but maintained their activated phenotype. CD18 expression correlated positively with eosinophil numbers in the esophagus and promoted the adherence of eosinophils to ICAM-1, ICAM-2, and to endothelial cells. The diminished expression of CD18 may be one mechanism behind the reduced entry of eosinophils into the esophagus in corticosteroid-treated EoE patients.
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2.
  • Ahlmanner, Filip, et al. (författare)
  • CD39+ regulatory T cells accumulate in colon adenocarcinomas and display markers of increased suppressive function
  • 2018
  • Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 9:97, s. 36993-37007
  • Tidskriftsartikel (refereegranskat)abstract
    • Increasing knowledge of the function and regulation of tumor-infiltrating lymphocytes has led to new insights in cancer immunotherapy. Regulatory T cells (Treg) accumulate in colon tumors, and we recently showed that CD39+ Treg from cancer patients inhibit transendothelial migration of conventional T cells. CD39 mediates the hydrolysis of ATP to immunosuppressive adenosine and adds to the immunosuppressive effects of Treg. Here, we further investigated the regulatory features of intratumoral CD39+ Treg in colon cancer. Using flow cytometry analyses of cells from 46 colon cancer patients, we confirm the accumulation of CD39+ Treg in the tumor tissue compared to unaffected colon tissue, and also show that tumor-infiltrating Treg express more CD39 and Foxp3 on a per cell basis. Furthermore, CD39+ Treg in tumors express markers indicating increased turnover and suppressive ability. In particular, tumor-infiltrating CD39+ Treg have high expression of surface molecules related to immunosuppression, such as ICOS, PD-L1 and CTLA-4. Functional suppression assays also indicate potent suppressive capacity of CD39+ Treg on proliferation and IFN-γ secretion by conventional T cells. In conclusion, our results identify tumor-infiltrating CD39+ Treg as a numerous and potentially important immunosuppressive subset, and suggest that immunotherapy aimed at reducing the activity of CD39+ Treg may be particularly useful in the setting of colon cancer. © 2018 Ahlmanner et al.
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3.
  • Akeus, Paulina, et al. (författare)
  • Altered chemokine production and accumulation of regulatory T cells in intestinal adenomas of APC(Min/+) mice.
  • 2014
  • Ingår i: Cancer immunology, immunotherapy : CII. - : Springer Science and Business Media LLC. - 1432-0851 .- 0340-7004. ; 63:8, s. 807-19
  • Tidskriftsartikel (refereegranskat)abstract
    • Tumor progression in the colon moves from aberrant crypt foci to adenomatous polyps to invasive carcinomas. The composition of the tumor-infiltrating leukocyte population affects the ability of the immune system to fight the tumor. T cell infiltration into colorectal adenocarcinomas, particularly T helper 1 (Th1) type T cells as well as increased regulatory T cell (Treg) frequencies, is correlated with improved prognosis. However, whether Th1 cells and Tregs are already present at the adenoma stage is not known. In this study, the APC(Min/+) mouse model of intestinal adenomatous polyposis was used to investigate tumor-associated lymphocyte subsets and the mechanisms of their accumulation into gastrointestinal adenomas. Compared to unaffected tissue, adenomas accumulated CD4(+)FoxP3(+) putative Treg in parallel with lower frequencies of conventional T cells and B cells. The accumulation of Treg was also observed in human adenomatous polyps. Despite high Treg numbers, the function of conventional T cells present in the APC(Min/+) adenomas was not different from those in the unaffected tissue. Adenomas displayed an altered chemokine balance, with higher CCL17 and lower CXCL11 and CCL25 expression than in the unaffected tissue. In parallel, CXCR3(+) Tregs were largely absent from adenomas. The data indicate that already in early stages of tumor development, the balance of lymphocyte-recruiting chemokines is altered possibly contributing to the observed shift toward higher frequencies of Treg.
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4.
  • Akeus, Paulina, et al. (författare)
  • Regulatory T cells control endothelial chemokine production and migration of T cells into intestinal tumors of APC(min/+) mice
  • 2018
  • Ingår i: Cancer Immunology Immunotherapy. - : Springer Science and Business Media LLC. - 0340-7004 .- 1432-0851. ; 67:7, s. 1067-1077
  • Tidskriftsartikel (refereegranskat)abstract
    • Tumor-infiltrating lymphocytes are crucial for anti-tumor immunity. We have previously shown that regulatory T cells (Treg) are able to reduce T-cell transendothelial migration in vitro and accumulation of effector T cells in intestinal tumors in vivo. Treg depletion also resulted in increased levels of the chemokines CXCL9 and CXCL10 specifically in the tumors. In this study, we investigated the mechanisms for Treg mediated suppression of T-cell migration into intestinal tumors in the APC(min/+) mouse model. By breeding APC(min/+) mice with DEREG mice, which harbour a high affinity diphtheria toxin receptor under the control of the FOXP3 promoter, we were able to deplete Treg in tumor-bearing mice. Using adoptive transfer experiments, we could document a markedly increased migration of T cells specifically into Treg depleted tumors, and that Treg depletion results in increased production of the CXCR3 ligand CXCL10 from endothelial cells in the tumors. Furthermore, we were able to demonstrate that T cells use CXCR3 to migrate into intestinal tumors. In addition, human colon adenocarcinomas express high levels of mRNA CXCR3 ligands and tumor endothelial cells produce CXCL9 and CXCL10 ex vivo. In conclusion, this study demonstrates that Treg reduce endothelial CXCL10 production, inhibit T-cell migration into tumors and that CXCR3 mediated signalling is crucial for lymphocyte accumulation in intestinal tumors. Thus, immunotherapy aimed at Treg depletion may be effective by increasing not only T effector cell activity, but also their accumulation in tumors.
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5.
  • Akeus, Paulina, et al. (författare)
  • Regulatory T cells reduce endothelial neutral sphingomyelinase 2 to prevent T-cell migration into tumors
  • 2021
  • Ingår i: European Journal of Immunology. - : Wiley. - 0014-2980 .- 1521-4141. ; 51:9, s. 2317-2329
  • Tidskriftsartikel (refereegranskat)abstract
    • Endothelial cells are key regulators of transendothelial migration and their secretion of chemokines and expression of adhesion molecules facilitates lymphocyte entry into tissues. Previously, we demonstrated that Tregs can reduce transendothelial migration of T cells into tumors by decreasing endothelial CXCL10 secretion, but the mechanism by which this occurs is still not known. In this study, we aimed to define how Tregs decrease transendothelial migration into tumors. mRNA sequencing of intestinal tumor endothelial cells from Treg depleted mice identified neutral sphingomyelinase 2 (nSMase2) as a gene downregulated in the presence of Tregs. nSMase2 is expressed in human umbilical vein endothelial cells (HUVECs) and was decreased after coculture with Tregs. Furthermore, blocking of nSMase2 activity in vitro decreased VCAM1, CX3CL1, and CXCL10 expression in HUVECs, mirroring the same decrease found in Treg cocultures. In the APC(min/+) mouse model of intestinal cancer, nSMase2 is lower in tumor endothelial cells than in unaffected small intestine and chronic treatment with a nSMase2 inhibitor suppressed the increased migration that is otherwise seen in the absence of Tregs. We conclude that nSMase2 is an important mediator in endothelial cells supporting transendothelial migration, which may be targeted by Tregs to reduce T-cell migration into tumors.
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6.
  • Akeus, Paulina, et al. (författare)
  • Treg-cell depletion promotes chemokine production and accumulation of CXCR3(+) conventional T cells in intestinal tumors.
  • 2015
  • Ingår i: European journal of immunology. - : Wiley. - 1521-4141 .- 0014-2980. ; 45:6, s. 1654-66
  • Tidskriftsartikel (refereegranskat)abstract
    • Colorectal cancer (CRC) is one of the most prevalent tumor types worldwide and tumor-infiltrating T cells are crucial for anti-tumor immunity. We previously demonstrated that Treg cells from CRC patients inhibit transendothelial migration of conventional T cells. However, it remains unclear if local Treg cells affect lymphocyte migration into colonic tumors. By breeding APC(Min/+) mice with depletion of regulatory T cells mice, expressing the diphtheria toxin receptor under the control of the FoxP3 promoter, we were able to selectively deplete Treg cells in tumor-bearing mice, and investigate the impact of these cells on the infiltration of conventional T cells into intestinal tumors. Short-term Treg-cell depletion led to a substantial increase in the frequencies of T cells in the tumors, attributed by both increased infiltration and proliferation of T cells in the Treg-cell-depleted tumors. We also demonstrate a selective increase of the chemokines CXCL9 and CXCL10 in Treg-cell-depleted tumors, which were accompanied by accumulation of CXCR3(+) T cells, and increased IFN-γ mRNA expression. In conclusion, Treg-cell depletion increases the accumulation of conventional T cells in intestinal tumors, and targeting Treg cells could be a possible anti-tumor immunotherapy, which not only affects T-cell effector functions, but also their recruitment to tumors.
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7.
  • Andersson Lundell, Anna-Carin, 1976, et al. (författare)
  • Development of gut-homing receptors on circulating B cells during infancy.
  • 2011
  • Ingår i: Clinical immunology. - : Elsevier BV. - 1521-7035 .- 1521-6616. ; 138:1, s. 97-106
  • Tidskriftsartikel (refereegranskat)abstract
    • B cell gut-homing is mainly mediated by α4β7, CCR9 and CCR10. We here studied the expression of these receptors on B cells from cord blood and from peripheral blood at 1, 4, 18 and 36months of age in a prospective cohort of Swedish infants. The proportion of all B cells expressing α4β7 as well as the fraction of CCR10+ B cells expressing α4β7 was highest in early infancy. Nearly all naïve B cells in all age groups expressed α4β7, whereas the expression on class-switched B cells decreased with age. Moreover, the proportion of both IgA+ and IgG+ B cells expressing α4β7, CCR9 and CCR10 were higher during the first months when compared to adults. In conclusion, the high fraction of circulating IgA+ and IgG+ B cells expressing CCR9 and CCR10 in the first months of life indicates activation of naïve B cells in the gut, coinciding with bacterial colonization.
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8.
  • Andric, Fanny, et al. (författare)
  • Immune Microenvironment in Sporadic Early-Onset versus Average-Onset Colorectal Cancer
  • 2023
  • Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 15:5
  • Tidskriftsartikel (refereegranskat)abstract
    • Simple Summary The incidence of non-hereditary cancer in the left colon and rectum is increasing in young patients worldwide for unknown reasons. To understand this phenomenon, the biology of early-onset colorectal cancer needs to be established. Here, we investigated the immune response to tumors by selecting a highly representative group of patients younger than 45 years matched to those aged 70-75 years, excluding hereditary cases. Both T-cell distribution in tumors and expression of 770 immune-related genes were overall similar between the groups. The findings suggest that the immune response in cancer of the left colon and rectum is not dependent on age and that early-onset colorectal cancer is likely not related to immune response deficiencies. The incidence of left-sided colon and rectal cancer in young people are increasing worldwide, but its causes are poorly understood. It is not clear if the tumor microenvironment is dependent on age of onset, and little is known about the composition of tumor-infiltrating T cells in early-onset colorectal cancer (EOCRC). To address this, we investigated T-cell subsets and performed gene expression immune profiling in sporadic EOCRC tumors and matched average-onset colorectal cancer (AOCRC) tumors. Left-sided colon and rectal tumors from 40 cases were analyzed; 20 EOCRC (<45 years) patients were matched 1:1 to AOCRC (70-75 years) patients by gender, tumor location, and stage. Cases with germline pathogenic variants, inflammatory bowel disease or neoadjuvant-treated tumors were excluded. For T cells in tumors and stroma, a multiplex immunofluorescence assay combined with digital image analysis and machine learning algorithms was used. Immunological mediators in the tumor microenvironment were assessed by NanoString gene expression profiling of mRNA. Immunofluorescence revealed no significant difference between EOCRC and AOCRC with regard to infiltration of total T cells, conventional CD4(+) and CD8(+) T cells, regulatory T cells, or gamma delta T cells. Most T cells were located in the stroma in both EOCRC and AOCRC. Immune profiling by gene expression revealed higher expression in AOCRC of the immunoregulatory cytokine IL-10, the inhibitory NK cell receptors KIR3DL3 and KLRB1 (CD161), and IFN-a7 (IFNA7). In contrast, the interferon-induced gene IFIT2 was more highly expressed in EOCRC. However, in a global analysis of 770 tumor immunity genes, no significant differences could be detected. T-cell infiltration and expression of inflammatory mediators are similar in EOCRC and AOCRC. This may indicate that the immune response to cancer in left colon and rectum is not related to age of onset and that EOCRC is likely not driven by immune response deficiency.
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9.
  • Banerjee, Debashish, et al. (författare)
  • Epithelial MUC1/Muc1 Promotes Cell migration, Reduces Apoptosis and Affects Levels of Mucosal Modulators During Acetylsalicylic Acid (Aspirin) Induced Gastropathy.
  • 2015
  • Ingår i: The Biochemical journal. - 1470-8728. ; 465:3, s. 423-431
  • Tidskriftsartikel (refereegranskat)abstract
    • MUC1 is a transmembrane mucin highly expressed in the stomach. While extensive research has uncovered many of its roles in cancer, knowledge about the functions of MUC1 in normal tissues is limited. Here we showed that acetylsalicylic acid (Aspirin, ASA) upregulated MUC1/Muc1 expression in the gastric mucosa of humans and wild type mice. ASA induced mucosal injury in all mice to a similar extent, however wild type animals and those chimeras with Muc1 on the epithelia recovered faster than Muc1 knock-out mice and chimeras carrying Muc1 on haematopoietic but not epithelial cells. MUC1 enhanced proliferation and migration of the human gastric cell line MKN-7, and increased resistance to apoptosis. The repeated treatment regime used caused a reduction in cyclooxygenase-1 expression, though wild type animals returned faster towards pre-treatment levels, and had increased cyclooxygenase-2 and vascular endothelial growth factor levels during recovery. Thus, we found that epithelial Muc1 is more important for the healing process than haematopoetic Muc1, and Muc1/MUC1 facilitates wound healing by enhancing cell migration and proliferation, protecting against apoptosis and mediating expression of mucosal modulators. Thus, MUC1 plays essential roles during wound healing, and development of treatment modalities targeting enhanced expression of MUC1 may be beneficial to treat mucosal wounds.
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10.
  • Bergin, Philip, 1975, et al. (författare)
  • Gastric gelatinase B/matrix metalloproteinase-9 is rapidly increased in Helicobacter felis-induced gastritis.
  • 2008
  • Ingår i: FEMS immunology and medical microbiology. - 0928-8244. ; 52:1, s. 88-98
  • Tidskriftsartikel (refereegranskat)abstract
    • It has previously been shown that matrix metalloproteinase-9 (MMP-9) levels, originating from macrophages, are considerably increased in human Helicobacter pylori-associated gastritis. Here, the early kinetics of the MMP-9 response resulting from Helicobacter infection in C57BL/6 and MMP-9 knock-out mice using the murine Helicobacter felis model were examined. H. felis infection induced severe gastritis in the murine stomach at just 2 weeks after infection. Before gastritis, an increase was observed in MMP-9-positive cells detected by immunohistochemistry in the basal lamina propria. This finding was corroborated by gelatin zymography of stomach samples. As the gastritis increased so did the concentration of MMP-9 and the incidence of gastric MMP-9-positive cells, their location corresponding to that of macrophages. In contrast, systemic levels of MMP-9 remained unchanged. When MMP-9-deficient mice were infected with H. felis, no significant difference in gastritis development was detected compared with disease development in wild-type animals. We conclude that MMP-9 production is an early event in the response to gastric Helicobacter infection, a feature that may favor the recruitment of immune cells early during infection. At later stages, however, the increased levels of MMP-9 may damage the integrity of the stomach mucosa.
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11.
  • Bergin, Philip, 1975, et al. (författare)
  • Increased production of matrix metalloproteinases in Helicobacter pylori-associated human gastritis.
  • 2004
  • Ingår i: Helicobacter. - : Wiley. - 1083-4389 .- 1523-5378. ; 9:3, s. 201-10
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND AND AIMS: Helicobacter pylori infection results in an active, chronic inflammation of the gastric mucosa. Previous studies have highlighted the importance of matrix metalloproteinases (MMPs) in diseases involving mucosal inflammation, prompting us to investigate MMP activity in H. pylori-induced gastritis. METHODS: Gastric biopsies were obtained from H. pylori-infected and uninfected volunteers, and MMP activity was assessed using substrate gel electrophoresis. MMP production was also evaluated by immunohistochemistry and real time-polymerase chain reaction. In parallel, tissue inhibitors of MMPs (TIMP) levels and TIMP-MMP complexes were examined in corresponding tissues using enzyme-linked immunosorbent assays and Western blotting. Finally, MMP production by gastric macrophages was determined after stimulation with H. pylori. RESULTS: Antral mucosa of H. pylori-infected subjects demonstrated a 19-fold higher MMP-9 activity than that of uninfected individuals. MMP-2 was present at lower levels, but was also increased in H. pylori-infected individuals, while there was no difference in the total levels of TIMP-1 and TIMP-2 between the groups of volunteers. Significant numbers of MMP-9-containing cells were only found in the H. pylori-infected antral mucosa. Tissue-resident macrophages were significantly increased in H. pylori-infected individuals, and double-staining showed MMP-9 colocalized to macrophages. Furthermore, gastric macrophages secreted MMP-9 in response to H. pylori bacteria. A corresponding 10-fold increase of gene expression of MMP-9 was seen in patients infected with H. pylori compared to uninfected individuals. CONCLUSIONS: Helicobacter pylori infection results in a substantial increase in MMP-9 and MMP-2 activity in the gastric mucosa, probably contributed to in large part by tissue-resident macrophages, while no changes were seen in the TIMP levels. The net increase in gastric MMP activity is likely to contribute to tissue damage during H. pylori-associated gastritis.
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12.
  • Bergin, Philip, 1975, et al. (författare)
  • Secretion of matrix metalloproteinase-9 by macrophages, in vitro, in response to Helicobacter pylori.
  • 2005
  • Ingår i: FEMS immunology and medical microbiology. - : Oxford University Press (OUP). - 0928-8244 .- 1574-695X. ; 45:2, s. 159-69
  • Forskningsöversikt (refereegranskat)abstract
    • We have previously shown that matrix metalloproteinase-9 (MMP-9) activity is greatly enhanced within the active chronic inflammation of Helicobacter pylori infected individuals, of which a major fraction derives from macrophages in the tissue. Here, we have investigated the ability of macrophages to secrete MMPs in response to H. pylori. Human macrophages secrete MMP-9 in response to live and inactivated H. pylori, as well as to specific bacterial products. Protein kinase C, phosphatiolylinositol 3-kinase and calcium uptake channels all play a role in MMP-9 secretion, whereas neither tumour necrosis factor alpha, interleukin-8, nor interleukin-1beta autocrine stimulation appear to contribute. We conclude that human macrophages have the ability to react directly against several H. pylori derived factors, utilising several signalling pathways.
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13.
  • Brisslert, Mikael, 1974, et al. (författare)
  • Helicobacter pylori induce neutrophil transendothelial migration: role of the bacterial HP-NAP
  • 2005
  • Ingår i: FEMS Microbiol Lett. ; 249:1, s. 95-103
  • 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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14.
  • Börgeson, Emma, et al. (författare)
  • AICAR ameliorates high-fat diet-associated pathophysiology in mouse and ex vivo models, independent of adiponectin.
  • 2017
  • Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 60:4, s. 729-739
  • Tidskriftsartikel (refereegranskat)abstract
    • In this study, we aimed to evaluate the therapeutic potential of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an activator of AMP-activated protein kinase, for ameliorating high-fat diet (HFD)-induced pathophysiology in mice. We also aimed to determine whether the beneficial effects of AICAR were dependent on adiponectin. Furthermore, human adipose tissue was used to examine the effect of AICAR ex vivo.Six-week-old male C57BL/6J wild-type and Adipoq (-/-) mice were fed a standard-fat diet (10% fat) or an HFD (60% fat) for 12weeks and given vehicle or AICAR (500μg/g) three times/week from weeks 4-12. Diet-induced pathophysiology was examined in mice after 11 weeks by IPGTT and after 12 weeks by flow cytometry and western blotting. Human adipose tissue biopsies from obese (BMI 35-50kg/m(2)) individuals were incubated with vehicle or AICAR (1mmol/l) for 6h at 37°C, after which inflammation was characterised by ELISA (TNF-α) and flow cytometry.AICAR attenuated adipose inflammation in mice fed an HFD, promoting an M1-to-M2 macrophage phenotype switch, while reducing infiltration of CD8(+) T cells. AICAR treatment of mice fed an HFD partially restored glucose tolerance and attenuated hepatic steatosis and kidney disease, as evidenced by reduced albuminuria (p<0.05), urinary H2O2 (p<0.05) and renal superoxide levels (p<0.01) in both wild-type and Adipoq (-/-) mice. AICAR-mediated protection occurred independently of adiponectin, as similar protection was observed in wild-type and Adipoq (-/-) mice. In addition, AICAR promoted an M1-to-M2 macrophage phenotype switch and reduced TNF-α production in tissue explants from obese human patients.AICAR may promote metabolic health and protect against obesity-induced systemic diseases in an adiponectin-independent manner. Furthermore, AICAR reduced inflammation in human adipose tissue explants, suggesting by proof-of-principle that the drug may reduce obesity-induced complications in humans.ClinicalTrials.gov NCT02322073.
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15.
  • Calander, Ann-Marie, 1957, et al. (författare)
  • Matrix metalloproteinase-9 (gelatinase B) deficiency leads to increased severity of Staphylococcus aureus-triggered septic arthritis.
  • 2006
  • Ingår i: Microbes and infection / Institut Pasteur. - : Elsevier BV. - 1286-4579. ; 8:6, s. 1434-9
  • Tidskriftsartikel (refereegranskat)abstract
    • Matrix metalloproteinases constitute a family of structurally related endopeptidases that are crucial for the normal turnover of the extracellular matrix. Elevated levels of MMP-9 have been demonstrated in synovial fluids of rheumatoid arthritis patients, and a correlation with the severity of the disease has been described. The aim of this study was to explore the impact of MMP-9 expression on joint inflammation and destruction in a model of bacterially induced septic arthritis. MMP-9 knock-out mice and C57Bl6 congenic controls were inoculated intravenously or intra-articularly with Staphylococcus aureus. Arthritis was evaluated clinically and by means of histology. Zymographic analyses were performed to study ex vivo induction of MMP-9 following exposure to S. aureus. The MMP-9 knock-out mice displayed a significantly higher frequency and severity, but not destructivity, of arthritis than did the wild-type mice. The knock-out mice also proved to harbour an increased number of bacteria locally in joints and systemically in kidneys, possibly by impaired extravasation and recruitment of leukocytes and a deficient early defence against infection. Our findings indicate that deficiency in MMP-9 increases the degree of joint inflammation due to decreased bacterial clearance.
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16.
  • Cardeno, Ana, et al. (författare)
  • Activated T follicular helper-like cells are released into blood after oral vaccination and correlate with vaccine specific mucosal B-cell memory
  • 2018
  • Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8
  • Tidskriftsartikel (refereegranskat)abstract
    • T follicular helper (Tfh)-like cells with potent B-cell helping ability are mobilized into human circulation after parenteral vaccination and are generally held to reflect ongoing germinal center reactions. However, whether mucosal vaccination induces systemic Tfh responses and how such responses may relate to IgA production are unknown. We investigated the frequencies, phenotype and function of circulating Tfh-like CD4(+) CXCR5(+) T cells (cTfh) in adults receiving an oral inactivated enterotoxigenic Escherichia coli vaccine. Subjects were classified as vaccine responders or weak/non-responders based on their intestine-derived antibody-secreting cell (ASC) IgA responses to major vaccine antigens. Oral immunization induced significantly increased proportions of cTfh cells expressing the cTfh activation marker inducible costimulator (ICOS) in ASC responders, but not in weak/non-responders. Vaccination also enhanced the expression of IL-21, Th17 markers and integrin beta 7 by activated cTfh cells, supporting functionality and gut homing potential. cTfh cells promoted total and vaccine specific IgA production from cocultured B cells. Magnitudes of cTfh responses assessed within a week after primary vaccinations correlated with memory intestine-derived vaccine specific IgA responses 1-2 years later. We conclude that activated ICOS+ Tfh-like cells are mobilized into blood after oral vaccination and may be used as biomarkers of vaccine specific mucosal memory in humans.
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17.
  • Das, S., et al. (författare)
  • beta 7 integrins contribute to intestinal tumor growth in mice
  • 2018
  • Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 13:9
  • Tidskriftsartikel (refereegranskat)abstract
    • The gut homing receptor integrin alpha 4 beta 7 is essential for the migration of pro-inflammatory T cells into the gut mucosa. Since intestinal neoplasia has been associated with chronic inflammation, we investigated whether interfering with gut-homing affects intestinal tumorigenesis. Using chemically induced and spontaneous intestinal tumor models we showed that lack of beta 7 integrin significantly impairs tumor growth without affecting tumor frequencies, with a mild translatable effect on overall survival. This correlates with human data showing lower MAdCAM-1 expression and disease-free survival in colorectal cancer patients. Thus, paradoxically in contrast to extra-intestinal tumors, blocking migration of immune cells into the gut might have a positive therapeutic effect on intestinal neoplasia.
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18.
  • Enarsson, Karin, 1975, et al. (författare)
  • CD4+ CD25high regulatory T cells reduce T cell transendothelial migration in cancer patients.
  • 2007
  • Ingår i: European journal of immunology. - : Wiley. - 0014-2980 .- 1521-4141. ; 37:1, s. 282-91
  • 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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19.
  • Enarsson, Karin, 1975, et al. (författare)
  • Differential mechanisms for T lymphocyte recruitment in normal and neoplastic human gastric mucosa
  • 2006
  • Ingår i: Clin Immunol. - : Elsevier BV. ; 118:1, s. 24-34
  • 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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20.
  • Enarsson, Karin, 1975, et al. (författare)
  • Function and recruitment of mucosal regulatory T cells in human chronic Helicobacter pylori infection and gastric adenocarcinoma.
  • 2006
  • Ingår i: Clinical immunology (Orlando, Fla.). - : Elsevier BV. - 1521-6616. ; 121:3, s. 358-68
  • 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.
  •  
21.
  • Enarsson, Karin, 1975, et al. (författare)
  • Helicobacter pylori induces transendothelial migration of activated memory T cells.
  • 2005
  • Ingår i: Infection and immunity. - 0019-9567. ; 73:2, s. 761-9
  • 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.
  •  
22.
  • Friman, Vanda, 1952, et al. (författare)
  • Intestinal and circulating antibody-forming cells in IgA-deficient individuals after oral cholera vaccination.
  • 1994
  • Ingår i: Clinical and experimental immunology. - 0009-9104. ; 95:2, s. 222-6
  • Tidskriftsartikel (refereegranskat)abstract
    • In search for a possible explanation for the different susceptibility to mucosal infections in IgA-deficient (IgAd) individuals, the frequency of total immunoglobulin-secreting cells (ISC) and vaccine-specific antibody-secreting cells (ASC) in intestinal mucosa and peripheral blood was determined by the enzyme-linked immunospot (ELISPOT) assay before and after peroral vaccination with a B subunit-whole cell cholera vaccine. Two groups of IgAd individuals, frequently infected and non-infected respectively, and normal controls were studied. Before cholera vaccination there were significantly higher frequencies of total IgM and IgG ISC in the gut, but not in the blood, in the IgAd individuals than in the controls. However, there were no significant differences between healthy and infection-prone IgAd individuals in this respect. In response to oral cholera vaccination, intestinal cholera toxin (CT)-specific IgG and IgM ASC were significantly more abundant among the IgAd individuals with a history of frequent infections than among the healthy IgAd individuals and controls. A similar difference in IgG and IgM ASC, although not significant, was also noted in blood. In IgAd individuals with frequent infections the vaccine induced variable anti-CT IgM ASC responses in the gut, ranging from no increase to a few strikingly high responses. In the controls, the CT-specific responses were dominated by IgA ASC. The data show that oral cholera vaccination evoked strong CT-specific IgG ASC responses, and in some cases also strong IgM ASC responses in the intestinal mucosa of IgAd patients with a history of frequent infections. The healthy IgAd individuals unexpectedly responded with lower numbers of CT-specific IgG ASC and did not show any increase of CT-specific IgM ASC in the intestinal mucosa. Thus, inability to mount a mucosal immune response to an oral antigen cannot in itself explain recurrent infections among many IgAd individuals.
  •  
23.
  • Gonzales, Lucia, et al. (författare)
  • Alkaline pH Is a Signal for Optimal Production and Secretion of the Heat Labile Toxin, LT in Enterotoxigenic Escherichia Coli (ETEC)
  • 2013
  • Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:9
  • Tidskriftsartikel (refereegranskat)abstract
    • Enterotoxigenic Escherichia coli (ETEC) cause secretory diarrhea in children and travelers to endemic areas. ETEC spreads through the fecal-oral route. After ingestion, ETEC passes through the stomach and duodenum before it colonizes the lower part of the small intestine, exposing bacteria to a wide range of pH and environmental conditions. This study aimed to determine the impact of external pH and activity of the Cyclic AMP receptor protein (CRP) on the regulation of production and secretion of heat labile (LT) enterotoxin. ETEC strain E2863wt and its isogenic mutant E2863ΔCRP were grown in LBK media buffered to pH 5, 7 and 9. GM1 ELISA, cDNA and cAMP analyses were carried out on bacterial pellet and supernatant samples derived from 3 and 5 hours growth and from overnight cultures. We confirm that CRP is a repressor of LT transcription and production as has been shown before but we show for the first time that CRP is a positive regulator of LT secretion both in vitro and in vivo. LT secretion increased at neutral to alkaline pH compared to acidic pH 5 where secretion was completely inhibited. At pH 9 secretion of LT was optimal resulting in 600 percent increase of secreted LT compared to unbuffered LBK media. This effect was not due to membrane leakage since the bacteria were viable at pH 9. The results indicate that the transition to the alkaline duodenum and/or exposure to high pH close to the epithelium as well as activation of the global transcription factor CRP are signals that induce secretion of the LT toxin in ETEC.
  •  
24.
  • Grindebacke, Hanna, 1977, et al. (författare)
  • Dynamic development of homing receptor expression and memory cell differentiation of infant CD4+CD25high regulatory T cells.
  • 2009
  • Ingår i: Journal of immunology (Baltimore, Md. : 1950). - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 183:7, s. 4360-70
  • Tidskriftsartikel (refereegranskat)abstract
    • Migration of CD4+CD25+FOXP3+ regulatory T cells (Treg) is important for suppressing immune responses in different tissues. Previous studies show that the majority of Treg at birth express gut homing receptor alpha(4)beta(7) and that only few express CCR4, while the reverse pattern is found in adults. The age at which homing receptor switch occurs in vivo is not known. In this study, we show, in a prospective study of human infants from birth to 3 years of age, that homing receptor switch from alpha(4)beta(7) to CCR4 commences between 1 1/2 and 3 years of age and that Treg at that age also had started their switch to a memory phenotype. The majority of naive Treg express alpha(4)beta(7) in infants but not in adults, while the majority of memory Treg express CCR4 both infants and adults. The homing receptor expression on Treg corresponds to their actual migration properties, because Treg from cord blood migrate foremost toward the gut-associated chemokine CCL25. CD4+FOXP3+ T cell numbers increase rapidly in the circulation during the first days of life indicating conversion to suppressive Treg from CD25(high) Treg precursors. These findings suggest that the gut is the primary site of Treg stimulation to exogenous Ags during the first 18 mo of life and that homing receptor switch toward a more extra-intestinal phenotype occurs thereafter.
  •  
25.
  • Hansson, Malin, 1967, et al. (författare)
  • CCL28 is increased in human Helicobacter pylori induced gastritis and mediates recruitment of gastric IgA-secreting cells.
  • 2008
  • Ingår i: Infection and Immunity. - 0019-9567. ; 76:7, s. 3304-11
  • Tidskriftsartikel (refereegranskat)abstract
    • Human Helicobacter pylori infection gives rise to an active chronic gastritis and is a major risk factor for the development of duodenal ulcer disease and gastric adenocarcinoma. The infection is accompanied by a large accumulation of immunoglobulin A (IgA)-secreting cells in the gastric mucosa, and following mucosal immunization only H. pylori-infected volunteers mounted a B-cell response in the gastric mucosa. To identify the signals for recruitment of gastric IgA-secreting cells, we investigated the gastric production of CCL28 (mucosa-associated epithelial chemokine) and CCL25 (thymus-expressed chemokine) in H. pylori-infected and uninfected individuals and the potential of gastric B-cell populations to migrate toward these chemokines. Gastric tissue from H. pylori-infected individuals contained significantly more CCL28 protein and mRNA than that from uninfected individuals, while CCL25 levels remained unchanged. Chemokine-induced migration of gastric lamina propria lymphocytes isolated from patients undergoing gastric resection was then assessed using the Transwell system. IgA-secreting cells and IgA+ memory B cells from H. pylori-infected tissues migrated toward CCL28 but not CCL25, while the corresponding cells from uninfected patients did not. Furthermore, IgG-secreting cells from H. pylori-infected patients did not migrate to CCL28 but instead to CXCL12 (SDF-1). However, chemokine receptor expression did not correlate to the migratory pattern of the different B-cell populations. These studies are the first to show increased CCL28 production during gastrointestinal infection in humans and provide an explanation for the large influx of IgA-secreting cells to the gastric mucosa in H. pylori-infected individuals.
  •  
26.
  • Hansson, Malin, 1967, et al. (författare)
  • DC-LAMP(+) Dendritic Cells Are Recruited to Gastric Lymphoid Follicles in Helicobacter pylori-Infected Individuals
  • 2013
  • Ingår i: Infection and Immunity. - : American Society for Microbiology. - 0019-9567 .- 1098-5522. ; 81:10, s. 3684-3692
  • Tidskriftsartikel (refereegranskat)abstract
    • Infection with Helicobacter pylori is associated with development of ulcer disease and gastrointestinal adenocarcinoma. The infection leads to a large infiltration of immune cells and the formation of organized lymphoid follicles in the human gastric mucosa. Still, the immune system fails to eradicate the bacteria, and the substantial regulatory T cell (Treg) response elicited is probably a major factor permitting bacterial persistence. Dendritic cells (DCs) are professional antigen-presenting cells that can activate naive T cells, and maturation of DCs is crucial for the initiation of primary immune responses. The aim of this study was to investigate the presence and localization of mature human DCs in H. pylori-infected gastric mucosa. Gastric antral biopsy specimens were collected from patients with H. pylori-associated gastritis and healthy volunteers, and antrum tissue was collected from patients undergoing gastric resection. Immunohistochemistry and flow cytometry showed that DCs expressing the maturation marker dendritic cell lysosome-associated membrane glycoprotein (DC-LAMP; CD208) are enriched in the H. pylori-infected gastric mucosa and that these DCs are specifically localized within or close to lymphoid follicles. Gastric DC-LAMP-positive (DC-LAMP(+)) DCs express CD11c and high levels of HLA-DR but little CD80, CD83, and CD86. Furthermore, immunofluorescence analyses demonstrated that DC-LAMP(+) DCs are in the same location as FoxP3-positive putative Tregs in the follicles. In conclusion, we show that DC-LAMP(+) DCs with low costimulatory capacity accumulate in the lymphoid follicles in human H. pylori-infected gastric tissue, and our results suggest that Treg-DC interactions may promote chronic infection by rendering gastric DCs tolerogenic.
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27.
  • Hansson, Malin, 1967, et al. (författare)
  • Dendritic cells express CCR7 and migrate in response to CCL19 (MIP-3beta) after exposure to Helicobacter pylori
  • 2006
  • Ingår i: Microbes Infect. - : Elsevier BV. - 1286-4579. ; 8:3, s. 841-50
  • Forskningsöversikt (refereegranskat)abstract
    • Helicobacter pylori infection induces chronic inflammation in the gastric mucosa with a marked increase in the number of lymphoid follicles consisting of infiltrating B and T cells, neutrophils, dendritic cells (DC) and macrophages. It has been suggested that an accumulation of mature DC in the tissue, resulting from a failure of DC to migrate to lymph nodes, may contribute to this chronic inflammation. Migration of DC to lymph nodes is regulated by chemokine receptor CCR7, expressed on mature DC, and the CCR7 ligands CCL19 and CCL21. In this study we analysed the maturation, in vitro migration and cytokine production of human DC after stimulation with live H. pylori. For comparison, DC responses to non-pathogenic Escherichia coli bacteria were also evaluated. Stimulation with H. pylori induced maturation of DC, i.e. up-regulation of the chemokine receptors CCR7 and CXCR4 and the maturation markers HLA-DR, CD80 and CD86. The H. pylori-stimulated DC also induced CD4(+) T-cell proliferation. DC stimulated with H. pylori secreted significantly more interleukin (IL)-12 compared to DC stimulated with E. coli, while E. coli-stimulated DC secreted more IL-10. Despite low surface expression of CCR7 protein following stimulation with H. pylori compared to E. coli, the DC migrated equally well towards CCL19 after stimulation with both bacteria. Thus, we could not detect any failure in the migration of H. pylori stimulated DC in vitro that may contribute to chronic gastritis in vivo, and our results suggest that H. pylori induces maturation and migration of DC to lymph nodes where they promote T cell responses.
  •  
28.
  •  
29.
  • Johansson, C, et al. (författare)
  • Differential expression of chemokine receptors on human IgA+ and IgG+ B cells.
  • 2005
  • Ingår i: Clinical and experimental immunology. - : Oxford University Press (OUP). - 0009-9104 .- 1365-2249. ; 141:2, s. 279-87
  • Tidskriftsartikel (refereegranskat)abstract
    • Organ-specific lymphocyte homing is dependent on the expression of tissue-specific homing receptors and selected chemokine receptors. During the effector phase of an immune response, IgA and IgG antibody-secreting cells (ASC) are differently distributed in the body. Still, B cell expression of L-selectin and the mucosal homing receptor integrin alpha4beta7 is not related to the isotype produced, but only to the site of antigen encounter. In this study, we examined if differences in chemokine responsiveness between IgA+ and IgG+ B cells could explain their different tissue localization. Circulating CD19+ B cells were isolated and their expression of IgA, IgG, and selected chemokine receptors was determined by flow cytometry. Few Ig+ cells expressed CCR2, CCR3, or CCR9, and there was no difference in the expression of these receptors between IgA+ and IgG+ cells. In contrast, CCR4, CCR5, and CXCR3 was expressed on significantly more IgG+ than IgA+ cells. The function of chemokine receptors on memory B cells and ASC was then tested in the transwell system. IgG+ memory cells migrated to a higher extent than IgA+ cells towards the CXCR3 ligand CXCL11/I-TAC, while there was only a small migration towards the CCR4 ligand CCL17/TARC and the CCR9 ligand CCL25/TECK. ASC migrated poorly to all chemokines tested. In conclusion, this study shows that IgG+ and IgA+ memory B cells have a differential expression of the Th1 associated chemokine receptor CXCR3, as well as of CCR4 and CCR5. In contrast, none of the studied chemokine receptors was preferentially expressed by IgA+ cells.
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30.
  • Kraft, Jamie D., et al. (författare)
  • Lipoxins modulate neutrophil oxidative burst, integrin expression and lymphatic transmigration differentially in human health and atherosclerosis
  • 2022
  • Ingår i: FASEB Journal. - Hoboken, NJ, United States : John Wiley & Sons. - 0892-6638 .- 1530-6860. ; 36:3
  • Tidskriftsartikel (refereegranskat)abstract
    • Dysregulated chronic inflammation plays a crucial role in the pathophysiology of atherosclerosis and may be a result of impaired resolution. Thus, restoring levels of specialized pro-resolving mediators (SPMs) to promote the resolution of inflammation has been proposed as a therapeutic strategy for patients with atherosclerosis, in addition to standard clinical care. Herein, we evaluated the effects of the SPM lipids, lipoxin A4 (LXA4) and lipoxin B4 (LXB4), on neutrophils isolated from patients with atherosclerosis compared with healthy controls. Patients displayed altered endogenous SPM production, and we demonstrated that lipoxin treatment in whole blood from atherosclerosis patients attenuates neutrophil oxidative burst, a key contributor to atherosclerotic development. We found the opposite effect in neutrophils from healthy controls, indicating a potential mechanism whereby lipoxins aid the endogenous neutrophil function in health but reduce its excessive activation in disease. We also demonstrated that lipoxins attenuated upregulation of the high-affinity conformation of the CD11b/CD18 integrin, which plays a central role in clot activation and atherosclerosis. Finally, LXB4 enhanced lymphatic transmigration of human neutrophils isolated from patients with atherosclerosis. This finding is noteworthy, as impaired lymphatic function is now recognized as an important contributor to atherosclerosis. Although both lipoxins modulated neutrophil function, LXB4 displayed more potent effects than LXA4 in humans. This study highlights the therapeutic potential of lipoxins in atherosclerotic disease and demonstrates that the effect of these SPMs may be specifically tailored to the need of the individual. © 2022 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.
  •  
31.
  • Kraft, Jamie D., et al. (författare)
  • Specialized Pro-Resolving Mediators and the Lymphatic System
  • 2021
  • Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1422-0067 .- 1661-6596. ; 22:5
  • Tidskriftsartikel (refereegranskat)abstract
    • Diminished lymphatic function and abnormal morphology are common in chronic inflammatory diseases. Recent studies are investigating whether it is possible to target chronic inflammation by promoting resolution of inflammation, in order to enhance lymphatic function and attenuate disease. Resolution of inflammation is an active process regulated by bioactive lipids known as specialized pro-resolving mediators (SPMs). SPMs can modulate leukocyte migration and function, alter cytokine/chemokine release, modify autophagy, among other immune-related activities. Here, we summarize the role of the lymphatics in resolution of inflammation and lymphatic impairment in chronic inflammatory diseases. Furthermore, we discuss the current literature describing the connection between SPMs and the lymphatics, and the possibility of targeting the lymphatics with innovative SPM therapy to promote resolution of inflammation and mitigate disease.
  •  
32.
  • Langenes, Veronica, et al. (författare)
  • Expression of the chemokine decoy receptor D6 is decreased in colon adenocarcinomas.
  • 2013
  • Ingår i: Cancer immunology, immunotherapy : CII. - : Springer Science and Business Media LLC. - 1432-0851 .- 0340-7004. ; 62:11, s. 1687-1695
  • Tidskriftsartikel (refereegranskat)abstract
    • Recruitment of immune cells to tumors is a complex process crucial for both inflammation-driven tumor progression and specific anti-tumor cytotoxicity. Chemokines control the directed migration of immune cells, and their actions are partly controlled by nonsignaling chemokine decoy receptors. The role of the receptors such as D6, Duffy antigen receptor for chemokines and ChemoCentryx chemokine receptor in immunity to tumors is still unclear. Using real-time PCR, we detected significantly decreased expression of D6 mRNA in colon tumors compared to unaffected mucosa. D6 protein was expressed by lymphatic endothelium and mononuclear cells in the colon lamina propria and detected by immunohistochemistry in two out of six tissue samples containing high D6 mRNA levels, whereas no staining was observed in any tissue samples expressing low mRNA levels. When examining the density of lymphatic vessels in colon tumors, we detected a marked increase in vessels identified by the lymphatic endothelial marker Lyve-1, excluding passive regulation of D6 due to decreased lymphatic vessel density. In parallel, the Treg-recruiting chemokine CCL22, which is sequestered by D6, was threefold increased in tumor tissue. Furthermore, we could show that low D6 expression correlated to more invasive tumors and that tumor location influences D6 expression, which is lower in the more distal parts of the colon. The data support that regulation of D6 by colon tumors results in altered levels of proinflammatory CC chemokines, thereby shaping the local chemokine network to favor tumor survival. This may have implications for the design of future immunotherapy for colon cancer.
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33.
  • Lebrero-Fernandez, Cristina, et al. (författare)
  • Altered expression of Butyrophilin (BTN) and BTN-like (BTNL) genes in intestinal inflammation and colon cancer
  • 2016
  • Ingår i: Immunity Inflammation and Disease. - : Wiley. - 2050-4527. ; 4:2, s. 191-200
  • Tidskriftsartikel (refereegranskat)abstract
    • Several Butyrophilin (BTN) and Btn-like (BTNL) molecules control T lymphocyte responses, and are genetically associated with inflammatory disorders and cancer. In this study, we present a comprehensive expression analysis of human and murine BTN and BTNL genes in conditions associated with intestinal inflammation and cancer. Using real-time PCR, expression of human BTN and BTNL genes was analyzed in samples from patients with ulcerative colitis, irritable bowel syndrome, and colon tumors. Expression of murine Btn and Btnl genes was examined in mouse models of spontaneous colitis (Muc2(-/-)) and intestinal tumorigenesis (Apc(Min/+)). Our analysis indicates a strong association of several of the human genes with ulcerative colitis and colon cancer; while especially BTN1A1, BTN2A2, BTN3A3, and BTNL8 were significantly altered in inflammation, colonic tumors exhibited significantly decreased levels of BTNL2, BTNL3, BTNL8, and BTNL9 as compared to unaffected tissue. Colonic inflammation in Muc2(-/-) mice significantly down-regulated the expression of particularly Btnl1, Btnl4, and Btnl6 mRNA, and intestinal polyps derived from Apc(Min/+) mice displayed altered levels of Btn1a1, Btn2a2, and Btnl1 transcripts. Thus, our data present an association of BTN and BTNL genes with intestinal inflammation and cancer and represent a valuable resource for further studies of this gene family.
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34.
  • Liang, Frank, et al. (författare)
  • Antigen Presenting Cells from Tumor and Colon of Colorectal Cancer Patients Are Distinct in Activation and Functional Status, but Comparably Responsive to Activated T Cells.
  • 2021
  • Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 13:20
  • Tidskriftsartikel (refereegranskat)abstract
    • Although mouse models of CRC treatments have demonstrated robust immune activation, it remains unclear to what extent CRC patients' APCs and TILs interact to fuel or quench treatment-induced immune responses. Our ex vivo characterization of tumor and adjacent colon cell suspensions suggest that contrasting environments in these tissues promoted inversed expression of T cell co-stimulatory CD80, and co-inhibitory programmed death (PD)-ligand1 (PD-L1) on intratumoral vs. colonic APCs. While putative tumor-specific CD103+CD39+CD8+ TILs expressed lower CD69 (early activation marker) and higher PD-1 (extended activation/exhaustion marker) than colonic counterparts, the latter had instead higher CD69 and lower PD-1 levels. Functional comparisons showed that intratumoral APCs were inferior to colonic APCs regarding protein uptake and upregulation of CD80 and PD-L1 after protein degradation. Our attempt to model CRC treatment-induced T cell activation in vitro showed less interferon (IFN)-γ production by TILs than colonic T cells. In this model, we also measured APCs' CD80 and PD-L1 expression in response to activated co-residing T cells. These markers were comparable in the two tissues, despite higher IFN- γ exposure for colonic APCs. Thus, APCs within distinct intratumoral and colonic milieus showed different activation and functional status, but were similarly responsive to signals from induced T cell activation.
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35.
  • Lindholm, Catharina, 1967, et al. (författare)
  • Mucosal vaccination increases endothelial expression of mucosal addressin cell adhesion molecule 1 in the human gastrointestinal tract.
  • 2004
  • Ingår i: Infection and immunity. - 0019-9567. ; 72:2, s. 1004-9
  • Forskningsöversikt (refereegranskat)abstract
    • Homing of leukocytes to various tissues is dependent on the interaction between homing receptors on leukocytes and their ligands, addressins, on endothelial cells. Mucosal immunization results in homing of antigen-specific lymphocytes back to the mucosa where they first encountered the antigen. However, it is unknown whether this homing of antigen-specific cells is mediated by an altered endothelial addressin expression after vaccination. Using different immunization routes with an oral cholera vaccine, we show that the endothelial expression of mucosal addressin cell adhesion molecule 1 (MAdCAM-1) is increased in the gastric and upper small intestinal mucosae after immunization through various local routes in the upper gastrointestinal tract. In contrast, rectal immunization did not influence the levels of MAdCAM-1 in the gastric or duodenal mucosa. Furthermore, we show that MAdCAM-1 can be induced on human endothelial cells by tumor necrosis factor alpha (TNF-alpha) and gamma interferon. The vaccine component cholera toxin B subunit (CTB) increased MAdCAM-1 expression on endothelial cells in cultured human gastric explants, an effect that seemed to be mediated by TNF-alpha. In conclusion, MAdCAM-1 expression is increased in the upper gastrointestinal tract after local immunizations with a vaccine containing CTB. This strongly suggests the involvement of MAdCAM-1 in the preferential homing of mucosal lymphocytes to their original site of activation.
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36.
  • Lopes, Ana I, et al. (författare)
  • Cytokine expression in pediatric Helicobacter pylori infection.
  • 2005
  • Ingår i: Clinical and diagnostic laboratory immunology. - 1071-412X. ; 12:8, s. 994-1002
  • Tidskriftsartikel (refereegranskat)abstract
    • Helicobacter pylori infection is one of the most common gastrointestinal infections worldwide and almost invariably causes chronic gastritis in the infected host. A predominant Th1 profile has been demonstrated in H. pylori-infected mucosa from adults, but no previous study has evaluated in situ cytokine expression in children. We therefore examined expression of proinflammatory, anti-inflammatory, and regulatory cytokines by immunohistochemistry in cryopreserved antral biopsy specimens from 10 H. pylori-infected and 10 uninfected children and correlated expression of cytokines with histology scores. Concomitant expression of interleukin-8 (IL-8), gamma interferon (IFN-gamma), IL-4, transforming growth factor beta, and tumor necrosis factor alpha was seen in 8/10 H. pylori-infected cases and in 5/10 noninfected cases; all H. pylori-infected subjects showed staining for at least two of the cytokines. The proportion of epithelial cytokine-specific staining did not differ significantly between the groups, either in surface or glandular epithelium. Furthermore, no significant differences were noticed between intraepithelial or lamina propria lymphocyte staining in the groups. There was, however, a tendency of higher numbers of IFN-gamma- and IL-8-positive cells in the H. pylori-infected group. IFN-gamma and IL-8 lamina propria lymphocyte expression correlated significantly with antrum chronic inflammation, but there was no correlation between histology scores and epithelial cytokine expression. When the same techniques were used, the cytokine response appeared to be smaller in H. pylori-infected children than in adults, and there was no clear Th1 dominance. These results therefore suggest a different mucosal immunopathology in children. It remains to be determined whether the gastric immune response is downregulated in children with H. pylori infection and whether this is relevant to the outcome of infection.
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37.
  • Lundin, Samuel B, 1970, et al. (författare)
  • The local and systemic T-cell response to Helicobacter pylori in gastric cancer patients is characterised by production of interleukin-10.
  • 2007
  • Ingår i: Clinical immunology (Orlando, Fla.). - : Elsevier BV. - 1521-6616. ; 125:2, s. 205-13
  • 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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38.
  • Meinicke, H., et al. (författare)
  • Tumour-associated changes in intestinal epithelial cells cause local accumulation of KLRG1(+) GATA3(+) regulatory T cells in mice
  • 2017
  • Ingår i: Immunology. - : Wiley. - 0019-2805. ; 152:1, s. 74-88
  • Tidskriftsartikel (refereegranskat)abstract
    • CD4(+) Foxp3(+) regulatory T (Treg) cells include differentiated populations of effector Treg cells characterized by the expression of specific transcription factors. Tumours, including intestinal malignancies, often present with local accumulation of Treg cells that can prevent tumour clearance, but how tumour progression leads to Treg cell accumulation is incompletely understood. Here using genetically modified mouse models we show that ablation of E-cadherin, a process associated with epithelial to mesenchymal transition and tumour progression, promotes the accumulation of intestinal Treg cells by the specific accumulation of the KLRG1(+) GATA3(+) Treg subset. Epithelial E-cadherin ablation activates the -catenin pathway, and we find that increasing -catenin signals in intestinal epithelial cells also boosts Treg cell frequencies through local accumulation of KLRG1(+) GATA3(+) Treg cells. Both E-cadherin ablation and increased -catenin signals resulted in epithelial cells with higher levels of interleukin-33, a cytokine that preferentially expands KLRG1(+) GATA3(+) Treg cells. Tumours often present reduced E-cadherin expression and increased -catenin signalling and interleukin-33 production. Accordingly, Treg cell accumulation in intestinal tumours from APC(min/+) mice was exclusively due to the increase in KLRG1(+) GATA3(+) Treg cells. Our data identify a novel axis through which epithelial cells control local Treg cell subsets, which may be activated during intestinal tumorigenesis.
  •  
39.
  • Muthuswamy, Rangarajan V., et al. (författare)
  • Impaired migration of IgA-secreting cells to colon adenocarcinomas.
  • 2013
  • Ingår i: Cancer immunology, immunotherapy : CII. - : Springer Science and Business Media LLC. - 1432-0851 .- 0340-7004. ; 62, s. 989-97
  • Tidskriftsartikel (refereegranskat)abstract
    • Local inflammation is a strong risk factor for the development of gastrointestinal adenocarcinomas. Mucosal regulatory T cells and IgA-secreting cells both contribute to reduce inflammatory responses, and their recruitment to tissues is dependent on local production of chemokines. More specifically, IgA-secreting cells are recruited to mucosal tissues by CCL28 signalling through CCR10. Here, we examined the recruitment of IgA-secreting plasma cells to tumor-associated mucosa in patients suffering from colon adenocarcinoma. Flow cytometric analyses of single cell suspensions from tumor-associated and unaffected colon mucosa showed a marked decrease in CD19(+)CD38(high)IgA(+) plasmablasts in the tumor-associated mucosa, while the total frequencies of B and T cells were similar. This finding was confirmed in ELISPOT assays, demonstrating a 64% reduction in the frequencies of IgA-secreting cells among cells from the tumor-associated mucosa. The few IgA(+) plasmablasts present in the tumor did not express CCR10, and functional migration assays demonstrated that IgA-secreting cells from tumor-associated mucosa did not migrate in response to CCL28. Taken together, our results show an impaired migration of IgA-secreting cells to colon tumors, presumably caused by a decreased production of CCL28 in the tumor. The lack of local IgA antibodies may lead to impaired barrier function and increased bacterial colonization, driving further inflammatory responses and promoting tumor growth.
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40.
  • Norder Grusell, E., et al. (författare)
  • Bacterial flora of the human oral cavity, and the upper and lower esophagus.
  • 2013
  • Ingår i: Diseases of the esophagus. - : Oxford University Press (OUP). - 1120-8694. ; 26:1, s. 84-90
  • Tidskriftsartikel (refereegranskat)abstract
    • This reference study aims to survey the bacterial flora of the healthy lower human esophagus and to compare it with that of the upper esophagus and oral mucosa. The use of biopsies, in addition to brush samples, allows inclusion of not only transient bacteria present on the surface but also bacteria residing in the epithelia, and the yield of the two methods can be compared. Forty patients scheduled for surgery for reasons with no known influence on esophageal flora and with no symptoms or endoscopic signs of esophageal disease were included. Samples were collected from the oral, upper esophageal, and lower esophageal mucosa using sealed brushes and biopsy forceps. Colonies cultivated on agar plates were classified and semiquantified. Twenty-three different bacterial species were identified, with similar strains present at the three sites. The most common group of bacteria was viridans streptococci, with an occurrence rate in brush samples and biopsies of 98% and 95%, respectively. The median number of species occurring in the oral cavity, upper esophagus, and lower esophagus was between 3 and 4 (range 0-7). The total number of species in the oral cavity was significantly higher when compared with either level in the esophagus, while the yields obtained by brush and biopsy sampling were highly correlated. Hence, the normal human esophagus is colonized with a resident bacterial flora of its own, which has similarities to that of the oral mucosa. There are diverse species that make up this flora, although in relatively low amounts. The most frequent inhabitants of the esophagus are streptococci, with an occurrence rate in brush samples and biopsies of 95-98%. Comparative studies of patients with eosinophilic esophagitis and gastroesophageal reflux disease are warranted.
  •  
41.
  • Oertli, Mathias, et al. (författare)
  • DC-derived IL-18 drives Treg differentiation, murine Helicobacter pylori-specific immune tolerance, and asthma protection.
  • 2012
  • Ingår i: The Journal of clinical investigation. - 1558-8238. ; 122:3, s. 1082-96
  • Tidskriftsartikel (refereegranskat)abstract
    • Persistent colonization with the gastric bacterial pathogen Helicobacter pylori causes gastritis and predisposes infected individuals to gastric cancer. Conversely, it is also linked to protection from allergic, chronic inflammatory, and autoimmune diseases. We demonstrate here that H. pylori inhibits LPS-induced maturation of DCs and reprograms DCs toward a tolerance-promoting phenotype. Our results showed that DCs exposed to H. pylori in vitro or in vivo failed to induce T cell effector functions. Instead, they efficiently induced expression of the forkhead transcription factor FoxP3, the master regulator of Tregs, in naive T cells. Depletion of DCs in mice infected with H. pylori during the neonatal period was sufficient to break H. pylori-specific tolerance. DC depletion resulted in improved control of the infection but also aggravated T cell-driven immunopathology. Consistent with the mouse data, DCs infiltrating the gastric mucosa of human H. pylori carriers exhibited a semimature DC-SIGN(+)HLA-DR(hi)CD80(lo)CD86(lo) phenotype. Mechanistically, the tolerogenic activity of H. pylori-experienced DCs was shown to require IL-18 in vitro and in vivo; DC-derived IL-18 acted directly on T cells to drive their conversion to Tregs. CD4(+)CD25(+) Tregs from infected wild-type mice but not Il18(-/-) or Il18r1(-/-) mice prevented airway inflammation and hyperresponsiveness in an experimental model of asthma. Taken together, our results indicate that tolerogenic reprogramming of DCs ensures the persistence of H. pylori and protects against allergic asthma in a process that requires IL-18.
  •  
42.
  • Quiding-Järbrink, Marianne, 1964, et al. (författare)
  • Decreased IgA antibody production in the stomach of gastric adenocarcinoma patients.
  • 2009
  • Ingår i: Clinical immunology. - : Elsevier BV. - 1521-7035 .- 1521-6616. ; 131:3, s. 463-71
  • 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.
  •  
43.
  • Quiding-Järbrink, Marianne, 1964, et al. (författare)
  • Enhanced M1 macrophage polarization in human Helicobacter pylori-associated atrophic gastritis and in vaccinated mice
  • 2010
  • Ingår i: PLOS one. - : Public Library of Science (PLoS). - 1932-6203. ; 5:11
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Infection with Helicobacter pylori triggers a chronic gastric inflammation that can progress to atrophy and gastric adenocarcinoma. Polarization of macrophages is a characteristic of both cancer and infection, and may promote progression or resolution of disease. However, the role of macrophages and their polarization during H. pylori infection has not been well defined. Methodology/Principal Findings By using a mouse model of infection and gastric biopsies from 29 individuals, we have analyzed macrophage recruitment and polarization during H. pylori infection by flow cytometry and real-time PCR. We found a sequential recruitment of neutrophils, eosinophils and macrophages to the gastric mucosa of infected mice. Gene expression analysis of stomach tissue and sorted macrophages revealed that gastric macrophages were polarized to M1 after H. pylori infection, and this process was substantially accelerated by prior vaccination. Human H. pylori infection was characterized by a mixed M1/M2 polarization of macrophages. However, in H. pylori-associated atrophic gastritis, the expression of inducible nitric oxide synthase was markedly increased compared to uncomplicated gastritis, indicative of an enhanced M1 macrophage polarization in this pre-malignant lesion. Conclusions/Significance These results show that vaccination of mice against H. pylori amplifies M1 polarization of gastric macrophages, and that a similar enhanced M1 polarization is present in human H. pylori-induced atrophic gastritis.
  •  
44.
  • Quiding-Järbrink, Marianne, 1964, et al. (författare)
  • Infections of the esophagus and the stomach.
  • 2009
  • Ingår i: Periodontology 2000. - : Wiley. - 1600-0757 .- 0906-6713. ; 49, s. 166-78
  • Forskningsöversikt (refereegranskat)
  •  
45.
  • Raghavan, Sukanya, 1974, et al. (författare)
  • Immune modulation by regulatory T cells in Helicobacter pylori-associated diseases.
  • 2012
  • Ingår i: Endocrine, metabolic & immune disorders drug targets. - 2212-3873. ; 12:1, s. 71-85
  • Forskningsöversikt (refereegranskat)abstract
    • Regulatory T cells (Treg) have the ability to suppress the activity of most other lymphoid cells as well as dendritic cells through cell-cell contact dependent mechanisms, which have not yet been fully defined. Treg are a key component of a functional immune system, and Treg deficiency is associated with severe autoimmunity and allergies. Antigen-specific Treg accumulate in gastric tissue during both Helicobacter pylori-induced gastritis and peptic ulcer disease (PUD). Several studies suggest that the local Treg response protects the gastric mucosa from exaggerated inflammation and tissue damage, and the risk of PUD is inversely related to Treg frequencies. At the same time the reduction of the inflammatory response achieved by Treg leads to increased bacterial density. Furthermore, the inability to mount a protective inflammatory response will lead to chronic infection and in some patients to the development of atrophic gastritis and gastric cancer progression. Treg actively infiltrate gastric adenocarcinomas and are predicted to promote tumor escape from cytotoxic immune responses. In addition, the presence of a potent Treg response will probably be an obstacle when constructing a future therapeutic vaccine against H. pylori. In this article, we will review the proposed mechanisms of action for Treg, their accumulation in the gastric mucosa in the different H. pylori-associated diseases, and how they may affect the immune response induced by H. pylori infection and the course of PUD and gastric adenocarcinomas.
  •  
46.
  • Raghavan, Sukanya, 1974, et al. (författare)
  • Regulatory T cells in gastrointestinal tumors
  • 2011
  • Ingår i: Expert Review of Gastroenterology & Hepatology. - 1747-4124. ; 5:4, s. 489-501
  • Forskningsöversikt (refereegranskat)abstract
    • Regulatory T cells (Tregs) have the ability to suppress the activity of most other lymphoid cells, as well as dendritic cells through cell-cell contact-dependent mechanisms, which have not yet been fully defined. Tregs are a key component of a functional immune system and Treg deficiency is associated with severe autoimmunity and allergies. However, Tregs specific for tumor-associated antigens are present in cancer patients and Tregs accumulate in many types of solid tumors, where they probably act to promote tumor escape from cytotoxic immune responses. Indeed, some studies even show a negative correlation between Treg infiltration and survival of the patient. Several studies indicate an active recruitment of Tregs to the tumor site and the mechanisms of Treg accumulation are starting to be better understood as a result of more detailed analysis of their adhesion molecule and chemokine receptor expression. In addition, in gastrointestinal tumors there is an increase in tumor-associated Tregs, but intriguingly, Treg infiltration into colorectal adenocarcinomas is associated with improved prognosis. In this article, we will review the proposed mechanisms of immune suppression by tumor-associated Tregs, how the tumor microenvironment favors immune evasion and Treg induction, the tumor-homing mechanisms of Tregs and how Tregs affect progression of gastric and colorectal tumors.
  •  
47.
  • Raghavan, Sukanya, 1974, et al. (författare)
  • Vaccination against Helicobacter pylori infection
  • 2016
  • Ingår i: Helicobacter pylori Research: From Bench to Bedside. - Tokyo : Springer Japan. ; , s. 575-602
  • Bokkapitel (refereegranskat)abstract
    • Helicobacter pylori is well adapted to colonize the human gastric mucosa and induces a relatively mild but persistent inflammation and activation of adaptive B- and T-cell responses. A subset of infected individuals experience symptoms or develop ulcer disease or gastric adenocarcinoma that might be treatable with antibiotics. At the same time, the resistance to antibiotics is rapidly increasing among H. pylori isolates, and access to an efficient vaccine would improve treatment options considerably. Still, the complex pathogenesis and many different virulence factors of the bacterium have made vaccine development a challenging task. In this review, we discuss the possibilities of constructing a future vaccine against H. pylori based on the choice of antigens and mucosal adjuvants and describe our knowledge of protective immune responses that may be necessary to generate for eradication of H. pylori. In addition, the preclinical and clinical testing of available vaccine candidates is reviewed. The immunological response to H. pylori infection is multifaceted, and inflammatory responses are mounted side by side with a prominent regulatory response. The potential problems caused by the immune response, comprising both tolerance induction by the infection and the risk of developing post-immunization gastritis, are also discussed. © Springer Japan 2016.
  •  
48.
  • Rodin, William, 1994, et al. (författare)
  • Isolation and Characterization of MAIT Cells from Tumor Tissues
  • 2020
  • Ingår i: MAIT Cells. Methods and Protocols. Helen KaipeIsabelle Magalhaes (red.). - New York, NY : Springer. - 9781071602065 ; , s. 39-53
  • Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
    • Mucosal-associated invariant T (MAIT) cell infiltration has been demonstrated in colorectal and hepatocellular carcinoma, and their ability to produce Th1- and Th17-associated cytokines, as well as their cytotoxic function, suggests that MAIT cells may have important functions in both reducing and promoting protective tumor immunity. Here, we describe enzymatic methods to isolate intraepithelial and lamina propria lymphocyte single cell suspensions from colon tissue and tumors containing viable MAIT cells, which can be used for further purification, flow cytometry analysis, or culture.
  •  
49.
  • Sharba, Sinan, et al. (författare)
  • Interleukin 4 induces rapid mucin transport, increases mucus thickness and quality and decreases colitis and Citrobacter rodentium in contact with epithelial cells
  • 2019
  • Ingår i: Virulence. - : Informa UK Limited. - 2150-5594 .- 2150-5608. ; 10:1, s. 97-117
  • Tidskriftsartikel (refereegranskat)abstract
    • Citrobacter rodentium infection is a murine model for pathogenic intestinal Escherichia coli infection. C. rodentium infection causes an initial decrease in mucus layer thickness, followed by an increase during clearance. We aimed to identify the cause of these changes and to utilize this naturally occurring mucus stimulus to decrease pathogen impact and inflammation. We identified that mucin production and speed of transport from Golgi to secretory vesicles at the apical surface increased concomitantly with increased mucus thickness. Of the cytokines differentially expressed during increased mucus thickness, IFN-gamma and TNF-alpha decreased the mucin production and transport speed, whereas IL-4, IL-13, C. rodentium and E. coli enhanced these aspects. IFN-gamma and TNF-alpha treatment in combination with C. rodentium and pathogenic E. coli infection negatively affected mucus parameters in vitro, which was relieved by IL-4 treatment. The effect of IL-4 was more pronounced than that of IL-13, and in wild type mice, only IL-4 was present. Increased expression of Il-4, Il-4-receptor alpha, Stat6 and Spdef during clearance indicate that this pathway contributes to the increase in mucin production. In vivo IL-4 administration initiated 10 days after infection increased mucus thickness and quality and decreased colitis and pathogen contact with the epithelium. Thus, during clearance of infection, the concomitant increase in IL-4 protects and maintains goblet cell function against the increasing levels of TNF-alpha and IFN-gamma. Furthermore, IL-4 affects intestinal mucus production, pathogen contact with the epithelium and colitis. IL-4 treatment may thus have therapeutic benefits for mucosal healing.
  •  
50.
  • Sotak, Matus, et al. (författare)
  • Lipoxins reduce obesity-induced adipose tissue inflammation in 3D-cultured human adipocytes and explant cultures
  • 2022
  • Ingår i: iScience. - : Elsevier BV. - 2589-0042. ; 25:7
  • Tidskriftsartikel (refereegranskat)abstract
    • Adipose tissue inflammation drives obesity-related cardiometabolic diseases. Enhancing endogenous resolution mechanisms through administration of lipoxin A4, a specialized pro-resolving lipid mediator, was shown to reduce adipose inflammation and subsequently protects againstobesity-inducedsystemic disease inmice. Here, we demonstrate that lipoxins reduce inflammation in 3D-cultured human adipocytes and adipose tissue explants from obese patients. Approximately 50% of patients responded particularlywell to lipoxins by reducing inflammatory cytokines and promoting an anti-inflammatory M2 macrophage phenotype. Responding patients were characterized by elevated systemic levels of C-reactive protein, which causes inflammation in cultured human adipocytes. Responders appeared more prone to producing anti-inflammatory oxylipins and displayed elevated prostaglandin D2 levels, which has been interlinked with transcription of lipoxin-generatingenzymes. Using explant cultures, this study provides the first proof-of-concept evidence supporting the therapeutic potential of lipoxins in reducing human adipose tissue inflammation. Our data further indicate that lipoxin treatment may require a tailored personalized-medicine approach.
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