| 1. |
- Dutta, Nikita, 1992, et al.
(author)
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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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In: Frontiers in Oncology. - : Frontiers Media SA. - 2234-943X. ; 12
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Journal article (peer-reviewed)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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| 2. |
- Lundgren, Anna, 1974, et al.
(author)
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Mucosal FOXP3-expressing CD4+ CD25high regulatory T cells in Helicobacter pylori-infected patients
- 2005
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In: Infect Immun. ; 73:1, s. 523-31
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Journal article (peer-reviewed)abstract
- Helicobacter pylori chronically colonizes the stomach and duodenum and causes peptic ulcers or gastric adenocarcinoma in 10 to 20% of infected individuals. We hypothesize that the inability of patients to clear H. pylori infections is a consequence of active suppression of the immune response. Here we show that H. pylori-infected individuals have increased frequencies of CD4(+) CD25(high) T cells in both the stomach and duodenal mucosa compared to uninfected controls. These cells have the phenotype of regulatory T cells, as they express FOXP3, a key gene for the development and function of regulatory T cells, as well as high levels of the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) protein. In contrast, mucosal CD4(+) CD25(low) and CD4(+) CD25(-) cells express little FOXP3 mRNA and low levels of the CTLA-4 protein. Mucosal CD4(+) CD25(high) T cells are present in individuals with asymptomatic H. pylori infections as well as in duodenal ulcer patients. The frequencies of CD4(+) CD25(high) cells are also increased in the stomachs of H. pylori-infected patients with gastric adenocarcinoma, particularly in cancer-affected tissues. These findings suggest that regulatory T cells may suppress mucosal immune responses and thereby contribute to the persistence of H. pylori infections.
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| 3. |
- Akter, S., et al.
(author)
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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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In: Helicobacter. - : Wiley. - 1083-4389 .- 1523-5378. ; 24:6
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Journal article (peer-reviewed)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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| 4. |
- Bhuiyan, Taufiqur Rahman, 1974, et al.
(author)
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Cholera caused by Vibrio cholerae O1 induces T-cell responses in the circulation.
- 2009
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In: Infection and immunity. - 1098-5522. ; 77:5, s. 1888-93
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Journal article (peer-reviewed)abstract
- Considerable effort is being made to understand the acute and memory antibody responses in natural cholera infection, while rather less is known about the roles of cellular immune responses involving T and B lymphocytes. We studied responses in adult patients hospitalized with cholera caused by Vibrio cholerae O1. Peripheral blood mononuclear cells from patients (n = 15) were analyzed by flow cytometry after stimulation with V. cholerae O1 membrane protein (MP) or toxin-coregulated pilus antigen (TcpA). The gamma interferon (IFN-gamma) and interleukin-13 (IL-13) responses in stimulated-lymphocyte supernatants were studied. The responses were compared with those of healthy controls (n = 10). Patients responded with increased frequencies of gut-homing CD4(+) T cells (CD4(+) beta7(+)), gut-homing CD8(+) T cells (CD8(+) beta7(+)), and gut-homing B cells (CD19(+) beta7(+)) at the early and/or late convalescent stages compared to the acute stage. After stimulation with MP or TcpA, proliferation of CD4(+) and CD8(+) T cells was increased at the acute stage and/or early convalescent stage compared to healthy controls. Increased IL-13 and IFN-gamma responses were observed after antigenic stimulation at the acute and convalescent stages compared to healthy controls. Thus, increases in the levels of gut-homing T and B cells, as well as involvement of CD8 and CD4 Th1-mediated (IFN-gamma) and CD4 Th2-mediated (IL-13) cytokine responses, take place in acute dehydrating disease caused by V. cholerae O1. Further studies are needed to determine if such responses are also stimulated after immunization with oral cholera vaccines and if these responses play a role in protection following exposure to cholera.
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| 5. |
- Bhuiyan, Taufiqur Rahman, 1974, et al.
(author)
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Comparison of mucosal B- and T-cell responses in Helicobacter pylori-infected subjects in a developing and a developed country.
- 2008
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In: FEMS immunology and medical microbiology. - 0928-8244. ; 54:1, s. 70-9
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Journal article (peer-reviewed)abstract
- Helicobacter pylori is highly endemic in developing countries, but comparatively little is known about mucosal immune responses to H. pylori in these settings. Therefore, we have compared B- and T-cell responses, with a focus on the gastrointestinal mucosa, in H. pylori-infected adults in a developing (Bangladesh) and a developed (Sweden) country. We found comparable numbers of CD19(+) B cells and CD4 (+)T cells and similar levels of H. pylori-specific IgA antibodies in gastric mucosa from Bangladeshi and Swedish volunteers. However, about threefold higher numbers of CD19(+) B cells and 12-fold increased levels of H. pylori-specific IgA antibodies were found in the duodenum of Bangladeshi subjects. The gastric and duodenal immune responses in Bangladeshi asymptomatic carriers and duodenal ulcer patients were comparable. Bangladeshi subjects had about twofold lower titers of H. pylori-specific IgA and IgG antibodies in the circulation compared with Swedish volunteers. In conclusion, our findings suggest that Bangladeshi individuals have comparable gastric immune responses, but lower systemic antibody responses to H. pylori, compared with Swedish volunteers. Increased inflammation is present in the duodenum of Bangladeshi volunteers, maybe as a result of frequent exposure to enteric infections in these individuals.
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| 6. |
- Bhuiyan, Taufiqur Rahman, 1974, et al.
(author)
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Evaluation of immune responses to an oral typhoid vaccine, Ty21a, in children from 2 to 5 years of age in Bangladesh
- 2014
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In: Vaccine. - : Elsevier BV. - 0264-410X. ; 32:9, s. 1055-1060
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Journal article (peer-reviewed)abstract
- Young children are very susceptible to typhoid fever, emphasizing the need for vaccination in under five age groups. The parenteral Vi polysaccharide vaccine is not immunogenic in children under 2 years and the oral Ty21a vaccine (Vivotif) available in capsular formulation is only recommended for those over 5 years. We studied immune responses to a liquid formulation of Ty21a in children 2-5 years of age. Since children in developing countries are in general hypo responsive to oral vaccines, the study was designed to determine if anti-helminthic treatment prior to vaccination, improves responses. In a pilot study in 20 children aged 4-5 years, the immune responses in plasma and in antibody in lymphocyte secretions (ALS) to the enteric coated capsule formulation of Ty21a was found to be comparable to a liquid formulation (P > 0.05). Based on this, children (n = 252) aged ≥2-<3 years and ≥3-<5 years were randomized to receive a liquid formulation of Ty21a with and without previous anti-helminthic treatment. The vaccine was well tolerated with only a few mild adverse events recorded in <1% of the children. De-worming did not improve immune responses and both age groups developed 32-71% IgA, IgG, and IgM responses in plasma and 63-86% IgA responses in ALS and stool specimens to a membrane preparation (MP) of Ty21a. An early MP specific proliferative T cell response was also seen. We recommend that safety and efficacy studies with a liquid formulation of the vaccine are carried out in children under five, including those less than two years of age to determine if Ty21a is protective in these age groups and applicable as a public health tool for controlling typhoid fever in high prevalence areas of typhoid fever including Bangladesh. © 2014 Elsevier Ltd. All rights reserved.
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| 7. |
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| 8. |
- Bhuiyan, Taufiqur Rahman, 1974, et al.
(author)
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Th1 and Th17 responses to Helicobacter pylori in Bangladeshi infants, children and adults
- 2014
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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:4
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Journal article (peer-reviewed)abstract
- Both Th1 and Th17 cells are important components of the immune response to Helicobacter pylori (Hp) in adults, but less is known about T cell responses to Hp during early childhood, when the infection is often acquired. We investigated Th1 and Th17 type responses to Hp in adults, children and infants in Bangladesh, where Hp is highly endemic. IL-17 and IFN-γ mRNA levels in gastric biopsies from Hp-infected Bangladeshi adults were analyzed and compared to levels in infected and uninfected Swedish controls. Since biopsies could not be collected from infants and children, cytokine responses in Bangladeshi infants (6-12 months), children (3-5 years) and adults (>19 years) were instead compared by stimulating peripheral blood mononuclear cells (PBMCs) with a Hp membrane preparation (MP) and analyzing culture supernatants by ELISA and cytometric bead array. We found significantly higher expression of IL-17 and IFN-γ mRNA in gastric mucosa of Hpinfected Bangladeshi and Swedish adults compared to uninfected Swedish controls. PBMCs from all age groups produced IL-17 and IFN-γ after MP stimulation, but little Th2 cytokines. IL-17 and IFN-γ were primarily produced by CD4+ T cells, since CD4 + T cell depleted PBMCs produced reduced amounts of these cytokines. Infant cells produced significantly more IL-17, but similar levels of IFN-γ, compared to adult cells after MP stimulation. In contrast, polyclonal stimulation induced lower levels IL-17 and IFN-γ in infant compared to adult PBMCs and CD4+ T cells. The strong IL-17 production in infants after MP stimulation was paralleled by significantly higher production of the IL-17 promoting cytokine IL-1β from infant compared to adult PBMCs and monocytes. In conclusion, these results show that T cells can produce high levels of IL-17 and IFN-β in response to Hp from an early age and indicate a potential role for IL-1β in promoting Th17 responses to Hp during infancy. © 2014 Bhuiyan et al.
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| 9. |
- Dahlén, Rahil, et al.
(author)
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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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In: Scandinavian Journal of Immunology. - : Wiley. - 0300-9475. ; 78:3, s. 275-284
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Journal article (peer-reviewed)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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| 10. |
- Enarsson, Karin, 1975, et al.
(author)
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Differential mechanisms for T lymphocyte recruitment in normal and neoplastic human gastric mucosa
- 2006
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In: Clin Immunol. - : Elsevier BV. ; 118:1, s. 24-34
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Research review (peer-reviewed)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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