5 results on '"Eltherington O"'
Search Results
2. Tolerogenic dendritic cells generated with dexamethasone and vitamin D3 regulate rheumatoid arthritis CD4+ T cells partly via transforming growth factor- β1.
- Author
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Anderson, A. E., Swan, D. J., Wong, O. Y., Buck, M., Eltherington, O., Harry, R. A., Patterson, A. M., Pratt, A. G., Reynolds, G., Doran, J.‐P., Kirby, J. A., Isaacs, J. D., and Hilkens, C. M. U.
- Subjects
DENDRITIC cells ,DEXAMETHASONE ,CHOLECALCIFEROL ,RHEUMATOID arthritis ,T cells ,TRANSFORMING growth factors-beta - Abstract
Tolerogenic dendritic cells (tolDC) are a new immunotherapeutic tool for the treatment of rheumatoid arthritis (RA) and other autoimmune disorders. We have established a method to generate stable tolDC by pharmacological modulation of human monocyte-derived DC. These tolDC exert potent pro-tolerogenic actions on CD4
+ T cells. Lack of interleukin (IL)−12p70 production is a key immunoregulatory attribute of tolDC but does not explain their action fully. Here we show that tolDC express transforming growth factor (TGF)-β1 at both mRNA and protein levels, and that expression of this immunoregulatory cytokine is significantly higher in tolDC than in mature monocyte-derived DC. By inhibiting TGF-β1 signalling we demonstrate that tolDC regulate CD4+ T cell responses in a manner that is at least partly dependent upon this cytokine. Crucially, we also show that while there is no significant difference in expression of TGF-βRII on CD4+ T cells from RA patients and healthy controls, RA patient CD4+ T cells are measurably less responsive to TGF-β1 than healthy control CD4+ T cells [reduced TGF-β-induced mothers against decapentaplegic homologue (Smad)2/3 phosphorylation, forkhead box protein 3 (FoxP3) expression and suppression of (IFN)-γ secretion]. However, CD4+ T cells from RA patients can, nonetheless, be regulated efficiently by tolDC in a TGF-β1-dependent manner. This work is important for the design and development of future studies investigating the potential use of tolDC as a novel immunotherapy for the treatment of RA. [ABSTRACT FROM AUTHOR]- Published
- 2017
- Full Text
- View/download PDF
3. The Mouse Papillomavirus Epigenetic Signature Is Characterised by DNA Hypermethylation after Lesion Regression.
- Author
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Tschirley AM, Stockwell PA, Rodger EJ, Eltherington O, Morison IM, Christensen N, Chatterjee A, and Hibma M
- Subjects
- Animals, Carcinoma, Squamous Cell genetics, DNA Methylation genetics, DNA, Viral genetics, Epigenomics methods, Female, Gene Expression genetics, Gene Expression Regulation, Neoplastic genetics, Gene Expression Regulation, Viral genetics, Mice, Mice, Inbred BALB C, Papillomavirus Infections virology, Promoter Regions, Genetic genetics, Skin Neoplasms genetics, Epigenesis, Genetic genetics, Papillomaviridae genetics, Papillomavirus Infections genetics
- Abstract
Papillomaviruses (PVs) are double-stranded DNA tumour viruses that can infect cutaneous and mucosal epidermis. Human papillomavirus (HPV) types have been linked to the causality of cutaneous squamous cell carcinoma (cSCC); however, HPV DNA is not always detected in the resultant tumour. DNA methylation is an epigenetic change that can contribute to carcinogenesis. We hypothesise that the DNA methylation pattern in cells is altered following PV infection. We tested if DNA methylation was altered by PV infection in the mouse papillomavirus (MmuPV1) model. Immunosuppressed mice were infected with MmuPV1 on cutaneous tail skin. Immunosuppression was withdrawn for some mice, causing lesions to spontaneously regress. Reduced representation bisulphite sequencing was carried out on DNA from the actively infected lesions, visibly regressed lesions, and mock-infected control mice. DNA methylation libraries were generated and analysed for differentially methylated regions throughout the genome. The presence of MmuPV1 sequences was also assessed. We identified 834 predominantly differentially hypermethylated fragments in regressed lesions, and no methylation differences in actively infected lesions. The promoter regions of genes associated with tumorigenicity, including the tumour suppressor protein DAPK1 and mismatch repair proteins MSH6 and PAPD7, were hypermethylated. Viral DNA was detected in active lesions and in some lesions that had regressed. This is the first description of the genome-wide DNA methylation landscape for active and regressed MmuPV1 lesions. We propose that the DNA hypermethylation in the regressed lesions that we report here may increase the susceptibility of cells to ultraviolet-induced cSCC.
- Published
- 2021
- Full Text
- View/download PDF
4. Targeting of tolerogenic dendritic cells to heat-shock proteins in inflammatory arthritis.
- Author
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Spiering R, Jansen MAA, Wood MJ, Fath AA, Eltherington O, Anderson AE, Pratt AG, van Eden W, Isaacs JD, Broere F, and Hilkens CMU
- Subjects
- Aged, Arthritis, Psoriatic pathology, Arthritis, Rheumatoid pathology, Bystander Effect, Case-Control Studies, Cell Proliferation, Epitopes immunology, Female, Humans, Killer Cells, Natural immunology, Male, Middle Aged, Phenotype, T-Lymphocytes, Regulatory immunology, Arthritis, Psoriatic immunology, Arthritis, Rheumatoid immunology, Dendritic Cells immunology, Heat-Shock Proteins metabolism, Immune Tolerance, Inflammation pathology
- Abstract
Background: Autologous tolerogenic dendritic cells (tolDC) are a promising therapeutic strategy for inflammatory arthritis (IA) as they can regulate autoantigen-specific T cell responses. Here, we investigated two outstanding priorities for clinical development: (i) the suitability of using heat-shock proteins (HSP), abundant in inflamed synovia, as surrogate autoantigens to be presented by tolDC and (ii) identification of functional biomarkers that confirm tolDC regulatory activity., Methods: Cell proliferation dye-labelled human peripheral blood mononuclear cells of IA (rheumatoid arthritis (RA) and psoriatic arthritis (PsA)) patients or healthy donors were cultured with HSP40-, HSP60- and HSP70-derived peptides or recall antigens (e.g. tuberculin purified protein derivative (PPD)) in the presence or absence of tolDC or control DC for 9 days. Functional characteristics of proliferated antigen-specific T-cells were measured using flow cytometry, gene expression profiling and cytokine secretion immunoassays. Repeated measures analysis of variance (ANOVA) with Bonferroni correction for comparisons between multiple groups and paired Student t test for comparisons between two groups were used to determine significance., Results: All groups showed robust CD4
+ T-cell responses towards one or more HSP-derived peptide(s) as assessed by a stimulation index > 2 (healthy donors: 78%, RA: 73%, PsA: 90%) and production of the cytokines IFNγ, IL-17A and GM-CSF. Addition of tolDC but not control DC induced a type 1 regulatory (Tr1) phenotype in the antigen-specific CD4+ T-cell population, as identified by high expression of LAG3, CD49b and secretion of IL-10. Furthermore, tolDC inhibited bystander natural killer (NK) cell activation in a TGFβ dependent manner., Conclusions: HSP-specific CD4+ T-cells are detectable in the majority of RA and PsA patients and can be converted into Tr1 cells by tolDC. HSP-loaded tolDC may therefore be suitable for directing T regulatory responses to antigens in inflamed synovia of IA patients. Tr1 markers LAG3, CD49b and IL-10 are suitable biomarkers for future tolDC clinical trials.- Published
- 2019
- Full Text
- View/download PDF
5. Tolerogenic dendritic cells generated with dexamethasone and vitamin D3 regulate rheumatoid arthritis CD4 + T cells partly via transforming growth factor-β1.
- Author
-
Anderson AE, Swan DJ, Wong OY, Buck M, Eltherington O, Harry RA, Patterson AM, Pratt AG, Reynolds G, Doran JP, Kirby JA, Isaacs JD, and Hilkens CM
- Subjects
- Arthritis, Rheumatoid immunology, Cells, Cultured, Cholecalciferol pharmacology, Dendritic Cells drug effects, Dendritic Cells transplantation, Dexamethasone pharmacology, Forkhead Transcription Factors metabolism, Humans, Immunomodulation, Interleukin-12 genetics, Interleukin-12 metabolism, Lymphocyte Activation, Smad2 Protein metabolism, Arthritis, Rheumatoid therapy, CD4-Positive T-Lymphocytes immunology, Dendritic Cells immunology, Immune Tolerance, Immunotherapy methods, Transforming Growth Factor beta1 metabolism
- Abstract
Tolerogenic dendritic cells (tolDC) are a new immunotherapeutic tool for the treatment of rheumatoid arthritis (RA) and other autoimmune disorders. We have established a method to generate stable tolDC by pharmacological modulation of human monocyte-derived DC. These tolDC exert potent pro-tolerogenic actions on CD4
+ T cells. Lack of interleukin (IL)-12p70 production is a key immunoregulatory attribute of tolDC but does not explain their action fully. Here we show that tolDC express transforming growth factor (TGF)-β1 at both mRNA and protein levels, and that expression of this immunoregulatory cytokine is significantly higher in tolDC than in mature monocyte-derived DC. By inhibiting TGF-β1 signalling we demonstrate that tolDC regulate CD4+ T cell responses in a manner that is at least partly dependent upon this cytokine. Crucially, we also show that while there is no significant difference in expression of TGF-βRII on CD4+ T cells from RA patients and healthy controls, RA patient CD4+ T cells are measurably less responsive to TGF-β1 than healthy control CD4+ T cells [reduced TGF-β-induced mothers against decapentaplegic homologue (Smad)2/3 phosphorylation, forkhead box protein 3 (FoxP3) expression and suppression of (IFN)-γ secretion]. However, CD4+ T cells from RA patients can, nonetheless, be regulated efficiently by tolDC in a TGF-β1-dependent manner. This work is important for the design and development of future studies investigating the potential use of tolDC as a novel immunotherapy for the treatment of RA., (© 2016 British Society for Immunology.)- Published
- 2017
- Full Text
- View/download PDF
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