What have we learnt from targeted anti-TNF therapy?

Feldmann, Marc; Williams, Richard O.; Paleolog, Ewa

doi:10.1136/ard.2009.117143

Cited by 43 publications

(34 citation statements)

References 23 publications

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“…Biologics, including anti-IL-6R agents, are used as drugs to reduce inflammation [48]. IL-6 neutralization strategies can suppress auto-immune arthritis through the inhibition of inflammatory Th17 responses [49] more efficiently than anti-TNF-α therapy [50]. As drugs that target IL-6 have been used in the clinic [51], it will be interesting to determine how these drugs affect the abundance, phenotype, and functional activity of Treg/Th17 cells in immune-mediated disease and whether these drugs present novel therapeutic avenues for the treatment of ACS.…”

Section: Discussionmentioning

confidence: 99%

Imbalanced Frequencies of Th17 and Treg Cells in Acute Coronary Syndromes Are Mediated by IL-6-STAT3 Signaling

Yuan

Deng

et al. 2013

PLoS ONE

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AimsExtensive evidence suggests inflammatory components participate in the pathogenic processes of acute coronary syndromes (ACS). In this study, we aimed to elucidate the role and mechanism underlying the imbalance of Th17 and Treg cell peripheral populations in the pathogenesis of ACS.Methods and ResultsUsing a flow cytometric analysis, we observed a significantly increased frequency of Th17 cells and a concurrently decreased CD4+CD25+Foxp3+ Treg cells in patients with ACS. To elucidate the mechanism of Th17/Treg imbalance in ACS, 22 inflammatory cytokines were measured using multiplexed immunobead-based assays. Of six elevated cytokines in ACS patients, only IL-6 was positively correlated with a higher Th17 cell level (r = 0.39, P<0.01). Relying on IL-6 stimulating and neutralizing studies, we demonstrated a direct role for IL-6 in sera from ACS patients with an increased frequency of Th17 cells. IL-6 induces the differentiation of Th17 cells from naïve CD4+ T cells through STAT3 activation and RORγt induction. However, we observed that high levels of TGF-β1 inhibited IL-6-dependent Th17 cell differentiation, indicating a complex interplay between the two cytokines in the control of Th17 and Treg cell populations.ConclusionsOur results demonstrate the role of IL-6-STAT3 signaling in ACS through increased Th17 cell differentiation. These findings indicate that IL-6 neutralizing strategies could present novel therapeutic avenues in the treatment of ACS.

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Section: Discussionmentioning

confidence: 99%

Imbalanced Frequencies of Th17 and Treg Cells in Acute Coronary Syndromes Are Mediated by IL-6-STAT3 Signaling

Yuan

Deng

et al. 2013

PLoS ONE

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“…Furthermore, the number of synovial lining layer CD68 macrophages provides a useful biomarker of response upon successful clinical intervention in the context of clinical trials 4–7. As macrophages are a major source of interleukin 6 (IL-6) and tumour necrosis factor α (TNFα), the recent success of anticytokine therapeutics supports the notion that macrophage-targeted therapies may be beneficial for the treatment of RA,8 and highlights a central role for macrophages in the progression of human disease pathology.…”

Section: Introductionmentioning

confidence: 99%

The liver X receptor pathway is highly upregulated in rheumatoid arthritis synovial macrophages and potentiates TLR-driven cytokine release

Asquith

Ballantine

Nijjar

et al. 2013

Annals of the Rheumatic Diseases

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Objectives Macrophages are central to the inflammatory processes driving rheumatoid arthritis (RA) synovitis. The molecular pathways that are induced in synovial macrophages and thereby promote RA disease pathology remain poorly understood. MethodsWe used microarray to characterise the transcriptome of synovial fluid (SF) macrophages compared to matched peripheral blood monocytes from RA patients (n=8).Results Using in silico pathway mapping, we found that pathways downstream of the cholesterol activated Liver X Receptors (LXRs), and those associated with toll-like receptor (TLR) signalling, were up-regulated in SF macrophages.Macrophage differentiation and TNFα promoted the expression of LXRα.Furthermore, in functional studies we demonstrated that activation of LXRs significantly augmented TLR driven cytokine and chemokine secretion. ConclusionThe LXR pathway is the most up-regulated pathway in RA synovial macrophages and activation of LXRs by ligands present within SF augments TLR driven cytokine secretion. Since the natural agonists of LXRs arise from cholesterol metabolism, this provides a novel mechanism that can promote RA synovitis. Abstract word count: 160

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“…Nonetheless, even with this class of diseases, treatment is not ideal. The beneficial responses are variable, particularly when anti-inflammatory therapy is started after the disease has become established; long-lasting remissions are not common; and adverse effects, particularly in the area of compromised host defense, can be substantial (6). These problems are likely to be even more pronounced with complex and often indolent chronic disease processes in which the primary trigger is thought to be something other than autoimmunity.…”

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confidence: 99%

Anti-Inflammatory Therapy in Chronic Disease: Challenges and Opportunities

Tabas

Glass

2013

Science

960

829

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A number of widespread and devastating chronic diseases, including atherosclerosis, type 2 diabetes, and Alzheimer’s disease, have a pathophysiologically important inflammatory component. In these diseases, the precise identity of the inflammatory stimulus is often unknown and, if known, is difficult to remove. Thus, there is interest in therapeutically targeting the inflammatory response. Although there has been success with anti-inflammatory therapy in chronic diseases triggered by primary inflammation dysregulation or autoimmunity, there are considerable limitations. In particular, the inflammatory response is critical for survival. As a result, redundancy, compensatory pathways, and necessity narrow the risk:benefit ratio of anti-inflammatory drugs. However, new advances in understanding inflammatory signaling and its links to resolution pathways, together with new drug development, offer promise in this area of translational biomedical research.

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What have we learnt from targeted anti-TNF therapy?

Cited by 43 publications

References 23 publications

Imbalanced Frequencies of Th17 and Treg Cells in Acute Coronary Syndromes Are Mediated by IL-6-STAT3 Signaling

Imbalanced Frequencies of Th17 and Treg Cells in Acute Coronary Syndromes Are Mediated by IL-6-STAT3 Signaling

The liver X receptor pathway is highly upregulated in rheumatoid arthritis synovial macrophages and potentiates TLR-driven cytokine release

Anti-Inflammatory Therapy in Chronic Disease: Challenges and Opportunities

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