Etanercept for refractory asthma therapy

Asthma is a chronic disease of the airways in which inflammation causes bronchial hyper-reactivity and consequent asthma attacks triggered by various stimuli. The bronchospasm attacks are usually relieved by short-acting beta2 agonists, and inflammation and bronchial hyper-reactivity are reduced by maintenance therapy and, in particular, by inhaled corticosteroids. In milder asthma subjects, airway inflammation is dominated by eosinophils, whereas in more severe asthma increased neutrophil counts were detected. In severe/refractory asthma, TNF-alpha is known to play a role in the maintenance of neutrophilic inflammation and of bronchial hyper-responsiveness and is not influenced by corticosteroid therapy. Etanercept, a TNF-alpha-blocking agent, could represent one of the potential therapies for refractory asthma based on demonstrated safety and efficacy.     

Targeting tumour necrosis factor-alpha in corticosteroid-dependent asthma

Asthma is a chronic inflammatory disease of the airways characterised by bronchospasm attacks triggered by various stimuli. The underlying pathogenic mechanism is eosinophil-dominated inflammation causing bronchial hyper-responsiveness, but in more severe asthma subjects, neutrophil cells and their directly related cytokines, such as TNF-alpha, are known to play a role in the inflammatory process and also in diminished corticosteroid sensitivity. The bronchospasm attacks are usually relieved by short-acting beta2-agonists, whereas maintenance therapy is represented mainly by inhaled corticosteroids. However, in severe persistent asthma or in difficult to treat asthma these can be ineffective even at high doses. Therefore, other therapeutic alternatives are needed, and etanercept, a TNF-alpha blocking agent, could represent one of them provided the safety and efficacy data are supportive.     

Mast cells and inflammatory heart disease: potential drug targets

Inflammation underlies the pathogenesis of many common cardiovascular diseases (CVD) such as myocardial infarction, atherosclerosis, myocarditis and dilated cardiomyopathy. Allergic disorders like allergic rhinitis and asthma, both chronic inflammatory conditions, have recently been linked to increased CVD and death. Studies have found that increased IgE levels, eosinophilia, positive skin-prick tests, self-reported asthma and enzymes that regulate leukotriene synthesis (5-lipoxygenase) predict a high risk for atherosclerosis, stroke and myocardial infarction. Mast cells (MCs), cells involved in the pathogenesis of allergy and asthma, are emerging as key players in the regulation of inflammation and fibrosis in the heart and vasculature. Our laboratory has found that MC numbers are increased in mice susceptible to developing chronic dilated cardiomyopathy. The fibrosis associated with chronic heart disease is increased by MC degranulation. MCs can also act as antigen-presenting cells increasing inflammation in the heart through Toll-like receptor-4 signaling and increased proinflammatory cytokine production. Similar inflammatory mechanisms are observed for myocarditis and atherosclerosis. Many of the drugs currently used to reduce heart disease act on mediators/ pathways downstream of MC degranulation. An improved understanding of the role of MCs in regulating inflammation and fibrosis will enable researchers and clinicians to better treat heart disease.     

Preparation and in vitro analysis of microcapsule thalidomide formulation for targeted suppression of TNF-alpha

Recent studies have implicated the cytokine tumor necrosis factor-alpha (TNF-alpha) in the inflammation associated with Crohn's disease (CD). Thalidomide has been shown to decrease this inflammation by the suppression of TNF-alpha secretion. However, side effects associated with thalidomide have precluded its widespread usage. In the present study we investigated the efficacy of a "targeted delivery approach" for thalidomide at the site of inflammation. We observed that alginate-poly-l-lysine-alginate (APA) polymer-based microcapsule formulations that encapsulate thalidomide could be designed. These capsules could be delivered at target sites where they almost entirely suppress TNF-alpha secretion in lipopolysaccharide activated RAW 264.7 macrophage cells in vitro. These findings indicate that targeted delivery of thalidomide using APA capsules could facilitate its usage in reducing the inflammation associated with chronic conditions such as Crohn's disease and ulcerative colitis.     

Airway smooth muscle: new targets for asthma pharmacotherapy

Asthma, a chronic disease increasing in prevalence worldwide, is characterised by reversible airway obstruction, airway inflammation and airway smooth muscle (ASM) cell hyperplasia. The traditional view of ASM in asthma, as a regulator of bronchomotor tone, is rapidly changing. New evidence suggests that ASM cells also play an important role in the perpetuation of airway inflammation and airway remodelling. This review discusses the synthetic function of ASM cells, defined as the ability to secrete cytokines, chemokines and growth factors and express surface receptors that are important for cell adhesion and leukocyte activation. Finally, the efficacy of established asthma therapies in modifying the synthetic function of ASM cells are compared and novel targets for pharmacological intervention are discussed.     

A carbohydrate fraction, AIP1 from Artemisia iwayomogi suppresses pulmonary eosinophilia and Th2-type cytokine production in an ovalbumin-induced allergic asthma. Down-regulation of TNF-alpha expression in the lung

Asthma is a chronic inflammatory disease of the airways characterized by reversible airway obstruction, airway hyperreactivity, and remodeling of the airways. The incidence of asthma is on the rise despite ongoing intensive asthma research. Artemisia iwayomogi, a member of the Compositae, is a perennial herb easily found around Korea and has been used as a traditional anti-inflammatory medicine in liver diseases. We investigated suppressive effects of AIP1, a water-soluble carbohydrate fraction from A. iwayomogi on ovalbumin-induced allergic asthma in BALB/c mice and studied the possible mechanisms of its anti-allergic action. AIP1 significantly reduced pulmonary eosinophilia and Th2 cytokine expression in the lungs as well as serum IgE levels. Flow cytometric analysis of lung-infiltrating cells showed that the surface levels of CD11c and MHC II in CD11c+MHC II+ cells, potent dendritic cells, decreased in animals treated with AIP1. Expression of TNF-alpha, one of several proinflammatory cytokines released into the airway during episodes of asthma, was down-regulated by AIP1 injection, suggesting that reduced expression of TNF-alpha could account for the suppression of pulmonary eosinophilia and Th2-type cytokine production by AIP1.     

Agents against cytokine synthesis or receptors

Various cytokines play a critical role in pathophysiology of chronic inflammatory lung diseases including asthma and chronic obstructive pulmonary disease (COPD). The increasing evidence of the involvement of these cytokines in the development of airway inflammation raises the possibility that these cytokines may become the novel promising therapeutic targets. Studies concerning the inhibition of interleukin (IL)-4 have been discontinued despite promising early results in asthma. Although blocking antibody against IL-5 markedly reduces the infiltration of eosinophils in peripheral blood and airway, it does not seem to be effective in symptomatic asthma, while blocking IL-13 might be more effective. On the contrary, anti-inflammatory cytokines themselves such as IL-10, IL-12, IL-18, IL-23 and interferon-gamma may have a therapeutic potential. Inhibition of TNF-alpha may also be useful in severe asthma or COPD. Many chemokines are also involved in the inflammatory response of asthma and COPD through the recruitment of inflammatory cells. Several small molecule inhibitors of chemokine receptors are now in development for the treatment of asthma and COPD. Antibodies that block IL-8 reduce neutrophilic inflammation. Chemokine CC3 receptor antagonists, which block eosinophil chemotaxis, are now in clinical development for asthma therapy. As many cytokines are involved in the pathophysiology of inflammatory lung diseases, inhibitory agents of the synthesis of multiple cytokines may be more useful tools. Several such agents are now in clinical development.     

The role of airway dendritic cell populations in regulation of T-cell responses to inhaled antigens: atopic asthma as a paradigm.

Chronic atopic asthma in adulthood represents the end stage of a disease process that is initiated during the perinatal period, when the naive immune system is first confronted with potentially allergenic airborne antigens. The initial phase involves compartmentalization of immunological memory into either the T-helper (Th)-1 or Th2 cytokine phenotypes, in atopic and nonatopics, respectively, and in a subset of atopics, this results in chronic Th2 cytokine-driven inflammation in the airways. Dendritic cells appear to play a key role in directing the memory generation process, and in subsequently controlling the intensity and duration of the ensuing Th-cell responses responsible for this inflammation.     

A role for parathyroid hormone-related protein in the pathogenesis of inflammatory/autoimmune diseases.

Our increased understanding of the critical role of cytokines in chronic inflammatory/autoimmune diseases has led to the recent development of effective anti-cytokine treatments. In particular, agents blocking the function of TNF-alpha, a cytokine first identified as an endotoxin-inducible mediator of tumor cell necrosis, are now licensed for the treatment of rheumatoid arthritis (RA) and inflammatory bowel disease. However, TNF-alpha is but one member of a cytokine network that is responsible for mediating these inflammatory disorders. Therefore, as our understanding of the pathophysiologic role of other members of this inflammatory network increases, other cytokines may similarly be identified as effective targets for treatment. In this article, we will review evidence which suggests that parathyroid hormone-related protein (PTHrP), a peptide which, like TNF-alpha, was first identified because of its effects in the setting of malignancy, may in fact serve an important non-neoplastic, physiologic function by mediating the inflammatory/autoimmune host response. Data identifying PTHrP as a member of the cytokine network induced in multi-organ inflammation and rheumatoid arthritis will be summarized, initial evidence comparing the therapeutic efficacy of PTHrP- vs. TNF-alpha-blockade in the treatment of endotoxemia will be reviewed, and potential future areas of research, including assessment of the effects of PTHrP blockade in the treatment of RA, will be discussed.     

CC-10004

CC-10004, a phosphodiesterase 4 inhibitor and selective cytokine inhibitor, is under development by Celgene for the potential treatment of asthma, chronic obstructive pulmonary disease, inflammation and psoriasis. By October 2004, phase II trials in psoriasis had commenced.     

Immunomodulatory effects of IL-12 secreted by Lactococcus lactis on Th1/Th2 balance in ovalbumin (OVA)-induced asthma model mice

Asthma is a chronic lung disease characterized by allergen-induced airway inflammation and orchestrated by Th2 cells. Interleukin-12, a Th1-promoting cytokine, is capable of inhibit the Th2-driven allergen-induced airway changes and therefore considered as an attractive molecule to treat asthma. Recent epidemiological and clinical studies suggest a possible role of Lactococcus lactis in the prevention of allergic diseases. In this study, we evaluated the immunomodulatory effects of live L. lactis secreting a biologically active form of IL-12 (LL-IL12) in a mouse model of ovalbumin (OVA)-induced asthma. Intranasal mice administration with LL-IL12 resulted in a shift Th2 to Th1 with elevated IFN-gamma and decreased IL-4 levels. In addition, a profound decrease in airway hyper-responsiveness and pulmonary inflammation was also observed in mice administered with LL-IL12. These promising preclinical results suggest the feasibility of this approach to be used in the treatment of asthma.     

Lipopolysaccharide-induced lung inflammation is inhibited by neutralization of GM-CSF

Granulocyte-macrophage colony-stimulating factor (GM-CSF) plays an important role in the pathogenesis of acute and chronic lung disease as a major regulator governing the functions of granulocyte and macrophage lineage populations. Chronic obstructive pulmonary disease (COPD) is a disease characterized by lung inflammation with accumulation of neutrophils and increased levels of pro-inflammatory cytokines including GM-CSF in the patient's lungs. We used intranasal administration of lipopolysaccharide (LPS) to mice to induce a disease that resembles COPD with pulmonary inflammation, neutrophil recruitment and release of pro-inflammatory mediators in the bronchoalveolar lavage fluid of the diseased mice. 2 h prior to LPS administration, mice were systemically treated with the murine GM-CSF neutralizing antibody mAb 22E9 per intraperitoneal injection. Intranasal challenge with LPS-induced an increase of total cell number and of neutrophils in the bronchoalveolar lavage fluid. Elevated levels of tumor necrosis factor alpha (TNF-alpha), keratinocyte cytokine and macrophage inflammatory protein-2 (MIP-2) were also observed at this time point. GM-CSF was no longer detectable in bronchoalveolar lavage fluid at 24 h due to its early expression with a peak reached 6 h after LPS challenge. Pretreatment of mice with GM-CSF neutralizing antibody dose-dependently inhibited the accumulation of neutrophils and reduced TNF-alpha and MIP-2 protein levels in bronchoalveolar lavage fluid. These data suggest that neutralization of GM-CSF may represent a novel treatment modality for lung inflammation and in particular for COPD.     

Interleukin-9 as a possible therapeutic target in both asthma and chronic obstructive airways disease

Asthma and chronic obstructive pulmonary disease (COPD) are important causes of morbidity and mortality worldwide. Both asthma and COPD are characterized by airflow limitation but distinct differences occur in the pulmonary inflammatory responses in the two conditions. Treatment options for asthma and COPD are limited (especially so for COPD), and both are in need of novel therapeutic interventions. Interleukin-9 (IL-9) is a potential target for such a therapy. This Th2-type cytokine, is secreted by a number of different cell types, and has multiple effects on a wide range of cells within the lung. In this review we will summarize current knowledge about the immunobiology of IL-9 and discuss the role played by IL-9 in inflammation in both asthma and COPD, and its potential as a therapeutic target.     

Potential role of antibiotics in the treatment of asthma

Although the role of antibiotic treatment in asthma is still disputed, clinical use of antimicrobials in this setting is more widespread than warranted on the basis of indications in the literature. Viral upper respiratory tract infections are known to be involved in asthma exacerbations. More recently, evidence of Mycoplasma pneumoniae and Chlamydia pneumoniae involvement in asthma attacks has been reported both in adult and paediatric populations. These pathogens are also involved in chronic asthma, and both in vitro and animal model studies indicate that atypical agents may play a role in the pathogenesis of the disease. Recent studies on asthma patients with evidence of atypical infection suggest that specific antimicrobial treatment (basically macrolides or fluoroquinolones) may confer additional advantages compared to standard therapy alone. Furthermore, a considerable amount of data has been gathered describing additional effects associated with macrolide treatment (reduced bronchial hyper-responsiveness, altered cytokine production, etc.). These non-antimicrobial effects have been defined as "anti-inflammatory activity". Should this information be confirmed, the use of macrolides in patients with asthma may be twofold: eradication of occult atypical infection; and reduction in the airway inflammation burden. Future lines of research in this field should attempt to determine whether specific antibiotic treatment may alter the natural history of asthma.     

Functional molecules in allergic bronchial asthma

Bronchial asthma is considered to be a chronic airway inflammatory disease, characterized by airway obstruction, airway eosinophilic inflammation, and airway hyperresponsiveness (AHR) to a variety of stimuli. AHR is thought to be an important symptom, because the severity of the disease is generally correlated with the degree of AHR. Recent clinical studies have demonstrated the involvement of airway inflammation in the development of allergen-induced AHR, although, the mechanism of allergen-induced AHR has not been fully elucidated and remains controversial. In vivo animal models might provide important information on this point. We have established a mouse model of allergic asthma, which is characterized by airway eosinophilia, IgE production, T helper type 2 (Th2) cytokine production in the airway, and AHR, and investigated the role of inflammatory cells and functional molecules. Results from gene-knockout and mutant mice demonstrated the involvement of T cells, mast cells, prostanoids, and Th2 cytokines including interleukin (IL)-4 and IL-5 in the development of allergen-induced airway inflammation and AHR. In contrast, treatment with anti-IL-4 monoclonal antibody (mAb) or anti-IL-5 mAb during allergen inhalation did not inhibit allergen-induced AHR, although the combination of these mAbs clearly inhibited the enhanced responsiveness. These data indicate that it is a better strategy for control of the disease to inhibit or suppress multifunctional molecules like corticosteroids rather than to inhibit a single factor, because bronchial asthma is a multifactorial disease.     

Interferon-gamma as a possible target in chronic asthma

The role of interferon-gamma (IFN-gamma) in asthma is controversial. However, this cytokine has been proposed to play a role both in acute severe asthma and chronic stable asthma. We have shown that in a chronic low-level challenge model of allergic asthma in mice, which replicates characteristic features of airway inflammation and remodelling, the mechanisms of airway hyperreactivity (AHR) are markedly different to those in short-term high-level challenge models. Notably, AHR is independent of various Th2 cytokines and their signalling pathways. However, administration of a neutralising antibody to IFN-gamma suppresses AHR. More recently, we have found that following chronic allergen challenge, but not acute challenge, IFN-gamma-producing CD4+ T cells are demonstrable in peribronchial lymph nodes, both in wild-type mice and in STAT6-/-mice. Treatment with anti-IFN-gamma decreases the number of IFN-gamma-producing CD4+ T cells in both wild-type and gene-targeted mice, providing a possible explanation for the ability of anti-IFN-gamma to inhibit AHR in the setting of chronic challenge. These data further strengthen the notion that the pathogenesis of the lesions of asthma, and especially of AHR, involves a co-operative interaction between Th2 and Th1 cytokines. This may be particularly relevant to acute exacerbations of asthma, in which setting there may be justification for therapeutic inhibition of IFN-gamma.     

Infliximab for chronic obstructive pulmonary disease: towards a more specific inflammation targeting?

Chronic obstructive pulmonary disease (COPD) is a predominantly smoking-related condition in which chronic progressive airways obstruction results because of inflammation that is triggered and maintained by the causative agent and enhanced during exacerbations. Inflammation is dominated by neutrophils, and macrophages and their mediators. TNF-alpha is a proinflammatory cytokine involved in COPD pathogenesis. Treatment of the stable disease is mainly inhalatory with anticholinergics, beta(2) agonsists and inhaled corticosteroids being involved in various stages of the disease. Novel therapeutic agents are currently under investigation for COPD treatment and some of them target various inflammation mediators. Infliximab is a monoclonal anti-TNF-alpha antibody with demonstrated efficacy in other autoimmune diseases, such as Crohn's disease and rheumatoid arthritis. The current study assesses the scientific rationale for the use of infliximab in COPD patients.     

TNF-alpha in asthma

Although only 5-10% of patients with asthma are relatively unresponsive to treatment with inhaled corticosteroids, refractory asthma represents an important condition, as these patients suffer considerable morbidity and mortality and consume a disproportionately large amount of health resource. Treatment options are limited and there is a large unmet clinical need for additional therapies. Tumour necrosis factor (TNF)-alpha is a pro-inflammatory cytokine that has been implicated in many aspects of the airway pathology in asthma, and which has recently been highlighted as potentially important in refractory asthma. The development of neutralising biological agents against TNF-alpha has allowed us to test the role of this cytokine in vivo. Preliminary studies have demonstrated an improvement in lung function, airway hyperresponsiveness and asthma quality-of-life, together with a reduction in exacerbation frequency, in patients treated with anti-TNF-alpha therapy.     

Drug discovery and development for inflammatory diseases

Numerous recent investigations have pointed to a key role of the pro-inflammatory, pleotropic cytokines TNF-alpha and IL-1 in host defence and inflammatory disease processes. TNF and IL-1 overexpression has been found in disease target tissue and in the circulation of patients with acute and chronic inflammatory diseases, and it was suggested early on in this field of basic medical research that TNF-alpha and IL-1 were crucial in these diseases. Over the last 10 years, several approaches to inhibit TNF-alpha and, in one case, IL-1 activity, have been developed by the biotechnology and pharmaceutical industries. These include neutralising antibodies to TNF-alpha as well as soluble TNF-alpha receptors with characteristic properties designed to bind the 17 kDa soluble trimeric TNF-alpha and the 26 kDa membrane-bound form of TNF-alpha. Clinical trials have demonstrated significant effects with these agents and it is likely that blocking TNF-alpha will become an important standard therapeutic option for clinicians. The data available from these trials contribute to the further understanding of inflammation by demonstrating the major role of these cytokines. This research and clinical background have provided the basis for a variety of lectures on novel drug discovery targets, the current status of previously identified targets and technologies to develop new therapeutics in inflammation. At this meeting, emphasis was placed upon drug targets and their validation in animal models and early stage clinical trials.     

Airway inflammation and tachykinins: prospects for the development of tachykinin receptor antagonists.

The tachykinins substance P and neurokinin A are contained within sensory airway nerves. Immune cells form an additional source of tachykinins in inflamed airways. Elevated levels of tachykinins have been recovered from the airways of patients with asthma and chronic obstructive pulmonary disease. Airway inflammation leads to an upregulation of tachykinin NK(1) and NK(2) receptors. Preclinical studies have indicated a role for the tachykinin NK(1), NK(2) and NK(3) receptors in bronchoconstriction, airway hyperresponsiveness and airway inflammation caused by allergic and nonallergic stimuli. Compounds that are able to block two or three tachykinin receptors hold promise for the treatment of airways diseases such as asthma and/or chronic obstructive pulmonary disease.