Selective IL-27 production by intestinal regulatory T cells permits gut-specific regulation of T17 cell immunity.

Regulatory T cells (T cells) are instrumental in establishing immunological tolerance. However, the precise effector mechanisms by which T cells control a specific type of immune response in a given tissue remains unresolved. By simultaneously studying T cells from different tissue origins under systemic autoimmunity, in the present study we show that interleukin (IL)-27 is specifically produced by intestinal T cells to regulate helper T17 cell (T17 cell) immunity.

Enhancing SIRT1 Gene Expression Using Small Activating RNAs: A Novel Approach for Reversing Metabolic Syndrome.

Metabolic syndrome (MetS) is a pathological condition characterized by abdominal obesity, insulin resistance, hypertension, and hyperlipidemia. Sirtuin 1 (SIRT1), a highly conserved histone deacetylase, is characterized as a key metabolic regulator and protector against aging-associated pathologies, including MetS. In this study, we investigate the therapeutic potential of activating SIRT1 using small activating RNAs (saRNA), thereby reducing inflammatory-like responses and re-establishing normal lipid metabolism.

Delivery of Oligonucleotides to the Liver with GalNAc: From Research to Registered Therapeutic Drug.

Targeted delivery of oligonucleotides to liver hepatocytes using N-acetylgalactosamine (GalNAc) conjugates that bind to the asialoglycoprotein receptor has become a breakthrough approach in the therapeutic oligonucleotide field. This technology has led to the approval of givosiran for the treatment of acute hepatic porphyria, and there are another seven conjugates in registrational review or phase 3 trials and at least another 21 conjugates at earlier stages of clinical development. This review highlights some of the recent chemical and preclinical advances in this space, leading to a large number of clinical candidates against a diverse range of targets in liver hepatocytes.

Differential gene expression in human tissue resident regulatory T cells from lung, colon, and blood.

As we learn more about how immune responses occur , it is becoming clear that each organ/tissue is characterized with its own anatomy and microenvironment which may affect and even determine the outcome of the immune responses. With emerging data from animal studies showing that regulatory T cells infiltrating non-lymphoid tissues exhibit unique phenotypes and transcriptional signatures and display functions beyond their well-established suppressive roles, there is an urgent need to explore the function of tissue Treg cells in humans. Here we characterized the transcriptome of Treg residing at the human mucosal tissue obtained from the normal area of cancer resections and their peripheral blood counterparts, identifying human lung and colon tissue Treg signature genes and their upstream regulators.

COPD monocytes demonstrate impaired migratory ability.

Background: Increased lung macrophage numbers in COPD may arise from upregulation of blood monocyte recruitment into the lungs. CCR5 is a monocyte chemokine receptor regulated by interleukin-6 (IL-6); the concentration of CCR5 ligands are known to be elevated in COPD lungs. The objective of this study was to investigate mechanisms of monocyte recruitment to the lung in COPD, including the role of CCR5 signalling.

Inhibitors of JAK-family kinases: an update on the patent literature 2013-2015, part 1.

Janus kinases (JAKs) are a family of four enzymes; JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2) that are critical in cytokine signalling and are strongly linked to both cancer and inflammatory diseases. There are currently two launched JAK inhibitors for the treatment of human conditions: tofacitinib for Rheumatoid arthritis (RA) and ruxolitinib for myeloproliferative neoplasms including intermediate or high risk myelofibrosis and polycythemia vera. Areas covered: This review covers patents claiming activity against one or more JAK family members in the period 2013-2015 inclusive, and covers 95 patents from 42 applicants, split over two parts.

Inhibitors of JAK-family kinases: an update on the patent literature 2013-2015, part 2.

Janus kinases (JAKs) are a family of four enzymes; JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2) that are critical in cytokine signalling and are strongly linked to both cancer and inflammatory diseases. There are currently two launched JAK inhibitors for the treatment of human conditions: tofacitinib for Rheumatoid arthritis (RA) and ruxolitinib for myeloproliferative neoplasms including intermediate or high risk myelofibrosis and polycythemia vera. Areas covered: This review covers patents claiming activity against one or more JAK family members in the period 2013-2015 inclusive, and covers 95 patents from 42 applicants, split over two parts.

Patient stratification and the unmet need in asthma.

Asthma is often described as an inflammatory disease of the lungs and in most patients symptomatic treatment with bronchodilators or inhaled corticosteroids is sufficient to control disease. Unfortunately there are a proportion of patients who fail to achieve control despite treatment with the best current treatment. These severe asthma patients have been considered a homogeneous group of patients that represent the unmet therapeutic need in asthma.

Research in progress: Medical Research Council United Kingdom Refractory Asthma Stratification Programme (RASP-UK).

The UK Refractory Asthma Stratification Programme (RASP-UK) will explore novel biomarker stratification strategies in severe asthma to improve clinical management and accelerate development of new therapies. Prior asthma mechanistic studies have not stratified on inflammatory phenotype and the understanding of pathophysiological mechanisms in asthma without Type 2 cytokine inflammation is limited. RASP-UK will objectively assess adherence to corticosteroids (CS) and examine a novel composite biomarker strategy to optimise CS dose; this will also address what proportion of patients with severe asthma have persistent symptoms without eosinophilic airways inflammation after progressive CS withdrawal.

OX40 blockade inhibits house dust mite driven allergic lung inflammation in mice and in vitro allergic responses in humans.

The costimulatory receptor OX40 is expressed on activated T cells and regulates T-cell responses. Here, we show the efficacy and mechanism of action of an OX40 blocking antibody using the chronic house dust mite (HDM) mouse model of lung inflammation and in vitro HDM stimulation of cells from HDM allergic human donors. We have demonstrated that OX40 blockade leads to a reduction in the number of eosinophils and neutrophils in the lavage fluid and lung tissue of HDM sensitized mice.

Increased levels of soluble interleukin-6 receptor and CCL3 in COPD sputum.

Background: COPD patients have increased numbers of macrophages and neutrophils in the lungs. Interleukin-6 (IL-6) trans-signaling via its soluble receptor sIL-6R, governs the influx of innate immune cells to inflammatory foci through regulation of the chemokine CCL3. We hypothesized that there would be enhanced levels of IL-6, sIL-6R and CCL3 in COPD sputum.

Cigarette smoke induced airway inflammation is independent of NF-κB signalling.

Rationale: COPD is an inflammatory lung disease largely associated with exposure to cigarette smoke (CS). The mechanism by which CS leads to the pathogenesis of COPD is currently unclear; it is known however that many of the inflammatory mediators present in the COPD lung can be produced via the actions of the transcription factor Nuclear Factor-kappaB (NF-κB) and its upstream signalling kinase, Inhibitor of κB kinase-2 (IKK-2). Therefore the NF-κB/IKK-2 signalling pathway may represent a therapeutic target to attenuate the inflammation associated with COPD.

Monoclonal antibodies for the treatment of asthma.

Asthma is a chronic inflammatory disease of the airways which can have a detrimental effect on quality of life and in extreme cases cause death. Although the majority of patients can control their asthma symptoms with a combination of steroids and beta agonists there is still a group of patients whose asthma remains symptomatic despite the best available treatment. These severe asthmatic patients represent the unmet medical need in asthma and are the focus of those developing novel monoclonal antibody based drugs.

P2X7 receptor and caspase 1 activation are central to airway inflammation observed after exposure to tobacco smoke.

Chronic Obstructive Pulmonary Disease (COPD) is a cigarette smoke (CS)-driven inflammatory airway disease with an increasing global prevalence. Currently there is no effective medication to stop the relentless progression of this disease. It has recently been shown that an activator of the P2X7/inflammasome pathway, ATP, and the resultant products (IL-1β/IL-18) are increased in COPD patients.

Asthma & COPD--IQPC's Second Conference.

The International Quality & Productivity Center's (IQPC) Second Asthma & COPD conference, held in Philadelphia, included topics covering new therapeutic developments in the field of asthma and COPD. This conference report highlights selected presentations on mAb treatments for asthma, including targeting IL-5, IL-13, IL-9 and TNFa, CCR3 inhibitors, histamine H4 receptor inhibition, novel mouse models of COPD and inhaled antisense asthma therapies. Investigational drugs discussed include mepolizumab (GlaxoSmithKline plc), benralizumab (BioWa Inc/Kyowa Hakko Kirin Co Ltd/MedImmune LLC), AMG-317 (Amgen Inc/Takeda Bio Development Center Ltd), TPI-ASM-8 (Pharmaxis Ltd) and AIR-645 (Altair Therapeutics Inc).

Liver X receptor agonists increase airway reactivity in a model of asthma via increasing airway smooth muscle growth.

The liver X receptors (LXRalpha/beta) are orphan nuclear receptors that are expressed in a large number of cell types and have been shown to have anti-inflammatory properties. Nuclear receptors have previously proved to be amenable targets for small molecular mass pharmacological agents in asthma, and so the effect of an LXR ligand was assessed in models of allergic airway inflammation. LXR agonist, GW 3965, was profiled in rat and mouse models of allergic asthma.

Estrogen receptor beta: expression profile and possible anti-inflammatory role in disease.

Estrogen receptor (ER) beta agonists have been demonstrated to possess anti-inflammatory properties in inflammatory disease models. The objective of this study was to determine whether ERbeta agonists affect in vitro and in vivo preclinical models of asthma. mRNA expression assays were validated in human and rodent tissue panels.

The role of IkappaB kinase 2, but not activation of NF-kappaB, in the release of CXCR3 ligands from IFN-gamma-stimulated human bronchial epithelial cells.

The severity of chronic obstructive pulmonary disease correlates with increased numbers of cytotoxic CD8(+) T lymphocytes in the lung parenchyma. CD8(+) T lymphocytes release IFN-gamma which stimulates airway epithelial cells to produce CXCR3 chemokines leading to further recruitment of CD8(+) T lymphocytes. To evaluate the signaling pathways involved in regulation of CXCR3 ligands, the human bronchial epithelial cell line BEAS-2B was stimulated with IFN-gamma and the release of the CXCR3 ligands was measured by ELISA.

Novel role for the liver X nuclear receptor in the suppression of lung inflammatory responses.

The liver X receptors (LXRalpha/beta) are part of the nuclear receptor family and are believed to regulate cholesterol and lipid homeostasis. It has also been suggested that LXR agonists possess anti-inflammatory properties. The aim of this work was to determine the effect of LXR agonists on the innate immune response in human primary lung macrophages and a pre-clinical rodent model of lung inflammation.

Impact of tobacco-smoke on key signaling pathways in the innate immune response in lung macrophages.

Many of the healthcare consequences of cigarette smoking could be due to its ability to compromise the immune system, and in respiratory diseases like chronic obstructive pulmonary disease (COPD), a constant low level of infection could be responsible for some of the symptoms/pathology. The aim was to assess the impact of cigarette smoke (CS) on the release of innate effector cytokines in THP-1 cells and human lung macrophages, and to determine the molecular mechanism behind the altered response. Cells were exposed to CS with and without endotoxin stimulus, cytokines, glutathione, mitogen-activated protein kinase (MAPK) phosphorylation, IkappaB kinase-2 (IKK-2) activity, nuclear factor kappa B (NF-kappaB), and activator protein-1 (AP-1) pathway activation was measured.

Dissociated steroids.

Glucocorticoids (GCs) are some of the most important drugs in clinical use today. They are mainly used to suppress disease-related inflammation and are widely used for the treatment of many inflammatory diseases including asthma and arthritis. However, GCs are also associated with debilitating side effects that place limitations on the long-term use of these drugs.

Repression of inflammatory gene expression in human pulmonary epithelial cells by small-molecule IkappaB kinase inhibitors.

The airway epithelium is critical in the pathogenesis of chronic inflammatory diseases, such as asthma and chronic obstructive pulmonary disease, and, by expressing numerous inflammatory genes, plays a prominent role in disease exacerbations. Since inflammatory gene expression often involves the transcription factor nuclear factor (NF)-kappaB, this signaling pathway represents a site for anti-inflammatory intervention. As the airway epithelium is targeted by inhaled therapeutic agents, for example corticosteroids, human A549 pulmonary cells and primary human bronchial epithelial (HBE) cells were selected to evaluate inhibitor of kappaB kinase (IKK) inhibitors.

Validation of the anti-inflammatory properties of small-molecule IkappaB Kinase (IKK)-2 inhibitors by comparison with adenoviral-mediated delivery of dominant-negative IKK1 and IKK2 in human airways smooth muscle.

Asthma and chronic obstructive pulmonary disease (COPD) are characterized by chronic airway inflammation. However, because patients with COPD and certain patients with asthma show little or no therapeutic benefit from existing corticosteroid therapies, there is an urgent need for novel anti-inflammatory strategies. The transcription factor nuclear factor-kappaB (NF-kappaB) is central to inflammation and is necessary for the expression of numerous inflammatory genes.