5 results on '"Hull DN"'
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2. Inflammatory disease status and response to TNF blockade are associated with mechanisms of endotoxin tolerance.
- Author
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Clanchy FI, Borghese F, Bystrom J, Balog A, Penn H, Hull DN, Mageed RA, Taylor PC, and Williams RO
- Subjects
- Animals, Humans, Mice, Intracellular Signaling Peptides and Proteins genetics, Intracellular Signaling Peptides and Proteins metabolism, Male, Interleukin-1 Receptor-Associated Kinases metabolism, Interleukin-1 Receptor-Associated Kinases genetics, Female, Protein Tyrosine Phosphatase, Non-Receptor Type 6 metabolism, Arthritis, Experimental immunology, Arthritis, Experimental drug therapy, DNA-Binding Proteins metabolism, DNA-Binding Proteins genetics, Monocytes immunology, Monocytes metabolism, Monocytes drug effects, Middle Aged, Adult, Inflammation immunology, Disease Models, Animal, Arthritis, Rheumatoid drug therapy, Arthritis, Rheumatoid immunology, Immune Tolerance drug effects, Tumor Necrosis Factor alpha-Induced Protein 3 metabolism, Tumor Necrosis Factor alpha-Induced Protein 3 genetics, Endotoxins immunology, Spondylitis, Ankylosing drug therapy, Spondylitis, Ankylosing immunology, Tumor Necrosis Factor-alpha metabolism, Tumor Necrosis Factor-alpha antagonists & inhibitors
- Abstract
The mechanisms of endotoxin tolerance (ET), which down-regulate inflammation, are well described in response to exogenous toll-like receptor ligands, but few studies have focused on ET-associated mechanisms in inflammatory disease. As blocking TNF can attenuate the development of ET, the effect of anti-TNF on the expression of key ET-associated molecules in inflammatory auto-immune disease was measured; changes in inflammatory gene expression were confirmed using an ET bioassay. The expression of immunomodulatory molecules was measured in a murine model of arthritis treated with anti-TNF and the expression of ET-associated molecules was measured in whole blood in rheumatoid arthritis (RA) and ankylosing spondylitis (AS) patients, before and after therapy. The expression of ET-associated genes was also measured in RA patient monocytes before and after therapy, in anti-TNF responders and non-responders. Tnfaip3, Ptpn6 and Irak3 were differentially expressed in affected paws, spleens, lymph nodes and circulating leucocytes in experimental murine arthritis treated with anti-TNF. Prior to therapy, the expression of TNFAIP3, INPP5D, PTPN6, CD38 and SIGIRR in whole blood differed between human healthy controls and RA or AS patients. In blood monocytes from RA patients, the expression of TNFAIP3 was significantly reduced by anti-TNF therapy in non-responders. Prior to therapy, anti-TNF non-responders had higher expression of TNFAIP3 and SLPI, compared to responders. Although the expression of TNFAIP3 was significantly higher in RA non-responders prior to treatment, the post-treatment reduction to a level similar to responders did not coincide with a clinical response to therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2024
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3. TLR expression profiles are a function of disease status in rheumatoid arthritis and experimental arthritis.
- Author
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Clanchy FIL, Borghese F, Bystrom J, Balog A, Penn H, Hull DN, Wells GMA, Kiriakidis S, Taylor PC, Sacre SM, Williams LM, Stone TW, Mageed RA, and Williams RO
- Subjects
- Animals, Arthritis, Experimental blood, Arthritis, Experimental diagnosis, Arthritis, Experimental pathology, Arthritis, Rheumatoid blood, Arthritis, Rheumatoid diagnosis, Arthritis, Rheumatoid surgery, Autoantibodies blood, Autoantibodies immunology, Collagen administration & dosage, Collagen immunology, Freund's Adjuvant administration & dosage, Freund's Adjuvant immunology, Gene Expression Profiling, Humans, Leukocytes metabolism, Mice, Severity of Illness Index, Synovial Membrane immunology, Synovial Membrane pathology, Arthritis, Experimental immunology, Arthritis, Rheumatoid immunology, Leukocytes immunology, Toll-Like Receptors metabolism
- Abstract
The role of the innate immune system has been established in the initiation and perpetuation of inflammatory disease, but less attention has been paid to its role in the resolution of inflammation and return to homeostasis. Toll-like receptor (TLR) expression profiles were analysed in tissues with differing disease status in rheumatoid arthritis (RA), ankylosing spondylitis (AS), and in experimental arthritis. TLR gene expression was measured in whole blood and monocytes, before and after TNF blockade. In RA and osteoarthritis synovia, the expression of TLRs was quantified by standard curve qPCR. In addition, four distinct stages of disease were defined and validated in collagen-induced arthritis (CIA), the gold standard animal model for RA - pre-onset, early disease, late disease and immunised mice that were resistant to the development of disease. TLR expression was measured in spleens, lymph nodes, blood cells, liver and the paws (inflamed and unaffected). In RA whole blood, the expression of TLR1, 4 and 6 was significantly reduced by TNF blockade but the differences in TLR expression profiles between responders and non-responders were less pronounced than the differences between RA and AS patients. In RA non-responders, monocytes had greater TLR2 expression prior to therapy compared to responders. The expression of TLR1, 2, 4 and 8 was higher in RA synovium compared to control OA synovium. Circulating cytokine levels in CIA resistant mice were similar to naïve mice, but anti-collagen antibodies were similar to arthritic mice. Distinct profiles of inflammatory gene expression were mapped in paws and organs with differing disease status. TLR expression in arthritic paws tended to be similar in early and late disease, with TLR1 and 2 moderately higher in late disease. TLR expression in unaffected paws varied according to gene and disease status but was generally lower in resistant paws. Disease status-specific profiles of TLR expression were observed in spleens, lymph nodes, blood cells and the liver. Notably, TLR2 expression rose then fell in the transition from naïve to pre-onset to early arthritis. TLR gene expression profiles are strongly associated with disease status. In particular, increased expression in the blood precedes clinical manifestation., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
- Published
- 2021
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4. Increase in circulating Th17 cells during anti-TNF therapy is associated with ultrasonographic improvement of synovitis in rheumatoid arthritis.
- Author
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Hull DN, Cooksley H, Chokshi S, Williams RO, Abraham S, and Taylor PC
- Subjects
- Adalimumab, Adult, Aged, Antirheumatic Agents, Arthritis, Rheumatoid diagnostic imaging, Enzyme-Linked Immunospot Assay, Etanercept, Female, Flow Cytometry, Humans, Image Interpretation, Computer-Assisted, Longitudinal Studies, Male, Middle Aged, Synovitis diagnostic imaging, Tumor Necrosis Factor-alpha antagonists & inhibitors, Arthritis, Rheumatoid immunology, Synovitis immunology, Th17 Cells immunology
- Abstract
Background: Anti-TNF agents have revolutionised rheumatoid arthritis (RA) treatment; however, a third of patients fail to achieve therapeutic responses. Unexpectedly, studies in murine and human arthritis have indicated that anti-TNF treatment can increase circulating T helper 17 (Th17) cells, but the relationship to treatment response is unclear. To identify immune correlates of anti-TNF treatment response, we conducted a longitudinal study using clinical, ultrasound and T cell assessments., Methods: Patients with RA (n = 25) were studied at protocol visits during the initial 12 weeks of anti-TNF treatment. Improvement in the disease activity score of 28 joints (DAS28) >1.2 defined treatment responders (n = 16) and non-responders (n = 9). Changes in synovial thickening and vascularity of 10 metacarpophalangeal joints were quantitatively assessed by grey scale and power Doppler ultrasound. The frequency of circulating Th17 cells was determined by IL17 enzyme-linked immunospot assay (Elispot) and flow cytometry (fluorescence-activated cell sorting (FACS))., Results: The frequency of circulating IL17-producing cells increased significantly 12 weeks after anti-TNF initiation (Elispot median (range) specific spot forming cells (spSFC)/10
6 360 (280-645) vs 632 (367 - 1167), p = 0.003). The increase in CD4 + IL17+ cells at 12 weeks was confirmed by FACS (median (range) %, 0.7 (0.5-0.9) vs 1.05 (0.6-1.3); p = 0.01). The increase in circulating Th17 cells inversely correlated with reduction in synovial vascularity (r = -0.68, p = 0.007) and thickening (r = -0.39; p = 0.04). Higher frequencies of circulating Th17 cells at baseline were associated with poorer anti-TNF treatment response defined by ultrasonographic measures., Conclusions: These results demonstrate a link between changes in circulating Th17 cells with resolution of ultrasonographic features of synovial inflammation and vascularity during anti-TNF treatment. The findings may reflect redistribution of Th17 cells from inflamed joints or TNF-driven regulation of Th17 cell production., Trial Registration: ClinicalTrials.gov: NCT01060098 . Registered 29 January 2010.- Published
- 2016
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5. Anti-tumour necrosis factor treatment increases circulating T helper type 17 cells similarly in different types of inflammatory arthritis.
- Author
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Hull DN, Williams RO, Pathan E, Alzabin S, Abraham S, and Taylor PC
- Subjects
- Adalimumab, Adult, Aged, Antibodies, Monoclonal, Humanized therapeutic use, Arthritis, Psoriatic blood, Arthritis, Rheumatoid blood, Enzyme-Linked Immunosorbent Assay, Etanercept, Female, Flow Cytometry, Humans, Immunoglobulin G therapeutic use, Interleukin-17 blood, Male, Middle Aged, Prospective Studies, Receptors, Tumor Necrosis Factor therapeutic use, Spondylitis, Ankylosing blood, Th17 Cells metabolism, Time Factors, Treatment Outcome, Antirheumatic Agents therapeutic use, Arthritis, Psoriatic drug therapy, Arthritis, Rheumatoid drug therapy, Spondylitis, Ankylosing drug therapy, Th17 Cells drug effects, Tumor Necrosis Factor-alpha antagonists & inhibitors
- Abstract
We investigated changes in circulating T helper type 17 (Th17) cells following anti-tumour necrosis factor (TNF) in rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) patients. Peripheral blood mononuclear cells (PBMC) were isolated from 25 RA, 15 AS and eight PsA patients at baseline 4 and 12 weeks after treatment, and Th17 cell frequencies were analysed using interleukin (IL)-17 enzyme-linked immunospot (ELISPOT) and flow cytometry. A significant increase in IL-17-producing cells was observed by ELISPOT in RA and AS patients at 12 weeks. Flow cytometry confirmed significant increases in CD4(+) IL-17(+) cells at 12 weeks in RA and AS and 4 weeks in PsA patients. Anti-TNF treatment increases circulating Th17 cells in three different diseases., (© 2015 British Society for Immunology.)
- Published
- 2015
- Full Text
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