| 1. |
- Cervenak, L, et al.
(författare)
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Abolished angiogenicity and tumorigenicity of Burkitt lymphoma by interleukin-10
- 2000
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Ingår i: Blood. - 0006-4971. ; 96:7, s. 73-2568
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Tidskriftsartikel (refereegranskat)abstract
- Because of its immunosuppressive properties, interleukin-10 (IL-10) is thought to play an important role in a number of human disease states, including inflammation, autoimmunity, and transplant rejection. In this study, we demonstrate that introduction of human or viral IL-10 genes into Burkitt's lymphoma cells markedly reduced their ability to grow as subcutaneous (sc) tumors in SCID mice. In vivo assays for angiogenesis revealed an inhibition of the angiogenic capacity of the IL-10-transfected lines. Recombinant human IL-10 abolished and viral IL-10 reduced vascular endothelial growth factor (VEGF)-165-induced neovascularization. Furthermore, IL-10 blocked the VEGF- and fibroblast growth factor (FGF)-2-induced proliferation of microvascular endothelial cells in vitro. The current observations suggest a direct role for IL-10 in the prevention of angiogenesis in human lymphoid malignancies.
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| 2. |
- 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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| 3. |
- Sjökvist Ottsjö, Louise, 1986, et al.
(författare)
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Defining the Roles of IFN-gamma and IL-17A in Inflammation and Protection against Helicobacter pylori Infection
- 2015
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:7
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Tidskriftsartikel (refereegranskat)abstract
- CD4(+) T cells have been shown to be essential for vaccine-induced protection against Helicobacter pylori infection. However, the effector mechanisms leading to reductions in the gastric bacterial loads of vaccinated mice remain unclear. We have investigated the function of IFN-gamma and IL-17A for vaccine-induced protection and inflammation (gastritis) using IFN-gamma-gene-knockout (IFN-gamma(-/-)) mice, after sublingual or intragastric immunization with H. pylori lysate antigens and cholera toxin. Bacteria were enumerated in the stomachs of mice and related to the gastritis score and cellular immune responses. We report that sublingually and intragastrically immunized IFN-gamma(-/-) mice had significantly reduced bacterial loads similar to immunized wild-type mice compared to respective unimmunized infection controls. The reduction in bacterial loads in sublingually and intragastrically immunized IFN-gamma(-/-) mice was associated with significantly higher levels of IL-17A in stomach extracts and lower gastritis scores compared with immunized wild-type mice. To study the role of IL-17A for vaccine-induced protection in sublingually immunized IFN-gamma(-/-) mice, IL-17A was neutralized in vivo at the time of infection. Remarkably, the neutralization of IL-17A in sublingually immunized IFN-gamma(-/-) mice completely abolished protection against H. pylori infection and the mild gastritis. In summary, our results suggest that IFN-gamma responses in the stomach of sublingually immunized mice promote vaccine-induced gastritis, after infection with H. pylori but that IL-17A primarily functions to reduce the bacterial load.
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| 4. |
- Sjökvist Ottsjö, Louise, 1986, et al.
(författare)
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The role of IL-17A and IFN gamma in vaccine-induced protection against Helicobacter pylori infection
- 2014
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Ingår i: Cytokine. - : Elsevier BV. - 1043-4666 .- 1096-0023. ; 70:1, s. 65-65
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Konferensbidrag (refereegranskat)abstract
- The aim of the project was to evaluate mechanisms of vaccine-induced protection against Helicobacter pylori infection in mice. In particular, to elucidate the role of cytokines induced by H. pylori infection in promoting the protective or pathogenic immune responses in the stomach. Our group has previously shown that sublingual (SL; under the tongue) vaccination with H. pylori antigens and cholera toxin as an adjuvant was efficient in reducing the bacterial load in the stomach of mice with enhanced IFNγ and IL-17A responses in the stomach compared to unvaccinated mice. Using gene knockout mice and neutralizing antibodies, the impact of cytokines IFNγ and IL-17A on the bacterial load, immune responses and gastric inflammation was addressed. We report that after SL vaccination, IFNγ gene knockout (IFNγ−/−) mice were protected against H. pylori infection and had elevated IL-17A production and lower inflammation scores in the stomach compared to vaccinated wild-type mice. Furthermore, in vivo neutralization of IL-17A in sublingually vaccinated IFNγ−/−mice totally abrogated protection against H. pylori infection. We next examined the mechanisms for induction and maintenance of IL −17A after SL vaccination by studying the role of cytokines IL−1β and IL-23 using gene knockout mice either lacking IL-1 signaling or IL-23 production respectively. Our results show that after SL vaccination with H. pylori antigens and cholera toxin, IL-23p19−/− mice, but not IL-1RI−/− mice were protected against H. pylori infection. Gastric IL-17A responses could not be induced after challenge in the absence of IL-1 signaling, but could be maintained in the absence of IL-23. In summary, we report that IL-17A is important in reducing the bacterial load on the stomach of vaccinated mice which is dependent on intact IL-1 signaling, while IFNγ may promote inflammation. Based on our results, mechanisms of vaccine-induced protection against H. pylori infection and the role of specific cytokines will be discussed.
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