Longitudinal analysis of the immune response in patients with COVID-19 identifies a myeloid signature associated with severe disease.
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IL-1 gene expression was investigated in human blood mononuclear cells. IL-1 alpha and IL-1 beta mRNA were induced with LPS or TNF. Kinetic measurements on Northern blots revealed that these stimuli elicited qualitatively similar changes... more
IL-1 gene expression was investigated in human blood mononuclear cells. IL-1 alpha and IL-1 beta mRNA were induced with LPS or TNF. Kinetic measurements on Northern blots revealed that these stimuli elicited qualitatively similar changes in IL-1 mRNA levels, and that expression of IL-1 mRNA was transient. IL-1 beta mRNA was the predominant mRNA species and remained elevated for somewhat longer than IL-1 alpha mRNA. TNF and IFN-gamma synergized to induce both species of IL-1 mRNA and IL-1 bioactivity. Transcriptional control, as measured by nuclear run on assays, partly determines the greater levels of IL-1 beta mRNA because the rate of IL-1 beta transcription was greater than that of IL-1 alpha. Cycloheximide (CHX) was able to induce IL-1 mRNA but did not induce transcription of either IL-1 gene. When added to cultures pretreated with TNF or LPS, CHX superinduced IL-1 mRNA, but IL-1 transcription was not increased. If added simultaneously CHX blocked TNF-induced IL-1 gene transcript...
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We confirm that IL-10 is produced comparatively late after the activation of human T cells via CD3 stimulation, after IL-2 and IFN-gamma. Furthermore we show that IL-10 production by human T cell lines, such as IFN-gamma and IL-2, is... more
We confirm that IL-10 is produced comparatively late after the activation of human T cells via CD3 stimulation, after IL-2 and IFN-gamma. Furthermore we show that IL-10 production by human T cell lines, such as IFN-gamma and IL-2, is inhibited by the immunosuppressive drugs cyclosporin A and FK506. However, a third immunosuppressive drug, rapamycin, normally associated with inhibiting the effects, but not the production, of cytokines, inhibited IL-10, but not IFN-gamma, production. This implies that IL-10 induction may be a secondary event in T cell activation. Since IL-2 is the major growth factor for T cells and is detected before IL-10, we focused on this factor as a potential activator of IL-10 production. We showed that IL-10 production by human T cell lines stimulated by immobilized anti-CD3 in the presence of neutralizing Abs to IL-2 and IL-2R (anti-CD25) was inhibited, whereas addition of exogenous IL-2 enhanced IL-10 production, indicating that IL-10 production by human T c...
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Transforming growth factor-beta 1 (TGF-beta 1) is one of a family of polypeptides involved in the regulation of cell growth and differentiation. The effects of human rTGF-beta 1 on the production of IL-1 and TNF by activated PBMC were... more
Transforming growth factor-beta 1 (TGF-beta 1) is one of a family of polypeptides involved in the regulation of cell growth and differentiation. The effects of human rTGF-beta 1 on the production of IL-1 and TNF by activated PBMC were studied. The addition of TGF-beta 1 alone caused an increase in the levels of mRNA for IL-1 alpha, IL-1 beta, and TGF-alpha. This was due to increased transcription rather than enhanced mRNA stability. The induced mRNA were of the appropriate size as assessed by Northern blotting. However, the mRNA did not appear to be translated into protein, inasmuch as the translation products of IL-1 beta and TNF-alpha were not detected by RIA or ELISA. Furthermore, in experiments utilizing a neutralizing antibody to TGF-beta 1, we were unable to unmask IL-1 biologic activities and unable to detect TNF biologic activity in the WEHI 164 cytotoxicity assay. TGF-beta inhibited in a dose-dependent manner the induction of IL-1 beta by LPS or TNF but not by PHA and PMA. ...
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Objectives: The Anti-Freaze-F trial will assess the feasibility of conducting a large randomised controlled trial to assess whether intra-articular injection of anti-TNF (adalimumab) can reduce pain and improve function in people with... more
Objectives: The Anti-Freaze-F trial will assess the feasibility of conducting a large randomised controlled trial to assess whether intra-articular injection of anti-TNF (adalimumab) can reduce pain and improve function in people with pain predominant early stage frozen shoulder. Methods and analysis: We are conducting a multi-centre, randomised feasibility study, with an embedded qualitative sub-study. We will recruit adults ≥18 years with a new episode of shoulder pain attributable to early stage frozen shoulder, recruited from at least five UK NHS musculoskeletal and related physiotherapy services. Participants (n=84) will be randomised (centralised computer generated 1:1 allocation) to receive either: 1) intra-articular injection of anti-TNF (adalimumab 160mg) or 2) placebo injection (saline [0.9% sodium chloride]), both under ultrasound guidance. A second injection of the allocated treatment (adalimumab 80mg) or equivalent volume of placebo will be administered 2-3 weeks later....
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Macrophages are integral to the pathogenesis of atherosclerosis, but the contribution of distinct macrophage subsets to disease remains poorly defined. Using single cell technologies and conditional ablation via... more
Macrophages are integral to the pathogenesis of atherosclerosis, but the contribution of distinct macrophage subsets to disease remains poorly defined. Using single cell technologies and conditional ablation via aLysMCre+Clec4a2flox/DTRmouse strain, we demonstrate that the expression of the C-type lectin receptor CLEC4A2 is a distinguishing feature of vascular resident macrophages endowed with athero-protective properties. Through genetic deletion and competitive bone marrow chimera experiments, we identify CLEC4A2 as an intrinsic regulator of macrophage tissue adaptation by promoting a bias in monocyte-to-macrophage in situ differentiation towards colony stimulating factor 1 (CSF1) in vascular health and disease. During atherogenesis, CLEC4A2 deficiency results in loss of resident vascular macrophages and their homeostatic properties causing dysfunctional cholesterol metabolism and enhanced toll-like receptor triggering, exacerbating disease. Our study demonstrates that CLEC4A2 lic...
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The COVID-19 pandemic caused by infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has led to more than 100,000 deaths in the United States. Several studies have revealed that the hyper-inflammatory response... more
The COVID-19 pandemic caused by infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has led to more than 100,000 deaths in the United States. Several studies have revealed that the hyper-inflammatory response induced by SARS-CoV-2 is a major cause of disease severity and death in infected patients. However, predictive biomarkers of pathogenic inflammation to help guide targetable immune pathways are critically lacking. We implemented a rapid multiplex cytokine assay to measure serum IL-6, IL-8, TNF-α, and IL-1β in hospitalized COVID-19 patients upon admission to the Mount Sinai Health System in New York. Patients (n=1484) were followed up to 41 days (median 8 days) and clinical information, laboratory test results and patient outcomes were collected. In 244 patients, cytokine measurements were repeated over time, and effect of drugs could be assessed. Kaplan-Meier methods were used to compare survival by cytokine strata, followed by Cox regression models to e...
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IL-33 mediates cross-talk between immune and stromal cells in localized fibrosis.
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A review of Love and Science: A Memoir by Jan Vilcek, Seven Stories Press, 2016
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The monocytic tumour, THP-1, expresses many of the properties of monocytes, both by cell surface staining and its capacity to produce monokines. It was used as a source of homogenous monocytic cells as a model to determine whether a... more
The monocytic tumour, THP-1, expresses many of the properties of monocytes, both by cell surface staining and its capacity to produce monokines. It was used as a source of homogenous monocytic cells as a model to determine whether a variety of highly purified or recombinant cytokines could induce HLA-DR expression and the production of interleukin-1 (IL-1). Interferon-gamma (IFN-gamma) alone induced HLA-DR. Tumour necrosis factor (TNF), lymphotoxin (LT) and granulocyte-macrophage colony-stimulating factor (GM-CSF) alone were able to induce IL-1 but not HLA-DR. When IFN-gamma was combined with TNF, induction of HLA-DR and IL-1 was enhanced in a synergistic manner. These effects were detectable at a pretranslational level as synergistic effects were observed on DR alpha mRNA and IL-1 beta mRNA levels. The results demonstrate the specificity of IFN-gamma as the inductive stimulus for HLA-DR expression by THP-1 cells. As IFN-gamma and TNF are products of activated T cells, the synergist...
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To investigate the role of the transcription factor nuclear factor-kB (NF-kappaB) in promoting inflammatory and destructive responses in human osteoarthritis (OA) synovial fibroblasts, by assessing the effect of NF-kappaB blockade on the... more
To investigate the role of the transcription factor nuclear factor-kB (NF-kappaB) in promoting inflammatory and destructive responses in human osteoarthritis (OA) synovial fibroblasts, by assessing the effect of NF-kappaB blockade on the production of cytokines and destructive enzymes. Infection with adenoviruses transferring the beta-galactosidase gene was used to ascertain that the OA fibroblasts could be infected (> 95%). Using an adenovirus transferring the inhibitory subunit IkappaBa, effective inhibition of NF-kappaB was achieved. The expression and production of several pro- and antiinflammatory cytokines and mediators, the major matrix metalloproteinases (MMP 1, 3, and 13), their main inhibitor tissue inhibitor of metalloproteinase-1 (TIMP-1), and the aggrecanases (ADAMTS4 and ADAMTS5) were measured by ELISA and/or reverse transcription-polymerase chain reaction, and their dependence on NF-kappaB evaluated. The production of interleukin 6 (IL-6), monocyte chemoattractant ...
Research Interests: Rheumatology, Immunology, Biology, Medicine, Osteoarthritis, and 15 moreHumans, Female, Pubmed, Male, The, Clinical Sciences, Aged, Middle Aged, Public health systems and services research, Matrix Metalloproteinases, Human Fibroblasts, Matrix Metalloproteinase, fibroblasts, Synovial membrane, and Inflammation Mediators
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Summary Serial urinary neopterin :creatinine ratios of 58 healthy adult sub jects were measured from 2 days prior to and up to 12 days post vaccination. An increase in the urinary neopterin of at least twice the baseline was detected in... more
Summary Serial urinary neopterin :creatinine ratios of 58 healthy adult sub jects were measured from 2 days prior to and up to 12 days post vaccination. An increase in the urinary neopterin of at least twice the baseline was detected in 24/ 46 subjects who received either a Mantoux skin test or a live viral vaccine (cell mediated immune group, median average increase above baseline = 206%(interquartile range 150-338% ), and 'in 5/12 who received non-live vaccines known to stimulate mainly humoral immunity (humoral immune group, median average increase above baseline = 165%((interquartile range 142-412%) ). The peaks in the urinary neopterin in the cell mediated group occurred between days 5 and 10 post-vaccination, with the mode on day 5. In contrast the 5 subjects in the humoral immune group all developed their peaks on day 7 or 8 . Three of these subjects received an influenza vaccine, one a typhoid vaccine and one a tetanus toxoid. No association was found between local or sy...
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SUMMARY Sjögren’s syndrome (SS) is characterized by a focal periductal salivary gland infiltrate consisting mainly of T and B lymphocytes. Most of the T cells bear the memory of CD4+ Th-1-like phenotype and express high levels of class... more
SUMMARY Sjögren’s syndrome (SS) is characterized by a focal periductal salivary gland infiltrate consisting mainly of T and B lymphocytes. Most of the T cells bear the memory of CD4+ Th-1-like phenotype and express high levels of class II, though CD8+ cells are also present. We have studied 17 labial salivary gland and 15 peripheral blood T cell clones from a patient with primary SS. The tissue clones were 71% CD8+ and 29% CD4+, and the peripheral blood-derived clones were 60% CD8+ and 40% CD4+. The CD4+ T cell clones from both the salivary gland and autologous peripheral blood were of the Th1 phenotype, in that they produced interferon-gamma (IFN-γ) and IL-2 but very little IL-4 after 24 h stimulation with phorbol myristate acetate and anti-CD3 antibody. The salivary gland-derived CD4+ clones produced 15 times more IL-10 (7.92 ng/ml) than peripheral blood-derived CD4+ clones (0.52 ng/ml, P≤0.02). The tissue CD8+ clones produced 1.2 times (P<0.04) more IFN-γ and CD4+ clones produ...
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PRR (pattern-recognition receptor) signalling is involved early in the immune response and therefore would be attractive to target during vaccination. The use of PRR ligands has shown some success; however, toxicity and non-specificity... more
PRR (pattern-recognition receptor) signalling is involved early in the immune response and therefore would be attractive to target during vaccination. The use of PRR ligands has shown some success; however, toxicity and non-specificity are issues with this strategy. The targeting of PRR intracellular signalling networks would allow for greater specificity and reduced systemic toxicity. The present review examines the successes seen with overexpression or repression of PRR signalling molecules.
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Treatment with a chimeric mAb to TNF-α has been shown to suppress inflammation and improve patient well-being in rheumatoid arthritis (RA), but the mechanisms of action of such treatment have not been fully explored. Here we show that in... more
Treatment with a chimeric mAb to TNF-α has been shown to suppress inflammation and improve patient well-being in rheumatoid arthritis (RA), but the mechanisms of action of such treatment have not been fully explored. Here we show that in vivo administration of anti-TNF-α Ab, using a longitudinal analysis, results in the rapid down-regulation of a spectrum of cytokines, cytokine inhibitors, and acute-phase proteins. Marked diurnal variation in the serum levels of some of these were detected. These results were consistent with the concept of a cytokine-dependent cytokine cascade, and the degree of clinical benefit noted after anti-TNF-α therapy is probably due to the reduction in many proinflammatory mediators apart from TNF-α, such as IL-6, which reached normal levels within 24 h. Serum levels of cytokine inhibitors such as soluble p75 and p55 TNFR were reduced as was IL-1 receptor antagonist. Reductions in acute-phase proteins occurred after serum IL-6 fell and included serum amyloi...
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Interleukin‐11 (IL‐11) is a cytokine belonging to the IL‐6 family which has both pro‐ and anti‐inflammatory potential. Like IL‐6 it can diminish tumour necrosis factor‐α and IL‐1 production, and augment immunoglobulin synthesis. We have... more
Interleukin‐11 (IL‐11) is a cytokine belonging to the IL‐6 family which has both pro‐ and anti‐inflammatory potential. Like IL‐6 it can diminish tumour necrosis factor‐α and IL‐1 production, and augment immunoglobulin synthesis. We have explored the immunomodulatory effects of IL‐11 treatment in mice in a model of inflammatory autoimmune joint disease, collagen‐induced arthritis (CIA). Recombinant human IL‐11 was administered at various doses to DBA/1 mice after the onset of CIA. IL‐11 treatment caused a significant reduction in the clinical severity of established CIA, which was associated with protection from joint damage, as assessed by histology. Although there was a suggestion at high doses of IL‐11 that the anticollagen type II (CII) response may have been augmented, there was no statistically significant effect of IL‐11 treatment on anti‐CII antibody levels. Similarly, the acute‐phase reactant serum amyloid P was only elevated in mice receiving very high doses (50–100 μg/day)...
Research Interests: Immunology, Rheumatoid Arthritis, Medicine, Collagen, Mice, and 15 moreAnimals, Male, Arthritis, Anti-inflammatory agents, Cytokine, Antibody, Tumor necrosis factor-alpha, Combination drug therapy, Joints, Recombinant Proteins, immunoglobulin G, Interleukin, collagen-induced arthritis, Paediatrics and reproductive medicine, and Serum amyloid A protein
Monoclonal antibody therapeutics have been approved for over 30 targets and diseases, most commonly cancer. Antibodies have become the new backbone of the pharmaceutical industry, which previously relied on small molecules. Compared with... more
Monoclonal antibody therapeutics have been approved for over 30 targets and diseases, most commonly cancer. Antibodies have become the new backbone of the pharmaceutical industry, which previously relied on small molecules. Compared with small molecules, monoclonal antibodies (mAbs) have exquisite target selectivity and hence less toxicity as a result of binding other targets. The clinical value of both mAbs and ligand traps has been proven. New applications of mAbs are being tested and mAbs have now been designed to target two (bi-specific, eg TNF-α and IL-17) or more targets simultaneously, augmenting their therapeutic potential. Because of space limitations and the wide ranging scope of this review there are regrettably, but inevitably, omissions and missing citations. We have chosen to highlight the first successes in inflammatory diseases and cancer, but a broader overview of approved mAbs and related molecules can be found in Table 1.
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Interest in CBG (cannabigerol) has been growing in the past few years, due to its anti-inflammatory properties and other therapeutic benefits. Here we report the synthesis of three new CBG derivatives (HUM-223, HUM-233 and HUM-234) and... more
Interest in CBG (cannabigerol) has been growing in the past few years, due to its anti-inflammatory properties and other therapeutic benefits. Here we report the synthesis of three new CBG derivatives (HUM-223, HUM-233 and HUM-234) and show them to possess anti-inflammatory and analgesic properties. In addition, unlike CBG, HUM-234 also prevents obesity in mice fed a high-fat diet (HFD). The metabolic state of the treated mice on HFD is significantly better than that of vehicle-treated mice, and their liver slices show significantly less steatosis than untreated HFD or CBG-treated ones from HFD mice. We believe that HUM-223, HUM-233 and HUM-234 have the potential for development as novel drug candidates for the treatment of inflammatory conditions, and in the case of HUM-234, potentially for obesity where there is a huge unmet need.
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Significance Fibrosis remains a major unmet medical need as therapeutic targets discovered in animal models have failed to translate. A major challenge for identifying novel targets is the limited availability of early-stage human disease... more
Significance Fibrosis remains a major unmet medical need as therapeutic targets discovered in animal models have failed to translate. A major challenge for identifying novel targets is the limited availability of early-stage human disease tissue. Here, we utilize Dupuytren’s disease (DD), a common localized fibrotic disorder, to evaluate the impact of epigenetic regulation of myofibroblasts and identify potential tractable targets in human fibrosis. We demonstrate that the epigenetic regulator CREBBP/EP300 is a critical determinant of the profibrotic phenotype. Furthermore, we identify collagen VI to be a key downstream target of CREBBP/EP300 and reveal valuable insights in the role it plays in key profibrotic functions, including contractile force, chemotaxis, and wound healing, and hence its potential as a therapeutic target.
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T helper (Th) cells are CD4+ effector T cells that play an instrumental role in immunity by shaping the inflammatory cytokine environment in a variety of physiological and pathological situations. Using a combined chemico-genetic approach... more
T helper (Th) cells are CD4+ effector T cells that play an instrumental role in immunity by shaping the inflammatory cytokine environment in a variety of physiological and pathological situations. Using a combined chemico-genetic approach we identify histone H3K27 demethylases KDM6A and KDM6B as central regulators of human Th subsets. The prototypic KDM6 inhibitor GSK-J4 increases genome-wide levels of the repressive H3K27me3 chromatin mark and leads to suppression of the key transcription factor RORγt during Th17 differentiation, whereas in mature Th17 cells an altered transcriptional program leads to a profound metabolic reprogramming with concomitant suppression of IL-17 cytokine levels and reduced proliferation. Single cell analysis reveals a specific shift from highly inflammatory cell subsets towards a resting state upon demethylase inhibition. The root cause of the observed anti-inflammatory phenotype in stimulated Th17 cells is reduced expression of key metabolic transcripti...
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Autologous EBV-transformed B cell lines (EBVL) from a patient with Graves' disease (GD) were transfected with the expression vector pREP4 encoding thyroid peroxidase (TPO), the thyroid-stimulating hormone receptor (TSHR), or... more
Autologous EBV-transformed B cell lines (EBVL) from a patient with Graves' disease (GD) were transfected with the expression vector pREP4 encoding thyroid peroxidase (TPO), the thyroid-stimulating hormone receptor (TSHR), or chloramphenicol acetyl transferase. The relevant proteins were expressed. The capacity of EBVL to present transfected Ag was assessed by using EBVL transfected with TPO (EBVL-TPO) to stimulate TPO-specific T cells cloned from autologous thyroid tissue; stimulation indices greater than 100 were consistently obtained, even at low APC:T cell ratios. EBVL-TPO and EBVL transfected with TSHR (EBVL-TSHR) were used to characterize the Ag specificity of five thyroid epithelial cell-specific T cell clones. Despite previous unresponsiveness to recombinant TPO or purified thyroglobulin, four of these clones responded vigorously to EBVL-TPO but none responded to EBVL-TSHR. Experiments were then performed to determine whether transfected EBVL were presenting endogenously ...
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Significance Current therapies to alleviate autoimmune conditions use global strategies that affect large compartments of the immune response. These strategies mop up the excesses of disease without slowing disease progression and carry a... more
Significance Current therapies to alleviate autoimmune conditions use global strategies that affect large compartments of the immune response. These strategies mop up the excesses of disease without slowing disease progression and carry a significant risk of infection. This article describes the selective inhibition of autoaggressive T cells with the ability to regress established arthritis and reveals an unexpected role for an immune receptor–ligand pair in bone homeostasis.
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SUMMARY We investigated the therapeutic potential of P-selectin glycoprotein ligand (PSGL)-1 in established collagen-induced arthritis (CIA) in DBA/1 mice. PSGL-1 is the high-affinity specific ligand for P-selectin and is thus important... more
SUMMARY We investigated the therapeutic potential of P-selectin glycoprotein ligand (PSGL)-1 in established collagen-induced arthritis (CIA) in DBA/1 mice. PSGL-1 is the high-affinity specific ligand for P-selectin and is thus important in cell recruitment to inflammatory sites. I-316 PSGL-1 or rPSGL-1Ig fusion protein were administered to mice after the onset of clinical arthritis for 10 days, and the effect of treatment on both clinical and histopathological progression of disease was studied. It was found that both PSGL-1 biologicals effectively suppressed progression of clinical arthritis, and this was accompanied by protection against damage of joint tissues. We sought to investigate a mechanism underlying the effect of rPSGL-1Ig on the reduction of clinical arthritis. Blockade of PSGL-1/P–selectin interaction blocks recruitment of leucocytes, thus we observed a notable reduction in viable cell numbers of synoviocytes from rPSGL-1Ig treated mice. In view of this finding we susp...
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Significance TNF signals via 2 receptors, TNFR1 and TNFR2. Anti-TNF biologics, which block signaling via both receptors, are now being used to treat millions of patients worldwide for immune-mediated inflammatory diseases. This study... more
Significance TNF signals via 2 receptors, TNFR1 and TNFR2. Anti-TNF biologics, which block signaling via both receptors, are now being used to treat millions of patients worldwide for immune-mediated inflammatory diseases. This study demonstrates that TNFR2 plays a major role in limiting the severity and duration of arthritis in animal models and that TNFR2 is important for maintaining the functional activity and phenotypic stability of Treg cells, which are major cellular mediators of immune homeostasis. Treg cells express the functionally important transcription factor FoxP3, and we show that TNFR2 is required for preventing DNA methylation at the Foxp3 promoter thereby maintaining its transcriptional activity. This suggests that specific blockade of TNFR1 would be advantageous.
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There is increasing evidence that NF-κB is a major, if not the major transcription factor regulating inflammation and immunity. While this implies that blocking NF-κB might be therapeutically beneficial, it raises clear questions... more
There is increasing evidence that NF-κB is a major, if not the major transcription factor regulating inflammation and immunity. While this implies that blocking NF-κB might be therapeutically beneficial, it raises clear questions regard-ing the balance between efficacy and safety. In this brief review we discuss the effects of NF-κB blockade in rheumatoid arthritis, inflammation and immunity, and con-sider possible therapeutic targets within the NF-κB family. NF-κB is a family of transcription factors central toimmunity and inflammation.1 NF-κB molecules existas homo- or heterodimeric complexes formed by com-binations of five distinct DNA binding subunits, p65/RelA, RelB, c-Rel, p50, and p52, and are, under most circumstances, found in the cytosol bound to IκB proteins. However, in response to various stimuli that include physical and chemical stress, viral and microbial products (for example, lipopolysac-charide (LPS)), and inflammatory cytokines (for example,
NF-κB is a family of transcription factors central to immunity and inflammation. 1 NF-κB molecules exist as homo-or heterodimeric complexes formed by combinations of five distinct DNA binding subunits, p65/RelA, RelB, c-Rel, p50, and p52,... more
NF-κB is a family of transcription factors central to immunity and inflammation. 1 NF-κB molecules exist as homo-or heterodimeric complexes formed by combinations of five distinct DNA binding subunits, p65/RelA, RelB, c-Rel, p50, and p52, and are, under most circumstances, found ...
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Tumor necrosis factor α (TNFα) is a cytokine implicated in the pathogenesis of numerous chronic and acute inflammatory conditions. In the present study, we have characterized the ability of TNFα in inducing eosinophil accumulation in rat... more
Tumor necrosis factor α (TNFα) is a cytokine implicated in the pathogenesis of numerous chronic and acute inflammatory conditions. In the present study, we have characterized the ability of TNFα in inducing eosinophil accumulation in rat skin and have shown the inhibitory effects of anti-α4 integrin and anti–vascular cell adhesion molecule-1 (VCAM-1) antibodies on this response. The intradermal injection of recombinant human TNFα induced a slowly developing, dose-dependent accumulation of 111In-eosinophils in rat skin that was maximal at the dose of 10−11 mol/site. Coadministration of TNFα with the soluble TNFα receptor (p55)-IgG fusion protein (TNFR-IgG) totally inhibited the 111In-eosinophil accumulation induced by the cytokine. The TNFα-induced 111In-eosinophil accumulation was not affected after pretreatment of rats with the platelet-activating factor (PAF) receptor antagonist UK-74,505 or the antihuman interleukin-8 monoclonal antibody (MoAb) DM/C7. In contrast, the intravenous...
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A major discovery of recent decades has been the existence of stem cells and their potential to repair many, if not most, tissues. With the aging population, many attempts have been made to use exogenous stem cells to promote tissue... more
A major discovery of recent decades has been the existence of stem cells and their potential to repair many, if not most, tissues. With the aging population, many attempts have been made to use exogenous stem cells to promote tissue repair, so far with limited success. An alternative approach, which may be more effective and far less costly, is to promote tissue regeneration by targeting endogenous stem cells. However, ways of enhancing endogenous stem cell function remain poorly defined. Injury leads to the release of danger signals which are known to modulate the immune response, but their role in stem cell-mediated repair in vivo remains to be clarified. Here we show that high mobility group box 1 (HMGB1) is released following fracture in both humans and mice, forms a heterocomplex with CXCL12, and acts via CXCR4 to accelerate skeletal, hematopoietic, and muscle regeneration in vivo. Pretreatment with HMGB1 2 wk before injury also accelerated tissue regeneration, indicating an ac...
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Dupuytren's disease is a common fibrotic condition of the hand that causes irreversible flexion contractures of the fingers, with no approved therapy for early stage disease. Our previous analysis of surgically-excised tissue defined... more
Dupuytren's disease is a common fibrotic condition of the hand that causes irreversible flexion contractures of the fingers, with no approved therapy for early stage disease. Our previous analysis of surgically-excised tissue defined tumour necrosis factor (TNF) as a potential therapeutic target. Here we assessed the efficacy of injecting nodules of Dupuytren's disease with a TNF inhibitor. Patients were randomised to receive adalimumab on one occasion in dose cohorts of 15 mg in 0.3 ml, 35 mg in 0.7 ml, or 40 mg in 0.4 ml, or an equivalent volume of placebo in a 3:1 ratio. Two weeks later the injected tissue was surgically excised and analysed. The primary outcome measure was levels of mRNA expression for α-smooth muscle actin (ACTA2). Secondary outcomes included levels of α-SMA and collagen proteins. The trial was registered with ClinicalTrial.gov (NCT03180957) and the EudraCT (2015-001780-40). We recruited 28 patients, 8 assigned to the 15 mg, 12 to the 35 mg and 8 to the...
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Natural killer (NK) cells are innate lymphocytes, important in immune surveillance and elimination of stressed, transformed, or virus-infected cells. They critically shape the inflammatory cytokine environment to orchestrate interactions... more
Natural killer (NK) cells are innate lymphocytes, important in immune surveillance and elimination of stressed, transformed, or virus-infected cells. They critically shape the inflammatory cytokine environment to orchestrate interactions of cells of the innate and adaptive immune systems. Some studies have reported that NK cell activation and cytokine secretion are controlled epigenetically, but have yielded only limited insight into the mechanisms. Using chemical screening with small-molecule inhibitors of chromatin methylation and acetylation, further validated by knockdown approaches, we here identified Jumonji-type histone H3K27 demethylases as key regulators of cytokine production in human NK cell subsets. The prototypic Jumonji domain-containing protein 3 (JMJD3/UTX) H3K27 demethylase inhibitor GSK-J4 increased global levels of the repressive H3K27me3 mark around transcription start sites of effector cytokine genes. Moreover, GSK-J4 reduced IFN-γ, TNFα, granulocyte-macrophage ...
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Dupuytren’s disease is a common fibrotic condition of the hand affecting 4% of the population and causes the fingers to curl irreversibly into the palm. It has a strong familial tendency, there is no approved treatment for early stage... more
Dupuytren’s disease is a common fibrotic condition of the hand affecting 4% of the population and causes the fingers to curl irreversibly into the palm. It has a strong familial tendency, there is no approved treatment for early stage disease, and patients with established digital contractures are most commonly treated by surgery. This is associated with prolonged recovery, and less invasive techniques have high recurrence rates.The myofibroblasts, the cells responsible for the excessive matrix deposition and contraction, are aggregated in nodules. Using excised diseased and control human tissue, we found that immune cells interspersed amongst the myofibroblasts secrete cytokines. Of these, only tumour necrosis factor (TNF) promoted the development of myofibroblasts. The clinically approved anti-TNF agents led to inhibition of the myofibroblast phenotype in vitro. This clinical trial is designed to assess the efficacy of the anti-TNF agent adalimumab on participants with early disea...
Adhesion of leukocytes to the vascular endothelium is an early event in inflammation. Since cell-cell signaling may be an important stimulus for endothelial activation, we focused in this study on the role of contact-mediated activation... more
Adhesion of leukocytes to the vascular endothelium is an early event in inflammation. Since cell-cell signaling may be an important stimulus for endothelial activation, we focused in this study on the role of contact-mediated activation by T lymphocytes of endothelial cells (EC). T lymphocytes were cultured with anti-CD3 monoclonal antibody or in the presence of a combination of TNF-alpha, interleukin (IL)-6, and IL-2, prior to fixation and coculture with human umbilical vein EC. Fixed, activated (anti-CD3- or cytokine-stimulated), but not unstimulated T cells, induced release of monocyte chemotactic protein-1, IL-8, and IL-6 by EC in a contact-dependent manner. Moreover, expression of tissue-factor antigen and activity was also significantly increased. Addition of anti-CD40 ligand antibody abolished T cell-induced activation of EC. Our data suggest that contact-mediated activation of EC by T cells, involving ligand:counter ligand interactions such as CD40:CD40 ligand, may represent a novel pathogenic mechanism of progression in inflammatory diseases such as atherosclerosis or rheumatoid arthritis.