| 1. |
- Akter, S., et al.
(författare)
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The frequency of circulating integrin alpha 4 beta 7(+) cells correlates with protection against Helicobacter pylori infection in immunized mice
- 2019
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Ingår i: Helicobacter. - : Wiley. - 1083-4389 .- 1523-5378. ; 24:6
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Tidskriftsartikel (refereegranskat)abstract
- Background Chronic Helicobacter pylori infection is the cause of peptic ulcers in a subpopulation of individuals and a risk factor for the development of gastric cancer. A vaccine against H pylori infection can prevent the acquisition of the infection and protect against reinfections. Clinical trials to date evaluating the efficacy of H pylori vaccines in human challenge models have shown moderate to poor protection with difficulties in predicting efficacy. Thus, while further studies are needed to design an effective vaccine, we also need to find relevant correlates for vaccine efficacy. Objective To find immune correlates to vaccine efficacy, the frequencies of neutrophils, eosinophils and inflammatory monocytes and CD4(+) T-cell memory and mucosa homing integrin alpha 4 beta 7(+) cells were assessed by flow cytometry in the blood of mice after vaccination. Materials and Methods H pylori antigens and cholera toxin or the multiple mutant CT (mmCT) were administered via the sublingual (SL) and intragastric route (IG). The vaccinated mice were infected with H pylori strain SS1 bacteria, and colonization in the stomach and immune responses were evaluated. Results The H pylori vaccine was effective in reducing bacterial load in the stomach of mice and enhancing immune responses compared to unvaccinated infection controls. In the blood of mice after SL or IG route of vaccination, we observed changes in frequencies of innate and adaptive immune cell subsets compared to infection controls. Remarkably, the frequency of circulating mucosal homing alpha 4 beta 7(+)CD4(+) T cells after vaccination correlated with low bacterial load in the stomach of individual mice irrespective of the immunization route. Conclusions Our study shows that the innate and adaptive immune cell subsets can be measured in the blood after vaccination and that increased frequency of alpha 4 beta 7(+)CD4(+) in the blood after immunization could be used as a predictive marker for the efficacy of vaccine against H pylori infection.
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| 2. |
- Dahlén, Rahil, et al.
(författare)
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Infliximab Inhibits Activation and Effector Functions of Peripheral Blood T Cells in vitro from Patients with Clinically Active Ulcerative Colitis
- 2013
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Ingår i: Scandinavian Journal of Immunology. - : Wiley. - 0300-9475. ; 78:3, s. 275-284
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Tidskriftsartikel (refereegranskat)abstract
- Many patients with inflammatory bowel disease (IBD) are undergoing therapy with infliximab, an antibody specific for TNF. However, the exact mechanisms of action of infliximab are not completely understood. The aim of this study was to determine the in vitro effects of infliximab on blood T cells derived from anti-TNF therapy-naive ulcerative colitis (UC) patients with clinically active disease. Peripheral blood mononuclear cells were stimulated polyclonally or by antigen in the presence or absence of infliximab. The T cell phenotype was investigated by flow cytometry, cytokine secretion was determined by ELISA, and cell proliferation was determined by thymidine assay or CFSE dye. Presence of infliximab resulted in reduced expression of CD25 in CD4(+) and CD8(+) T cell populations and inhibited secretion of IFN-, IL-13, IL-17A, TNF as well as granzyme A. Infliximab also suppressed CD4(+) and CD8(+) T cell proliferation. These effects of infliximab were recorded both in T cells activated by polyclonal and antigen-specific stimulation. The effects of infliximab on T cell apoptosis and induction of FOXP3(+)CD4(+) T regulatory cells were ambiguous and depended on the originating cellular source and/or the stimulation mode and strength. In conclusion, infliximab is able to reduce T cell activation as measured by CD25, proliferation and cytokine secretion in vitro from UC patients with clinically active disease. These data suggest that suppression of T cell activity may be important for infliximab-mediated disease remission in patients with UC.
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| 3. |
- Dutta, Nikita, 1992, et al.
(författare)
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Combinatory analysis of immune cell subsets and tumor-specific genetic variants predict clinical response to PD-1 blockade in patients with non-small cell lung cancer
- 2023
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Ingår i: Frontiers in Oncology. - : Frontiers Media SA. - 2234-943X. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Immunotherapy by blocking programmed death protein-1 (PD-1) or programmed death protein-ligand1 (PD-L1) with antibodies (PD-1 blockade) has revolutionized treatment options for patients with non-small cell lung cancer (NSCLC). However, the benefit of immunotherapy is limited to a subset of patients. This study aimed to investigate the value of combining immune and genetic variables analyzed within 3-4 weeks after the start of PD-1 blockade therapy to predict long-term clinical response.Blood collected from patients with NSCLC were analyzed for changes in the frequency and concentration of immune cells using a clinical flow cytometry assay. Next-generation sequencing (NGS) was performed on DNA extracted from archival tumor biopsies of the same patients. Patients were categorized as clinical responders or non-responders based on the 9 months' assessment after the start of therapy.We report a significant increase in the post-treatment frequency of activated effector memory CD4+ and CD8+ T-cells compared with pre-treatment levels in the blood. Baseline frequencies of B cells but not NK cells, T cells, or regulatory T cells were associated with the clinical response to PD-1 blockade. NGS of tumor tissues identified pathogenic or likely pathogenic mutations in tumor protein P53, Kirsten rat sarcoma virus, Kelch-like ECH-associated protein 1, neurogenic locus notch homolog protein 1, and serine/threonine kinase 11, primarily in the responder group. Finally, multivariate analysis of combined immune and genetic factors but neither alone, could discriminate between responders and non-responders.Combined analyses of select immune cell subsets and genetic mutations could predict early clinical responses to immunotherapy in patients with NSCLC and after validation, can guide clinical precision medicine efforts.
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| 4. |
- Navabi, Nazanin, 1969, et al.
(författare)
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Helicobacter pylori Infection Impairs the Mucin Production Rate and Turnover in the Murine Gastric Mucosa
- 2013
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Ingår i: Infection and Immunity. - 0019-9567. ; 81:3, s. 829-837
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Tidskriftsartikel (refereegranskat)abstract
- To protect the surface of the stomach, the epithelial cells secrete a mucus layer, which is mainly comprised of the MUC5AC mucin. Further protection is provided by a thick glycocalyx on the apical surface of the epithelial cell, with the cell surface mucin MUC1 as a major component. Here, we investigate the production rate and turnover of newly synthesized mucin in mice and analyze the effects of early colonization and chronic infection with H. pylori. Metabolic incorporation of an azido GalNAc analog (GalNAz) was used as a nonradioactive method to perform pulse experiments in the whole animal. First, the subcellular movement of newly synthesized mucin and mucin turnover was determined in uninfected mice. Based on the time line for mucin transport and dissemination, 2, 6, and 12 h after GalNAz injection was selected to collect the stomachs from mice infected with H. pylori strain SS1 during early colonization (7 days) and chronic infection (90 days). The results demonstrated that the speed from the start of glycosylation to the final destination is faster for the membrane-bound mucin to reach the glycocalyx (2 h) than for the secretory mucins to become secreted into the mucus layer (5 h). Furthermore, infection with H. pylori reduces the rate of mucin turnover and decreases the levels of Muc1. Since H. pylori colonizes this mucus niche, the decreased turnover rate indicates that H. pylori creates a more stable and favorable environment for itself by impairing the defense mechanism for clearing the mucosal surface of pathogens by mucus flow.
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| 5. |
- Adamsson, Jenni, 1977, et al.
(författare)
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Gastric expression of IL-17A and IFNγ in Helicobacter pylori infected individuals is related to symptoms
- 2017
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Ingår i: Cytokine. - : Elsevier BV. - 1043-4666. ; 99, s. 30-34
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Tidskriftsartikel (refereegranskat)abstract
- Background: Chronic infection with Helicobacter pylori leads to gastritis and in a subpopulation of infected individuals to ulcers and cancer. Bacterial virulence factors and host immune inflammatory responses are risk factors related to disease. CD4+ T cells secrete cytokines that promote inflammation and an anti-bacterial response in the gastric mucosa during infection. The aim of the study was to investigate the pattern of expression of CD4+ T cell derived cytokines, IL-17A and IFNγ in paired antrum and corpus biopsies and correlate it to H. pylori infection outcome. Methods: Gene and protein expression of IL-17A and IFNγ was analyzed in gastric biopsies from H. pylori infected subjects with non-ulcer dyspepsia (NUD) or gastric ulcer; and for comparison uninfected individuals. Results: Upregulation of IL-17A and IFNγ gene expression was seen in corpus and antrum biopsies of H. pylori infected individuals with NUD compared to in uninfected controls. The expression of these cytokines correlated significantly with each other. Immunofluorescence staining revealed increased frequencies of IL-17A+ and IFNγ+ cells in antrum biopsies of gastric ulcer patients compared to of H. pylori infected NUD individuals; positive cells were not detected in any of the biopsies of uninfected controls. The frequencies of IFNγ and IL-17A+ cells correlated positively with inflammation in the antrum, but not the corpus, of H. pylori infected individuals. In the antrum, while there was no significant evidence of correlation between IFNγ and bacterial score, a positive correlation between bacterial score and IL-17A+ cells was seen. Conclusions: In H. pylori infected individuals, the frequencies of IFNγ and IL-17A+ cells were increased in the antrum, particularly in patients with H. pylori induced gastric ulcers. Even though H. pylori colonized both the corpus and antrum regions of the stomach, the cytokine responses and subsequent pathology were mainly detected in the antrum. © 2017 Elsevier Ltd
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| 6. |
- Ahlmanner, Filip, et al.
(författare)
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CD39+ regulatory T cells accumulate in colon adenocarcinomas and display markers of increased suppressive function
- 2018
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 9:97, s. 36993-37007
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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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| 7. |
- Akeus, Paulina, et al.
(författare)
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Altered chemokine production and accumulation of regulatory T cells in intestinal adenomas of APC(Min/+) mice.
- 2014
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Ingår i: Cancer immunology, immunotherapy : CII. - : Springer Science and Business Media LLC. - 1432-0851 .- 0340-7004. ; 63:8, s. 807-19
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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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| 8. |
- Akeus, Paulina, et al.
(författare)
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Regulatory T cells control endothelial chemokine production and migration of T cells into intestinal tumors of APC(min/+) mice
- 2018
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Ingår i: Cancer Immunology Immunotherapy. - : Springer Science and Business Media LLC. - 0340-7004 .- 1432-0851. ; 67:7, s. 1067-1077
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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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| 9. |
- Akeus, Paulina, et al.
(författare)
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Treg-cell depletion promotes chemokine production and accumulation of CXCR3(+) conventional T cells in intestinal tumors.
- 2015
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Ingår i: European journal of immunology. - : Wiley. - 1521-4141 .- 0014-2980. ; 45:6, s. 1654-66
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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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| 10. |
- Bergin, Philip, 1975, et al.
(författare)
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Gastric gelatinase B/matrix metalloproteinase-9 is rapidly increased in Helicobacter felis-induced gastritis.
- 2008
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Ingår i: FEMS immunology and medical microbiology. - 0928-8244. ; 52:1, s. 88-98
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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. |
- Eklund, Ella A, et al.
(författare)
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KRAS mutations impact clinical outcome in metastatic non-small cell lung cancer.
- 2022
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 14:9
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Tidskriftsartikel (refereegranskat)abstract
- There is an urgent need to identify new predictive biomarkers for treatment response to both platinum doublet chemotherapy (PT) and immune checkpoint blockade (ICB). Here, we evaluated whether treatment outcome could be affected by KRAS mutational status in patients with metastatic (Stage IV) non-small cell lung cancer (NSCLC). All consecutive patients molecularly assessed and diagnosed between 2016-2018 with Stage IV NSCLC in the region of West Sweden were included in this multi-center retrospective study. The primary study outcome was overall survival (OS). Out of 580 Stage IV NSCLC patients, 35.5% harbored an activating mutation in the KRAS gene (KRASMUT). Compared to KRAS wild-type (KRASWT), KRASMUT was a negative factor for OS (p = 0.014). On multivariate analysis, KRASMUT persisted as a negative factor for OS (HR 1.478, 95% CI 1.207-1.709, p < 0.001). When treated with first-line platinum doublet (n = 195), KRASMUT was a negative factor for survival (p = 0.018), with median OS of 9 months vs. KRASWT at 11 months. On multivariate analysis, KRASMUT persisted as a negative factor for OS (HR 1.564, 95% CI 1.124-2.177, p = 0.008). KRASMUT patients with high PD-L1 expression (PD-L1high) had better OS than PD-L1highKRASWT patients (p = 0.036). In response to first-line ICB, KRASMUT patients had a significantly (p = 0.006) better outcome than KRASWT patients, with a median OS of 23 vs. 6 months. On multivariable Cox analysis, KRASMUT status was an independent prognostic factor for better OS (HR 0.349, 95% CI 0.148-0.822, p = 0.016). kRAS mutations are associated with better response to treatment with immune checkpoint blockade and worse response to platinum doublet chemotherapy as well as shorter general OS in Stage IV NSCLC.
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| 12. |
- Flach, Carl-Fredrik, 1977, et al.
(författare)
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A truncated form of HpaA is a promising antigen for use in a vaccine against Helicobacter pylori.
- 2011
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Ingår i: Vaccine. - : Elsevier BV. - 1873-2518 .- 0264-410X. ; 29:6, s. 1235-1241
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Tidskriftsartikel (refereegranskat)abstract
- HpaA is a Helicobacter pylori-specific lipoprotein that has been shown to be an effective protective antigen for mucosal vaccination against H. pylori infection in mice. However, detergents are needed for the purification of full-length HpaA (HpaA(full)), which might confer toxicity, thus making HpaA(full) unsuitable for use in a human vaccine. We here describe a recombinantly produced truncated version of HpaA (HpaA(trunc)), which is easily purified without the use of detergents. Evaluation in the murine H. pylori infection model showed that sublingual immunization with HpaA(trunc) was equally immunogenic and protective as immunization with HpaA(full). Immunization with a combination of HpaA(trunc) and recombinant UreB protein induced strong immune responses to both antigens and importantly had a strong synergistic effect on protection, associated with synergistically increased expression of IL-17 in the stomach. Notably, sublingual immunization with HpaA(trunc) and UreB was superior to corresponding intragastric immunization with regard to the level of protection induced. In conclusion, HpaA(trunc) is a promising, readily produced, non-toxic recombinant antigen for inclusion in a mucosal vaccine against H. pylori infection, which may preferably be given sublingually together with UreB.
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| 13. |
- Flach, Carl-Fredrik, 1977, et al.
(författare)
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Mucosal vaccination increases local chemokine production attracting immune cells to the stomach mucosa of Helicobacter pylori infected mice.
- 2012
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Ingår i: Vaccine. - : Elsevier BV. - 1873-2518 .- 0264-410X. ; 30:9, s. 1636-1643
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Tidskriftsartikel (refereegranskat)abstract
- Background: Vaccination is an attractive approach for the prevention of Helicobacter pylori infection and disease. In a mouse model, infection induces an accumulation of dendritic cells, macrophages, granulocytes, and B- and T cells to the stomach mucosa, which is further heightened when the infection is preceded by a mucosal immunization. We have studied the chemokines and chemokine receptors guiding infection- and vaccination-induced immune cells to the stomach and their relation to protection against H. pylori infection in mice. Materials and methods: C57BL/6 mice were immunized sublingually with H. pylori lysate antigens and cholera toxin adjuvant or left unimmunized, and then challenged with live H. pylori bacteria. Stomach tissue was taken at 3, 7, 14 and 21 days after challenge and bacterial colonization, chemokine and chemokine receptor gene expression, and influx of cells into the stomach mucosa were evaluated. Results: RT-PCR array screening revealed differential expression of a broad range of chemokine and chemokine receptor genes between immunized and unimmunized mice. A significant upregulation of chemokines known to attract, among other cells, eosinophils (CCL8), T cells (CXCL10, CXCL11) and neutrophils (CXCL2, CXCL5) and of their cognate receptors CCR3, CXCR3 and CXCR2, preceded or coincided with vaccine-induced protection, which was first evident 7 days after infection and was then sustained at the later time-points. Consistent with the increase in chemokines and chemokine receptors flow cytometric analysis indicated a sequential accumulation of CD4+ T cells, eosinophils, neutrophils and CD103+ dendritic cells in the gastric lamina propria of immunized mice. Conclusions: This study provides insights into vaccination-induced chemokines that guide the influx of protective immune cells into the stomach of H. pylori infected mice.
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| 14. |
- Flach, Carl-Fredrik, 1977, et al.
(författare)
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Pro-inflammatory cytokine gene expression in the stomach correlates with vaccine-induced protection against Helicobacter pylori infection in mice: an important role for interleukin-17 during the effector phase. : Immune correlates to H. pylori protection
- 2011
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Ingår i: Infection and immunity. - 1098-5522. ; 79:2, s. 879-886
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Tidskriftsartikel (refereegranskat)abstract
- CD4(+) T cells have been shown to be essential for vaccine-induced protection against Helicobacter pylori infection in mice. Less is known about relative contributions of individual cell subpopulations, such as TH1 and TH17 cells, and their associated cytokines. The aim of the present study was to find immune correlates to vaccine-induced protection and further study their role in protection against H. pylori infection. Immunized and unimmunized mice were challenged with H. pylori and immune responses were compared. Vaccine-induced protection was assessed by measuring H. pylori colonization in the stomach. Gastric gene expression of TH1- and/or TH17-associated cytokines was analyzed by quantitative PCR and contributions of individual cytokines to protection were evaluated by antibody-mediated in vivo neutralization. By analyzing immunized and unimmunized mice a significant inverse correlation could be demonstrated between levels of interleukin (IL)-12p40, tumor necrosis factor α (TNF), interferon γ (IFNγ) and IL-17 gene expression and number of H. pylori in the stomach of individual animals after challenge. In a kinetic study, up-regulation of TNF, IFNγ and IL-17 coincided with vaccine-induced protection 7 days after H. pylori challenge and was sustained for at least 21 days. In vivo neutralization of these cytokines during the effector phase of the immune response revealed a significant role for IL-17, but not for IFNγ or TNF, in vaccine-induced protection. In conclusion, although both TH1- and TH17-associated gene expression in the stomach correlate with vaccine-induced protection against H. pylori infection, our study indicates that mainly TH17 effector mechanisms are of critical importance to protection.
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| 15. |
- George-Chandy, Annie, 1969, et al.
(författare)
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Oral tolerance induction by mucosal administration of cholera toxin B-coupled antigen involves T-cell proliferation in vivo and is not affected by depletion of CD25+ T cells.
- 2006
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Ingår i: Immunology. - : Wiley. - 0019-2805 .- 1365-2567. ; 118:3, s. 311-20
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Tidskriftsartikel (refereegranskat)abstract
- Oral administration of antigens coupled to the B subunit of the cholera toxin (CTB) can dramatically reduce the amount of antigen needed for tolerance induction and has been used in several animal models to suppress conditions where the immune system overreacts to foreign and self-antigens. In this study, the cellular events following oral administration of CTB-coupled antigen was investigated. As a model system, limited numbers of CSFE-labelled cells from influenza haemagglutinin peptide (HApep) T-cell transgenic mice were transferred to wild type mice and the mice were then given CTB-coupled HApep orally. The inductive events of CTB-induced tolerance was characterized by extensive proliferation of HApep-specific T cells in the mesenteric lymph nodes (MLNs) and in the spleen. The proliferating cells up-regulated the gut homing molecule alpha4beta7 and down-regulated the high endothelial venule binding molecule L-selectin. Addition of the whole cholera toxin (CT) to CTB-HApep showed a similar pattern as CTB-HApep feeding, with antigen-specific proliferation in the MLN and spleen and expression of alpha4beta7 on the proliferating cells. However, addition of CT to CTB-HApep, produced a stronger and faster proliferative response and abrogated CTB-HA mediated oral tolerance. Feeding of CTB-HApep expanded CD25+ cells in the MLNs. CTB-induced oral tolerance could, however, not be explained by CD25+ dependent regulatory activity, as oral administration of CTB-HApep to mice depleted of CD25+ cells still gave rise to systemic tolerance. Thus, several mechanisms might co-orchestrate the systemic tolerance seen in response to feeding with CTB-coupled antigen.
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| 16. |
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| 17. |
- Hallqvist, Andreas, 1973, et al.
(författare)
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Immune checkpoint blockade and biomarkers of clinical response in non–small cell lung cancer
- 2020
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Ingår i: Scandinavian Journal of Immunology. - : Wiley. - 0300-9475 .- 1365-3083. ; 92:6
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Tidskriftsartikel (refereegranskat)abstract
- Immunotherapy with PD-1 and PD-L1 inhibitors has revolutionized the treatment for patients with NSCLC the last years with increased overall survival and in particular increased number of long-time survivors in patients with metastatic disease. It is now a treatment of choice for patients with distant metastases (stage IV) and in conjunction with chemoradiotherapy for patients with limited spread confined to the chest (stage III). PD-1 inhibition has been proven to be superior to standard chemotherapy, both as a single treatment and when combined with either chemotherapy or CTLA-4 inhibition. Despite the success of immunotherapy, the majority of patients do not respond or relapse within a short time frame. Biomarkers that would help to properly select patients with a high likelihood of clinical response to PD-1 and PD-L1 inhibitors are scarce and far from optimal, and only one (PD-L1 expression) has reached clinical practice. Thus for immunotherapy to be effective, the discovery and validation of additional biomarkers is critical for patient selection and prediction of clinical response. In this mini-review, we give an overview of current clinical management of NSCLC including treatment landscape with regard to immunotherapy, as well as discuss the current genetic and immune cell biomarker studies and their potential for introduction into clinical practice. © 2020 The Authors. Scandinavian Journal of Immunology published by John Wiley & Sons Ltd on behalf of The Scandinavian Foundation for Immunology
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| 18. |
- Holmgren, Jan, 1944, et al.
(författare)
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Mucosal adjuvants and anti-infection and anti-immunopathology vaccines based on cholera toxin, cholera toxin B subunit and CpG DNA
- 2005
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Ingår i: Immunology Letters. - : Elsevier. - 0165-2478 .- 1879-0542. ; 97:2, s. 181-8
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Tidskriftsartikel (refereegranskat)abstract
- Mucosal immunisation may be used both to protect the mucosal surfaces against infections and as a means for immunological treatment of peripheral immunopathological disorders through the induction of systemic antigen-specific tolerance ('oral tolerance'). The development of mucosal vaccines, whether for prevention of infectious diseases or for oral tolerance immunotherapy, requires efficient antigen delivery and adjuvant systems that can help to present the appropriate vaccine or immunotherapy antigens to the mucosal immune system. The most potent (but also toxic) mucosal adjuvants are cholera toxin (CT) and the closely related Escherichia coli heat-labile enterotoxin (LT), and much effort and significant progress have been made recently to generate toxicologically acceptable derivatives of these toxins with retained adjuvant activity. Among these are the non-toxic, recombinantly produced cholera toxin B-subunit (CTB). CTB is a specific protective antigen component of a widely registered oral cholera vaccine as well as a promising vector for either giving rise to mucosal anti-infective immunity or for inducing peripheral anti-inflammatory tolerance to chemically or genetically linked foreign antigens administered mucosally. CT and CTB have also recently been used as combined vectors and adjuvants for markedly promoting ex vivo dendritic cell (DC) vaccination with different antigens and also steering the immune response to the in vivo-reinfused DCs towards either broad Th1 + Th2 + CTL immunity (CT) or Th2 or tolerance (CTB). Another type of mucosal adjuvants is represented by bacterial DNA or synthetic oligodeoxynucleotides containing CpG-motifs, which especially when linked to CTB have been found to effectively stimulate both innate and adaptive mucosal immune responses. The properties and clinical potential of these different classes of adjuvants are being discussed. © 2004 Elsevier B.V. All rights reserved.
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| 19. |
- Holmgren, Jan, 1944, et al.
(författare)
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Preclinical immunogenicity and protective efficacy of an oral Helicobacter pylori inactivated whole cell vaccine and multiple mutant cholera toxin: A novel and non-toxic mucosal adjuvant
- 2018
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Ingår i: Vaccine. - : Elsevier BV. - 0264-410X. ; 36:41, s. 6223-6230
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Tidskriftsartikel (refereegranskat)abstract
- Mucosal vaccines against Helicobacter pylori consisting of either whole cell bacteria or recombinant antigens can induce immune protection against challenge in mice only when co-administrated with a strong mucosal adjuvant such as cholera toxin (CT) or Escherichia coli heat labile enterotoxin (LT). The strong enterotoxicity of these adjuvants however preclude their use in human vaccines. The recently developed multiple mutant CT (mmCT) is a strong, yet practically non-toxic novel mucosal adjuvant which here was admixed with a formalin-inactivated H. pylori whole cell vaccine (WCV) as a potential vaccine candidate against H. pylori infection. We report that intragastric immunizations with H. pylori WCV together with mmCT, similar to immunization with WCV together with CT, resulted in 50-125-fold reduction in colonization of H. pylori in the stomach of mice associated with rises in both serum IgG and intestinal-mucosal IgA anti-H. pylori antibody responses and strong T cell and IFN gamma and IL-17A cytokine responses. Data presented in this study also supports that the proposed vaccine can be grown in a bioreactor and would be effective against infection caused by a multitude of pathogenic H. pylori strains isolated from patients from various continents. The results warrant immunization studies in humans to evaluate the safety, immunogenicity and efficacy of the proposed H. pylori WCV and mmCT. (C) 2018 Published by Elsevier Ltd.
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| 20. |
- Longet, S., et al.
(författare)
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An oral alpha-galactosylceramide adjuvanted Helicobacter pylori vaccine induces protective IL-1R-and IL-17R-dependent Th1 responses
- 2019
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Ingår i: Npj Vaccines. - : Springer Science and Business Media LLC. - 2059-0105. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- Helicobacter pylori causes chronic gastric infection that can lead to peptic ulcers and is an identified risk factor for gastric cancer development. Although much effort has been put into the development of a Helicobacter pylori vaccine over the last three decades, none has yet reached clinical application. Specific challenges pertaining to effective H. pylori vaccine development include the lack of proven vaccine-effective antigens and safe mucosal adjuvants to enhance local immune responses as well as the lack of accepted correlates of protection. Herein, we demonstrate that prophylactic intragastric immunisation with a whole-cell killed H. pylori antigen administered together with the non-toxic oral adjuvant alpha-galactosylceramide (alpha-GalCer) induced effective immune protection against H. pylori infection in mice, which was of similar magnitude as when using the "gold standard" cholera toxin as adjuvant. We further describe that this alpha-GalCer-adjuvanted vaccine formulation elicited strong intestinal and systemic Th1 responses as well as significant antigen-specific mucosal and systemic antibody responses. Finally, we report that the protective intestinal Th1 responses induced by alpha-GalCer are dependent on CD1d, IL-1R as well as IL-17R signalling. In summary, our results show that alpha-GalCer is a promising adjuvant for inclusion in an oral vaccine against H. pylori infection.
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| 21. |
- Nyström, Johanna, 1977, et al.
(författare)
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Mucosal immune responses are related to reduction of bacterial colonization in the stomach after therapeutic Helicobacter pylori immunization in mice
- 2006
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Ingår i: Microbes Infect. - : Elsevier BV. - 1286-4579. ; 8:2, s. 442-9
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to investigate the capacity of oral and parenteral therapeutic immunization to reduce the bacterial colonization in the stomach after experimental Helicobacter pylori infection, and to evaluate whether any specific immune responses are related to such reduction. C57BL/6 mice were infected with H. pylori and thereafter immunized with H. pylori lysate either orally together with cholera toxin or intraperitoneally (i.p.) together with alum using immunization protocols that previously have provided prophylactic protection. The effect of the immunizations on H. pylori infection was determined by quantitative culture of H. pylori from the mouse stomach. Mucosal and systemic antibody responses were analyzed by ELISA in saponin extracted gastric tissue and serum, respectively, and mucosal CD4+ T cell responses by an antigen specific proliferation assay. Supernatants from the proliferating CD4+ T cells were analyzed for Th1 and Th2 cytokines. The oral, but not the parenteral therapeutic immunization induced significant decrease in H. pylori colonization compared to control infected mice. The oral immunization resulted in markedly elevated levels of serum IgG+M as well as gastric IgA antibodies against H. pylori antigen and also increased H. pylori specific mucosal CD4+ T cell proliferation with a Th1 cytokine profile. Although the parenteral immunization induced dramatic increases in H. pylori specific serum antibody titers, no increases in mucosal antibody or cellular immune responses were observed after the i.p. immunization compared to control infected mice. These findings suggest that H. pylori specific mucosal immune responses with a Th1 profile may provide therapeutic protection against H. pylori.
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| 22. |
- Pandya, Jayesh M., et al.
(författare)
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Effects of conventional immunosuppressive treatment on CD244+(CD28null) and FOXP3+T cells in the inflamed muscle of patients with polymyositis and dermatomyositis
- 2016
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Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6354 .- 1478-6362. ; 18
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Tidskriftsartikel (refereegranskat)abstract
- Background: T-cell infiltrates may persist in muscle tissue of polymyositis (PM) and dermatomyositis (DM) patients despite aggressive immunosuppressive treatment. Here, we investigated to what extent persistent T cells in affected muscle were FOXP3+, a marker for regulatory T cells (Tregs), or CD244+, a marker for CD28null T cells, and whether their presence correlated to clinical outcome. The sensitivity of CD28null T cells towards glucocorticoid and Treg-mediated immunosuppression was also investigated. Methods: Muscle biopsies from 16 newly diagnosed or untreated patients with PM/DM were investigated by immunohistochemistry for expression of CD3, FOXP3 and CD244 before and after treatment with glucocorticoids and immunosuppressive agents. For clinical evaluation, serum levels of creatine kinase, muscle performance (FI and MMT8), disease activity (MITAX) and disability (HAQ) were measured. In vitro suppressive effects of glucocorticoids and Tregs on T-cell activation were measured by CD69 upregulation. Results: Before treatment, CD244+ cells were present at higher proportions compared to FOXP3+ cells in the inflamed muscle. Following treatment, FOXP3+ cell numbers decreased while CD244+ cells persisted. Patients with impaired muscle function (< 75 % FI) post-treatment had higher levels of CD244+ cells in the follow-up biopsy compared to those with FI > 75 %. MITAX and HAQ correlated with the number of CD244+ cells post-treatment. CD4+CD28null T cells displayed lower sensitivity towards both glucocorticoid and Treg-mediated immunosuppression in vitro compared to their CD28+ counterparts. Conclusions: Poor outcome in patients with myositis following immunosuppressive therapy was linked to persistence of CD244+ (CD28null) T cells in muscle tissue, suggesting their resistance against immunosuppression. A relative loss of regulatory T cells could also contribute to poor clinical outcome given their recently ascribed role in muscle tissue regeneration.
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| 23. |
- Quiding-Järbrink, Marianne, 1964, et al.
(författare)
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Enhanced M1 macrophage polarization in human Helicobacter pylori-associated atrophic gastritis and in vaccinated mice
- 2010
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Ingår i: PLOS one. - : Public Library of Science (PLoS). - 1932-6203. ; 5:11
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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.
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| 24. |
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| 25. |
- Raghavan, Sukanya, 1974, et al.
(författare)
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Conditional Deletion of Pdcd1 Identifies the Cell-Intrinsic Action of PD-1 on Functional CD8 T Cell Subsets for Antitumor Efficacy
- 2021
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Programmed cell death-1 (PD-1) blockade has a profound effect on the ability of the immune system to eliminate tumors, but many questions remain about the cell types involved and the underlying mechanisms of immune activation. To shed some light on this, the cellular and molecular events following inhibition of PD-1 signaling was investigated in the MC-38 colon carcinoma model using constitutive (PD-1 KO) and conditional (PD1cKO) mice and in wild-type mice treated with PD-1 antibody. The impact on both tumor growth and the development of tumor immunity was assessed. In the PD-1cKO mice, a complete deletion of Pdcd1 in tumor-infiltrating T cells (TILs) after tamoxifen treatment led to the inhibition of tumor growth of both small and large tumors. Extensive immune phenotypic analysis of the TILs by flow and mass cytometry identified 20-different T cell subsets of which specifically 5-CD8 positive ones expanded in all three models after PD-1 blockade. All five subsets expressed granzyme B and interferon gamma (IFN gamma). Gene expression analysis of the tumor further supported the phenotypic analysis in both PD-1cKO- and PD-1 Ab-treated mice and showed an upregulation of pathways related to CD4 and CD8 T-cell activation, enhanced signaling through costimulatory molecules and IFN gamma, and non-T-cell processes. Altogether, using PD-1cKO mice, we define the intrinsic nature of PD-1 suppression of CD8 T-cell responses in tumor immunity.
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