Interleukin-6 Blockade Research Articles

Interleukin-1 receptor antagonist treatment in acute ischaemic stroke does not alter systemic markers of anti-microbial defence.

Background: Blockade of the cytokine interleukin-1 (IL-1) with IL-1 receptor antagonist (IL-1Ra) is a candidate treatment for stroke entering phase II/III trials, which acts by inhibiting harmful inflammatory responses. Infection is a common complication after stroke that significantly worsens outcome and is related to stroke-induced deficits in systemic immune function thought to be mediated by the sympathetic nervous system. Therefore, immunomodulatory treatments for stroke, such as IL-1Ra, carry a risk of aggravating stroke-associated infection. Our primary objective was to determine if factors associated with antibody-mediated antibacterial defences were further compromised in patients treated with IL-1Ra after stroke. Methods: We assessed plasma concentrations of immunoglobulin isotypes and complement components in stroke patients treated with IL-1Ra or placebo and untreated non-stroke controls using multiplex protein assays. Activation of the sympathetic nervous system (SNS) was determinedby measuring noradrenaline, a major SNS mediator. Results: There were significantly lower plasma concentrations of IgM, IgA, IgG1 and IgG4 in stroke-patients compared to non-stroke controls, however there were no differences between stroke patients treated with placebo or IL-1Ra. Concentrations of complement components associated with the classical pathway were increased and those associated with the alternative pathways decreased in stroke patients, neither being affected by treatment with IL-1Ra. Noradrenaline concentrations were increased after stroke in both placebo and IL-1Ra-treated stroke patients compared to non-stroke controls. Conclusion: These data show treatment with IL-1Ra after stroke does not alter circulating immunoglobulin and complement concentrations and is therefore unlikely to further aggravate stroke-associated infection susceptibility through altered availability of these key anti-microbialmediators.

Anakinra for corticosteroid-dependent and colchicine-resistant pericarditis: The IRAP (International Registry of Anakinra for Pericarditis) study.

Novel therapies are needed for recurrent pericarditis, particularly when corticosteroid dependent and colchicine resistant. Based on limited data, interleukin-1 blockade with anakinra may be beneficial. The aim of this multicentre registry was to evaluate the broader effectiveness and safety of anakinra in a 'real world' population. This registry enrolled consecutive patients with recurrent pericarditis who were corticosteroid dependent and colchicine resistant and treated with anakinra. The primary outcome was the pericarditis recurrence rate after treatment. Secondary outcomes included emergency department visits, hospitalisations, corticosteroid use and adverse events. Among 224 patients (46 ± 14 years old, 63% women, 75% idiopathic), the median duration of disease was 17 months (interquartile range 9-33). Most patients had elevated C-reactive protein (91%) and pericardial effusion (88%). After a median treatment of 6 months (3-12), pericarditis recurrences were reduced six-fold (2.33-0.39 per patient per year), emergency department admissions were reduced 11-fold (1.08-0.10 per patient per year), hospitalisations were reduced seven-fold (0.99-0.13 per patient per year). Corticosteroid use was decreased by anakinra (respectively from 80% to 27%; P < 0.001). No serious adverse events occurred; adverse events consisted mostly of transient skin reactions (38%) at the injection site. Adverse events led to discontinuation in 3%. A full-dose treatment duration of over 3 months followed by a tapering period of over 3 months were the therapeutic schemes associated with a lower risk of recurrence. In patients with recurrent pericarditis, anakinra appears efficacious and safe in reducing recurrences, emergency department admissions and hospitalisations.

Expert recommendations on the interleukin 6 blockade in patients with rheumatoid arthritis

ObjectiveTo draft recommendations on interleukin 6 (IL-6) blockade in rheumatoid arthritis (RA), based on best evidence and experience. MethodsA group of 10 experts on IL-6 blockade in RA was selected. The 2 coordinators formulated 23 questions about IL-6 blockade (indications, efficacy, safety, etc.). A systematic review was conducted to answer the questions. Using this information, inclusion and exclusion criteria were established, as were the search strategies (Medline, EMBASE and the Cochrane Library were searched). Two different reviewers selected the articles. Evidence tables were created. At the same time, European League Against Rheumatism and American College of Rheumatology abstracts were evaluated. Based on this evidence, the coordinators proposed preliminary recommendations that the experts discussed and voted on in a nominal group meeting. The level of evidence and grade of recommendation were established using the Oxford Centre for Evidence Based Medicine and the level of agreement with the Delphi technique (2 rounds). Agreement was established if at least 80% of the experts voted yes (yes/no). ResultsThe 8 preliminary recommendations were accepted after the Delphi process. They covered aspects such as the use of these therapies in monotherapy, in combination, in patients with refractory disease or intolerant patients, response evaluation, optimisation and risk management. ConclusionsThe manuscript aims to solve frequently asked questions and aid in decision making strategies when treating RA patients with IL-6 blockade.

Using the Immunophenotype to Predict Response to Biologic Drugs in Rheumatoid Arthritis.

Tumour necrosis factor (TNF)-α is a key mediator of inflammation in rheumatoid arthritis, and its discovery led to the development of highly successful anti-TNF therapy. Subsequently, other biologic drugs targeting immune pathways, namely interleukin-6 blockade, B cell depletion, and T cell co-stimulation blockade, have been developed. Not all patients respond to a biologic drug, leading to a knowledge gap between biologic therapies available and the confident prediction of response. So far, genetic studies have failed to uncover clinically informative biomarkers to predict response. Given that the targets of biologics are immune pathways, immunological study has become all the more pertinent. Furthermore, advances in single-cell technology have enabled the characterization of many leucocyte subsets. Studying the blood immunophenotype may therefore, define biomarker profiles relevant to each individual patient’s disease and treatment outcome. This review summarises our current understanding of how immune biomarkers might be able to predict treatment response to biologic drugs.

5233Interleukin-1 blockade with Anakinra in ST-segment elevation acute myocardial infarction: Results from the VCUART3 study

Abstract Background ST-segment elevation myocardial infarction (STEMI) is associated with an intense inflammatory response that predicts an increased risk of death and heart failure (HF). In the current study we tested whether anakinra, a recombinant Interleukin-1 (IL-1) receptor antagonist, given once daily (standard dose) or twice daily reduced systemic inflammation in patients with STEMI. Methods We enrolled patients with STEMI within 12 hours of presentation at 3 sites. After revascularization, patients were randomly assigned to receive anakinra 100 mg twice daily, anakinra 100 mg once daily alternating with placebo once daily every 12 hours, or placebo twice daily, for 14 days in a 1:1:1 ratio. The primary efficacy outcome was the area under the curve for C-reactive protein levels (CRP-AUC) using a high-sensitivity assay at 14 days comparing anakinra (both arms) versus placebo followed by a comparison between each of the anakinra arms with placebo. Two pre-specified exploratory clinical efficacy endpoints, adjudicated by a blinded event committee, were assessed: a composite endpoint of all-cause death for any reason or incidence of HF (defined as new-onset HF requiring hospitalization or a new prescription of a loop diuretic, D+HF) and a composite endpoint of death and HF hospitalization (D+HHF) at 1 year. Data are expressed as median and interquartile range or number and percentage. Kaplan-Meyer survival curves were compared using Log-rank test (Mantel-Cox). (ClinicalTrials.gov number, NCT01950299) Results Of 311 patients screened, 99 subjects (80 [81%] males, 57 [58%] Caucasians, 55 [49–62] years of age) were randomly assigned to anakinra twice daily (N=31), anakinra once daily (N=33) or placebo (N=35). There were no significant imbalances in the demographic characteristics between groups (all P&gt;0.05). The CRP-AUC was significantly lower in the anakinra group than in the placebo group (67 [39–120] versus 214 [131–394] mg/dl, P&lt;0.001; and P&lt;0.001 for each anakinra arm versus placebo separately, without significant differences between the two anakinra arms, P=0.41). Treatment with anakinra was associated with a significant reduction versus placebo in the incidence of D+HF (6/64 [9.4%] versus 9/35 [25.7%], P=0.046), and of D+HHF (0/64 [0] versus 4/35 [11.4%], P=0.011), without any significant difference between the two anakinra arms. Anakinra was not associated with any treatment-related serious adverse events, nor with excess infections compared with placebo (14.1% vs 14.3%, P=0.87). Conclusions Among patients with STEMI, IL-1 blockade significantly reduced the systemic inflammatory response compared with placebo, without any significant difference between standard or high dose regimens. Prespecified exploratory analyses on clinical endpoints demonstrate reduced incidence of HF and reduced HF hospitalizations, supporting the concept of beneficial effects with IL-1 blockade in patients with acute myocardial infarction. Acknowledgement/Funding Funded by NHLBI 1R34HL121402; Drug supply from Swedish Orphan Biovitrum

Interleukin-6 (IL-6) Blockade with Siltuximab Peri-Autologous Hematopoietic Stem Cell Transplantation (AHCT) May Reduce Symptom Burden by Altering the Cytokine Milieu in Older Patients with Multiple Myeloma (MM)

Elevated inflammatory markers during blood count nadir after AHCT for multiple myeloma (MM), such as IL-6, have been associated with symptom burden post-AHCT (Wang, 2014). As older pts can experience significant toxicities with AHCT, we aimed to mitigate fatigue and additional side effects using siltuximab (anti-IL-6 antibody, EUSA Pharma).

253Effects of Interleukin-1 blockade with Anakinra on cardiac function in ST-segment elevation acute myocardial infarction: results from the VCUART3 echocardiography study

Abstract Background ST-segment elevation myocardial infarction (STEMI) is associated with an intense acute inflammatory response further promoting cardiac dysfunction and heart failure (HF). Pilot proof-of-concept studies with anakinra, recombinant Interleukin-1 (IL-1) receptor antagonist, have shown feasibility and safety of IL-1 blockade in patients with STEMI. In the current study we analyzed the effects of anakinra on left ventricular (LV) dimensions and function in patients with STEMI. Methods We enrolled patients with STEMI within 12 hours of presentation at 3 sites in the United States of America. After revascularization, patients were randomly assigned to receive anakinra 100 mg twice daily, anakinra 100 mg once daily alternated with placebo once daily every 12 hours, or placebo twice daily, for 14 days in a 1:1:1 ratio. A transthoracic echocardiogram was completed within 24 hours of admission and at 1 year follow up to measure LV end-diastolic and end-systolic volumes (LVEDV and LVESV, respectively), stroke volume (SV) and ejection fraction (LVEF). (ClinicalTrials NCT01950299) Results Paired echocardiography studies (follow up study obtained 362 days [336–375] after the baseline study) were available in 63 of the 99 patients (63%): 23 of 35 patients in the placebo group (66%) and 40 of the 64 patients in the anakinra group (62%, P&gt;0.05 for missing studies between the 2 groups; P&gt;0.05 for duration of follow up). Baseline LVEDV, LVESV, SV and LVEF was not significantly different comparing placebo and anakinra (all P&gt;0.05). Patients treated with anakinra had a significant improvement in LVEF from 49.8% (41.8–60.0%) to 54.0% (46.0–58.4%, P=0.028) and SV from 43.6 ml (37.6–52.1 ml) to 48.7 ml (40.9–62.5 ml, P=0.008), whereas no significant changes occurred within the placebo group (LVEF: from 51.7% [40.1–56.0%] to 53.5% [43.4–59.4%], P=0.25; SV: from 47.7 ml [40.1–56.8 ml], to 53.0 ml [44.9–57.4 ml], P=0.81). The between-groups differences, however, were not statistically significant. No significant changes were noted in LVEDV and LVESV in either group. The interval changes in CRP between admission and 72 hours, expression of the acute inflammatory response, inversely correlated with the LVEF at follow up (R=-0.30, P=0.026), with higher levels of CRP corresponding to lower LVEF values Conclusions A significant improvement in cardiac systolic function was seen in patients treated with IL-1 receptor antagonist, anakinra, following STEMI, and not in patients with placebo. Further studies are however required to determine whether the benefits of IL-1 blockade in the prevention and treatment of HF are mediated by the effects on cardiac function. Acknowledgement/Funding Funded by NHLBI 1R34HL121402; Drug supply from Swedish Orphan Biovitrum

P6388Effects of Interleukin-1 blockade with anakinra in patients with ST-segment elevation acute myocardial infarction on recurrent ischemic events: results from the VCUART3 study

Abstract Background ST-segment elevation myocardial infarction (STEMI) is associated with an intense acute inflammatory response and an increased risk of recurrent ischemic events. Prior studies of IL-1 blockade have shown conflicting results regarding the risk of future events. Methods We enrolled patients with STEMI within 12 hours of presentation at 3 sites in the United States of America. After revascularization, patients were randomly assigned to receive anakinra 100 mg twice daily, anakinra 100 mg once daily (standard dose) alternated with placebo once daily every 12 hours, or placebo every 12 hours for 14 days in 1:1:1 ratio. Prespecified exploratory endpoints for recurrent ischemic events, adjudicated by an independent committee, evaluated the composite risk of subsequent acute myocardial infarction (AMI, World Health Organization classification Type 1), unstable angina, or urgent revascularization. Data are expressed as median and interquartile range or number and percentage. Cox regression analysis was used to generate unadjusted hazard ratios and confidence intervals. (ClinicalTrials.gov number, NCT01950299) Results Of 311 patients screened, 99 subjects (81% males, 58% Caucasians, 55 [49–62] years of age) were randomly assigned to anakinra twice daily (N=31), anakinra once daily (N=33) or placebo (N=35). The cohort included patients with hypertension (57%), tobacco use (55%), diabetes mellitus (30%), and prior diagnosis of coronary artery disease (21%) without statistically significant imbalances in the demographic characteristics between groups (all P&gt;0.05). Discharge medications for the index STEMI admission, in addition to the study medication, included aspirin (100%), statins (100%), P2Y12 inhibitors (100%), beta-blockers (90%), and angiotensin converting enzyme inhibitor/angiotensin receptor blocker (84%), without statistically significant imbalances between the 3 groups. Over the 1-year follow-up, recurrent ischemic events occurred in 5/35 (14.3%) patients treated with placebo and 6/64 (9.1%) patients treated with anakinra (hazard ratio = 0.68 [0.20–2.24], P=0.53). No differences were observed between high- and low-dose anakinra treatment groups. Conclusions A two week treatment with IL-1 receptor antagonist, anakinra, did not significantly decrease or increase recurrent ischemic events over the course of a 1-year follow-up in patients with STEMI. Acknowledgement/Funding Funded by NHLBI 1R34HL121402; Drug supply by Swedish Orphan Biovitrum

DRUG-INDUCED ENCEPHALOPATHY WITH IMPAIRED COGNITIVE FUNCTIONS DURING TOCILIZUMAB USE

Blockade of interleukin-6 (IL-6) is one of the most promising areas in the treatment of a number of immunoinflammatory diseases. Tocilizumab (TCZ), the first registered anti-IL-6 receptor monoclonal antibody, has been used effectively by rheumatologists since 2010. During this period, the spectrum of adverse reactions (ARs) of TCZ has been clearly defined. However, the multifaceted biological effects of IL-6 determine the probability of unexpected ARs. The article describes a clinical case of drug-induced encephalopathy with cognitive dysfunction during TCZ therapy.

Exercise-induced changes in visceral adipose tissue mass are regulated by IL-6 signaling: A randomized controlled trial

Visceral adipose tissue is harmful to metabolic health. Exercise training reduces visceral adipose tissue mass, but the underlying mechanisms are not known. Interleukin-6 (IL-6) stimulates lipolysis and is released from skeletal muscle during exercise. We hypothesized that exercise-induced reductions in visceral adipose tissue mass are mediated by IL-6. In this randomized placebo-controlled trial we assigned abdominally obese adults to tocilizumab (IL-6 receptor antibody) or placebo during a 12-week intervention with either exercise or no exercise. While exercise reduced visceral adipose tissue mass, this effect of exercise was abolished in the presence of IL-6 blockade. Changes in body weight and total adipose tissue mass showed similar tendencies, whereas lean body mass did not differ between groups. Also, IL-6 blockade worsened the lipid profile, an effect not reversed by exercise. Thus, IL-6 is required for exercise to reduce visceral adipose tissue mass and emphasizes a potentially important metabolic consequence of IL-6 blockade.

Targeting Granulocyte-Monocyte Colony-Stimulating Factor Signaling in Rheumatoid Arthritis: Future Prospects.

Rheumatoid arthritis (RA) is a systemic, autoimmune disease that affects joints and extra-articular structures. In the last decade, the management of this chronic disease has dramatically changed with the introduction of several targeted mechanisms of action, such as tumor necrosis factor-α inhibition, T-cell costimulation inhibition, B-cell depletion, interleukin-6 blockade, and Janus kinase inhibition. Beyond its well-known hematopoietic role on the proliferation and differentiation of myeloid cells, granulocyte-monocyte colony-stimulating factor (GM-CSF) is a proinflammatory mediator acting as a cytokine, with a proven pathogenetic role in autoimmune disorders such as RA. In vitro studies clearly demonstrated the effect of GM-CSF in the communication between resident tissue cells and activated macrophages at chronic inflammation sites, and confirmed the elevation of GM-CSF levels in inflamed synovial tissue of RA subjects compared with healthy controls. Moreover, a pivotal role of GM-CSF in the perception of pain has been clearly confirmed. Therefore, blockade of the GM-CSF pathway by monoclonal antibodies directed against the cytokine itself or its receptor has been investigated in refractory RA patients. Overall, the safety profile of GM-CSF inhibitors seems to be very favorable, with a particularly low incidence of infectious complications. The efficacy of this new mechanism of action is comparable with main competitors, even though the response rates reported in phase II randomized controlled trials (RCTs) appear to be numerically lower than the response rates observed with other biological disease-modifying antirheumatic drugs already licensed for RA. Mainly because of this reason, nowadays the development program of most GM-CSF blockers for RA has been discontinued, with the exception of otilimab, which is under evaluation in two phase III RCTs with a head-to head non-inferiority design against tofacitinib. These studies will likely be useful for better defining the potential role of GM-CSF inhibition in the therapeutic algorithm of RA. On the other hand, the potential role of GM-CSF blockade in the treatment of other rheumatic diseases is now under investigation. Phase II trials are ongoing with the aim of evaluating mavrilimumab for the treatment of giant cell arteritis, and namilumab for the treatment of spondyloarthritis. Moreover, GM-CSF inhibitors have been tested in osteoarthritis and diffuse subtype of systemic sclerosis. This review aims to describe in detail the available evidence on the GM-CSF blocking pathway in RA management, paving the way to a possible alternative treatment for RA patients. Novel insights regarding the potential use of GM-CSF blockers for alternative indications will be also addressed.

8. An autoinflammatory syndrome resembling Castleman’s disease with excellent response to IL-6 blockade

Introduction Autoinflammatory diseases are an emerging group, characterised by recurrent inflammatory episodes due to dysregulated innate immunity. Common features include fevers, rash, arthralgia, lymphadenopathy and systemic symptoms. Castleman’s disease is a rare lymphoproliferative disease, associated with the overproduction of interleukin-6 (IL-6). Its two main variants: unicentric and multicentric differ in aetiology and clinical outcomes. The cytokine storm driven by IL-6 can mimic autoinflammatory disease. We present the case of an acquired autoinflammatory syndrome in a 33-year-old male with the clinical phenotype of Castleman’s but no culprit lymph node detected radiologically. Symptoms dramatically improved with yocilizumab, an IL-6 blocker.

6. The Stillness after the storm: a challenging diagnostic and therapeutic case of adult-onset Still’s disease

6. The Stillness after the storm: a challenging diagnostic and therapeutic case of adult-onset Still’s disease

Inhibition of Interleukin-23–Mediated Inflammation with a Novel Small Molecule Inverse Agonist of RORγt

Blockade of interleukin (IL)-23 or IL-17 with biologics is clinically validated as a treatment of psoriasis. However, the clinical impact of targeting other nodes within the IL-23/IL-17 pathway, especially with small molecules, is less defined. We report on a novel small molecule inverse agonist of retinoid acid-related orphan receptor (ROR) γt and its efficacy in preclinical models of psoriasis and arthritis. 1-(2,4-Dichloro-3-((1,4-dimethyl-6-(trifluoromethyl)-1H-indol-2-yl)methyl)benzoyl)piperidine-4-carboxylic acid (A-9758) was optimized from material identified from a high-throughput screening campaign. A-9758 is selective for RORγt and exhibits robust potency against IL-17A release both in vitro and in vivo. In vivo, we also show that IL-23 is sufficient to drive the accumulation of RORγt+ cells, and inhibition of RORγt significantly attenuates IL-23-driven psoriasiform dermatitis. Therapeutic treatment with A-9758 (i.e., delivered during active disease) was also effective in blocking skin and joint inflammation. Finally, A-9758 exhibited efficacy in an ex vivo human whole blood assay, suggesting small molecule inverse agonists of RORγt could be efficacious in human IL-17-related diseases. SIGNIFICANCE STATEMENT: Using a novel small molecule inverse agonist, and preclinical assays, we show that RORγt is a viable target for the inhibition of RORγt/Th17-driven diseases such as psoriasis. Preclinical models of psoriasis show that inhibition of RORγt blocks both the accumulation and effector function of IL-17-producing T cells.

Serum Interleukin-23/17 Levels in Ankylosing Spondylitis Patients Treated with Nonsteroidal Anti-Inflammatory Drugs: A Prospective Cohort Study.

Etiopathogenesis of ankylosing spondylitis (AS), a major subtype of a group of chronic inflammatory diseases known as spondyloarthropathies, is not clearly understood yet. In this study, we aimed to investigate the interleukin 23 (IL-23)/interleukin-17 (IL-17) pathway, which is a new cytokine pathway in inflammatory diseases. We evaluated serum IL-17 and IL-23 levels after 1-year follow-up in AS patients using only nonsteroidal anti inflammatory drugs (at need or continue). Forty-four AS patients and 40 healthy controls were included in the study. Clinical evaluations of disease activity were performed. Serum tumor necrosis factor-α (TNF-α), IL-6, IL-17, and IL-23 levels were evaluated. IL-17 and IL-23 levels of the patient group at baseline and 12 months were lower than the control group. There was no significant difference between the baseline and 12th month evaluations of the patient group. TNF-α levels were similar in all groups (in the baseline and 12th month of the patient group and in the control group). Although our results are in contrast to the literature findings, the IL-23/IL-17 pathway is a newly discovered pathway, and there may still be unknowns. New studies involving larger patient groups are needed for the factors affecting serum IL-23/IL-17 levels in patients with AS. We also think that it will be useful to make more comprehensive and long-term studies about which patients will respond well to IL-23/IL-17 blockade.

Interleukin-1 receptor antagonist treatment in acute ischaemic stroke does not alter systemic markers of anti-microbial defence

Background: Blockade of the cytokine interleukin-1 (IL-1) with IL-1 receptor antagonist (IL-1Ra) is a candidate treatment for stroke entering phase II/III trials, which acts by inhibiting harmful inflammatory responses. Infection is a common complication after stroke that significantly worsens outcome and is related to stroke-induced deficits in systemic immune function thought to be mediated by the sympathetic nervous system. Therefore, immunomodulatory treatments for stroke, such as IL-1Ra, carry a risk of aggravating stroke-associated infection. Our primary objective was to determine if factors associated with antibody-mediated antibacterial defences were further compromised in patients treated with IL-1Ra after stroke. Methods: We assessed plasma concentrations of immunoglobulin isotypes and complement components in stroke patients treated with IL-1Ra or placebo and untreated non-stroke controls using multiplex protein assays. Activation of the sympathetic nervous system (SNS) was determined by measuring noradrenaline, a major SNS mediator. Results: There were significantly lower plasma concentrations of IgM, IgA, IgG1 and IgG4 in stroke-patients compared to non-stroke controls, however there were no differences between stroke patients treated with placebo or IL-1Ra. Concentrations of complement components associated with the classical pathway were increased and those associated with the alternative pathways decreased in stroke patients, neither being affected by treatment with IL-1Ra. Noradrenaline concentrations were increased after stroke in both placebo and IL-1Ra-treated stroke patients compared to non-stroke controls. Conclusion: These data show treatment with IL-1Ra after stroke does not alter circulating immunoglobulin and complement concentrations and is therefore unlikely to further aggravate stroke-associated infection susceptibility through altered availability of these key anti-microbial mediators.

Interleukin-1 receptor antagonist treatment in acute ischaemic stroke does not alter systemic markers of anti-microbial defence.

Background: Blockade of the cytokine interleukin-1 (IL-1) with IL-1 receptor antagonist (IL-1Ra) is a candidate treatment for stroke entering phase II/III trials, which acts by inhibiting harmful inflammatory responses. Infection is a common complication after stroke that significantly worsens outcome and is related to stroke-induced deficits in systemic immune function thought to be mediated by the sympathetic nervous system. Therefore, immunomodulatory treatments for stroke, such as IL-1Ra, carry a risk of aggravating stroke-associated infection. Our primary objective was to determine if factors associated with antibody-mediated antibacterial defences were further compromised in patients treated with IL-1Ra after stroke. Methods: We assessed plasma concentrations of immunoglobulin isotypes and complement components in stroke patients treated with IL-1Ra or placebo and untreated non-stroke controls using multiplex protein assays. Activation of the sympathetic nervous system (SNS) was determinedby measuring noradrenaline, a major SNS mediator. Results: There were significantly lower plasma concentrations of IgM, IgA, IgG1 and IgG4 in stroke-patients compared to non-stroke controls, however there were no differences between stroke patients treated with placebo or IL-1Ra. Concentrations of complement components associated with the classical pathway were increased and those associated with the alternative pathways decreased in stroke patients, neither being affected by treatment with IL-1Ra. Noradrenaline concentrations were increased after stroke in both placebo and IL-1Ra-treated stroke patients compared to non-stroke controls. Conclusion: These data show treatment with IL-1Ra after stroke does not alter circulating immunoglobulin and complement concentrations and is therefore unlikely to further aggravate stroke-associated infection susceptibility through reduced availability of these key anti-microbialmediators.

IL-6 Trans-signaling Controls Liver Regeneration After Partial Hepatectomy.

Interleukin-6 (IL-6) is critically involved in liver regeneration after partial hepatectomy (PHX). Previous reports suggest that IL-6 trans-signaling through the soluble IL-6/IL-6R complex is involved in this process. However, the long-term contribution of IL-6 trans-signaling for liver regeneration after PHX is unknown. PHX-induced generation of the soluble IL-6R by ADAM (a disintegrin and metallo) proteases enables IL-6 trans-signaling, in which IL-6 forms an agonistic complex with the soluble IL-6 receptor (sIL-6R) to activate all cells expressing the signal-transducing receptor chain glycoprotein 130 (gp130). In contrast, without activation of ADAM proteases, IL-6 in complex with membrane-bound IL-6R and gp130 activates classic signaling. Here, we describe the generation of IL-6 trans-signaling mice, which exhibit boosted IL-6 trans-signaling and abrogated classic signaling by genetic conversion of all membrane-bound IL-6R into sIL-6R proteins phenocopying hyperactivation of ADAM-mediated shedding of IL-6R as single substrate. Importantly, although IL-6R deficient mice were strongly affected by PHX, survival and regeneration of IL-6 trans-signaling mice was indistinguishable from control mice, demonstrating that IL-6 trans-signaling fully compensates for disabled classic signaling in liver regeneration after PHX. Moreover, we monitored the long-term consequences of global IL-6 signaling inhibition versus IL-6 trans-signaling selective blockade after PHX by IL-6 monoclonal antibodies and soluble glycoprotein 130 as fragment crystallizable fusion, respectively. Both global IL-6 blockade and selective inhibition of IL-6 trans-signaling results in a strong decrease of overall survival after PHX, accompanied by decreased signal transducer and activator of transcription 3 phosphorylation and proliferation of hepatocytes. Mechanistically, IL-6 trans-signaling induces hepatocyte growth factor production by hepatic stellate cells. Conclusion: IL-6 trans-signaling, but not classic signaling, controls liver regeneration following PHX.

Targeting IL-17 attenuates hypoxia-induced pulmonary hypertension through downregulation of β-catenin

BackgroundThe role of interleukin 17 (IL-17) in hypoxic pulmonary hypertension (HPH) remains unclear. This study is designed to explore whether IL-17 is a potential target for HPH treatment.MethodsClinic samples from...

Prevention of radiotherapy-induced arterial inflammation by interleukin-1 blockade.

AimsRadiotherapy-induced cardiovascular disease is an emerging problem in a growing population of cancer survivors where traditional treatments, such as anti-platelet and lipid-lowering drugs, have limited benefits. The aim of the study was to investigate vascular inflammatory patterns in human cancer survivors, replicate the findings in an animal model, and evaluate whether interleukin-1 (IL-1) inhibition could be a potential treatment.Methods and resultsIrradiated human arterial biopsies were collected during microvascular autologous free tissue transfer for cancer reconstruction and compared with non-irradiated arteries from the same patient. A mouse model was used to study the effects of the IL-1 receptor antagonist, anakinra, on localized radiation-induced vascular inflammation. We observed significant induction of genes associated with inflammasome biology in whole transcriptome analysis of irradiated arteries, a finding supported by elevated protein levels in irradiated arteries of both, pro-caspase and caspase-1. mRNA levels of inflammasome associated chemokines CCL2, CCL5 together with the adhesion molecule VCAM1, were elevated in human irradiated arteries as was the number of infiltrating macrophages. A similar pattern was reproduced in Apoe−/− mouse 10 weeks after localized chest irradiation with 14 Gy. Treatment with anakinra in irradiated mice significantly reduced Ccl2 and Ccl5 mRNA levels and expression of I-Ab.ConclusionAnakinra, administered directly after radiation exposure for 2 weeks, ameliorated radiation induced sustained expression of inflammatory mediators in mice. Further studies are needed to evaluate IL-1 blockade as a treatment of radiotherapy-induced vascular disease in a clinical setting.