Bronchial Thermoplasty in Patients With Severe Asthma at 5 Years: The Post-FDA Approval Clinical Trial Evaluating Bronchial Thermoplasty in Severe Persistent Asthma Study.

BACKGROUND: Bronchial thermoplasty is a device-based treatment for subjects ≥ 18 years of age with severe asthma poorly controlled with inhaled corticosteroids and long-acting beta-agonists. The Post-FDA Approval Clinical Trial Evaluating Bronchial Thermoplasty in Severe Persistent Asthma (PAS2) study collected data on patients with severe asthma undergoing this procedure. RESEARCH QUESTION: What are the 5-year efficacy and safety results in patients with severe asthma who have undergone bronchial thermoplasty? STUDY DESIGN AND METHODS: This was a prospective, open-label, observational, multicenter study conducted in the United States and Canada. Subjects 18 to 65 years of age who were taking inhaled corticosteroids ≥ 1,000 µg/d (beclomethasone or equivalent) and long-acting beta-agonists ≥ 80 µg/d (salmeterol or equivalent) were included. Severe exacerbations, hospitalization, ED visits, and medication usage were evaluated for the 12 months prior to and at years 1 through 5 posttreatment. Spirometry was evaluated at baseline and at years 1 through 5 posttreatment. RESULTS: A total of 284 subjects were enrolled at 27 centers; 227 subjects (80%) completed 5 years of follow-up. By year 5 posttreatment, the proportion of subjects with severe exacerbations, ED visits, and hospitalizations was 42.7%, 7.9%, and 4.8%, respectively, compared with 77.8%, 29.4%, and 16.1% in the 12 months prior to treatment. The proportion of subjects on maintenance oral corticosteroids decreased from 19.4% at baseline to 9.7% at 5 years. Analyses of subgroups based on baseline clinical and biomarker characteristics revealed a statistically significant clinical improvement among all subgroups. INTERPRETATION: Five years after treatment, subjects experienced decreases in severe exacerbations, hospitalizations, ED visits, and corticosteroid exposure. All subgroups demonstrated clinically significant improvement, suggesting that bronchial thermoplasty improves asthma control in different asthma phenotypes. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT01350336; URL: www. CLINICALTRIALS: gov.

Rapid onset of effect of benralizumab on morning peak expiratory flow in severe, uncontrolled asthma.

BACKGROUND: Benralizumab is a unique eosinophil-depleting monoclonal antibody that significantly reduces asthma exacerbations, improves lung function and asthma symptoms, and permits the reduction of maintenance oral corticosteroid dosage for patients with severe, uncontrolled eosinophilic asthma. OBJECTIVE: To assess benralizumab's onset of action and efficacy by examining change in morning peak expiratory flow (PEF) after initiation of treatment in the phase 3 clinical trials SIROCCO, CALIMA, and ZONDA. METHODS: Mixed-model repeated-measures analysis was used to calculate PEF using daily least squares mean changes from baseline in morning PEF as well as differences between the benralizumab every 8 weeks (first 3 doses every 4 weeks) and placebo groups. A Bayesian nonlinear mixed-effects approach with an exponential relationship was used to model trial data to determine time to clinically meaningful improvement in morning PEF (defined as ≥25 L/min). RESULTS: Least squares mean morning PEF improvement from baseline was numerically greater by Day 2 after initiation of benralizumab therapy in all 3 trials. The Bayesian nonlinear mixed-effects model indicated that PEF improvement reached the clinically meaningful threshold within 3 weeks in SIROCCO and CALIMA and 2 weeks in ZONDA. CONCLUSION: In 3 phase 3 randomized clinical trials, benralizumab provided notable improvement in morning PEF 2 days after initiation and clinically meaningful improvements within 3 weeks for patients with severe, uncontrolled eosinophilic asthma. The rapid improvement in PEF demonstrated in these trials suggests that benralizumab's unique mechanism of action rapidly improves lung function for patients with severe, eosinophilic asthma. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT01928771 (SIROCCO), NCT01914757 (CALIMA), and NCT02075255 (ZONDA).

Long-term outcomes of bronchial thermoplasty in subjects with severe asthma: a comparison of 3-year follow-up results from two prospective multicentre studies.

Bronchial thermoplasty is an endoscopic therapy for severe asthma. The previously reported, randomised sham-controlled AIR2 (Asthma Intervention Research 2) trial showed a significant reduction in severe asthma exacerbations, emergency department visits and hospitalisations after bronchial thermoplasty. More "real-world" clinical outcome data is needed.This article compares outcomes in bronchial thermoplasty subjects with 3 years of follow-up from the ongoing, post-market PAS2 (Post-FDA Approval Clinical Trial Evaluating Bronchial Thermoplasty in Severe Persistent Asthma) study with those from the AIR2 trial.279 subjects were treated with bronchial thermoplasty in the PAS2 study. We compared the first 190 PAS2 subjects with the 190 bronchial thermoplasty-treated subjects in the AIR2 trial at 3 years of follow-up. The PAS2 subjects were older (mean age 45.9 versus 40.7 years) and more obese (mean body mass index 32.5 versus 29.3 kg·m-2) and took higher doses of inhaled corticosteroids (mean dose 2301 versus 1961 µg·day-1). More PAS2 subjects had experienced severe exacerbations (74% versus 52%) and hospitalisations (15.3% versus 4.2%) in the 12 months prior to bronchial thermoplasty. At year 3 after bronchial thermoplasty, the percentage of PAS2 subjects with severe exacerbations, emergency department visits and hospitalisations significantly decreased by 45%, 55% and 40%, respectively, echoing the AIR2 results.The PAS2 study demonstrates similar improvements in asthma control after bronchial thermoplasty compared with the AIR2 trial despite enrolling subjects who may have had poorer asthma control.

A four-dimensional computed tomography comparison of healthy and asthmatic human lungs.

The purpose of this study was to explore new insights in non-linearity, hysteresis and ventilation heterogeneity of asthmatic human lungs using four-dimensional computed tomography (4D-CT) image data acquired during tidal breathing. Volumetric image data were acquired for 5 non-severe and one severe asthmatic volunteers. Besides 4D-CT image data, function residual capacity and total lung capacity image data during breath-hold were acquired for comparison with dynamic scans. Quantitative results were compared with the previously reported analysis of five healthy human lungs. Using an image registration technique, local variables such as regional ventilation and anisotropic deformation index (ADI) were estimated. Regional ventilation characteristics of non-severe asthmatic subjects were similar to those of healthy subjects, but different from the severe asthmatic subject. Lobar airflow fractions were also well correlated between static and dynamic scans (R2>0.84). However, local ventilation heterogeneity significantly increased during tidal breathing in both healthy and asthmatic subjects relative to that of breath-hold perhaps because of airway resistance present only in dynamic breathing. ADI was used to quantify non-linearity and hysteresis of lung motion during tidal breathing. Non-linearity was greater on inhalation than exhalation among all subjects. However, exhalation non-linearity among asthmatic subjects was greater than healthy subjects and the difference diminished during inhalation. An increase of non-linearity during exhalation in asthmatic subjects accounted for lower hysteresis relative to that of healthy ones. Thus, assessment of non-linearity differences between healthy and asthmatic lungs during exhalation may provide quantitative metrics for subject identification and outcome assessment of new interventions.

Identification of airway mucosal type 2 inflammation by using clinical biomarkers in asthmatic patients.

BACKGROUND: The Airways Disease Endotyping for Personalized Therapeutics (ADEPT) study profiled patients with mild, moderate, and severe asthma and nonatopic healthy control subjects. OBJECTIVE: We explored this data set to define type 2 inflammation based on airway mucosal IL-13-driven gene expression and how this related to clinically accessible biomarkers. METHODS: IL-13-driven gene expression was evaluated in several human cell lines. We then defined type 2 status in 25 healthy subjects, 28 patients with mild asthma, 29 patients with moderate asthma, and 26 patients with severe asthma based on airway mucosal expression of (1) CCL26 (the most differentially expressed gene), (2) periostin, or (3) a multigene IL-13 in vitro signature (IVS). Clinically accessible biomarkers included fraction of exhaled nitric oxide (Feno) values, blood eosinophil (bEOS) counts, serum CCL26 expression, and serum CCL17 expression. RESULTS: Expression of airway mucosal CCL26, periostin, and IL-13-IVS all facilitated segregation of subjects into type 2-high and type 2-low asthmatic groups, but in the ADEPT study population CCL26 expression was optimal. All subjects with high airway mucosal CCL26 expression and moderate-to-severe asthma had Feno values (≥35 ppb) and/or high bEOS counts (≥300 cells/mm3) compared with a minority (36%) of subjects with low airway mucosal CCL26 expression. A combination of Feno values, bEOS counts, and serum CCL17 and CCL26 expression had 100% positive predictive value and 87% negative predictive value for airway mucosal CCL26-high status. Clinical variables did not differ between subjects with type 2-high and type 2-low status. Eosinophilic inflammation was associated with but not limited to airway mucosal type 2 gene expression. CONCLUSION: A panel of clinical biomarkers accurately classified type 2 status based on airway mucosal CCL26, periostin, or IL-13-IVS gene expression. Use of Feno values, bEOS counts, and serum marker levels (eg, CCL26 and CCL17) in combination might allow patient selection for novel type 2 therapeutics.

Mitochondrial-targeted antioxidant therapy decreases transforming growth factor-ß-mediated collagen production in a murine asthma model.

Asthma is a disease of acute and chronic inflammation in which cytokines play a critical role in orchestrating the allergic inflammatory response. IL-13 and transforming growth factor (TGF)-ß promote fibrotic airway remodeling, a major contributor to disease severity. Improved understanding is needed, because current therapies are inadequate for suppressing development of airway fibrosis. IL-13 is known to stimulate respiratory epithelial cells to produce TGF-ß, but the mechanism through which this occurs is unknown. Here, we tested the hypothesis that reactive oxygen species (ROS) are a critical signaling intermediary between IL-13 or allergen stimulation and TGF-ß-dependent airway remodeling. We used cultured human bronchial epithelial cells and an in vivo mouse model of allergic asthma to map a pathway where allergens enhanced mitochondrial ROS, which is an essential upstream signal for TGF-ß activation and enhanced collagen production and deposition in airway fibroblasts. We show that mitochondria in airway epithelium are an essential source of ROS that activate TGF-ß expression and activity. TGF-ß from airway epithelium stimulates collagen expression in fibroblasts, contributing to an early fibrotic response to allergen exposure in cultured human airway cells and in ovalbumin-challenged mice. Treatment with the mitochondrial-targeted antioxidant, (2-(2,2,6,6-Tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium chloride (mitoTEMPO), significantly attenuated mitochondrial ROS, TGF-ß, and collagen deposition in OVA-challenged mice and in cultured human epithelial cells. Our findings suggest that mitochondria are a critical source of ROS for promoting TGF-ß activity that contributes to airway remodeling in allergic asthma. Mitochondrial-targeted antioxidants may be a novel approach for future asthma therapies.

Phase I/II randomized trial of aerobic exercise in Parkinson disease in a community setting.

OBJECTIVES: To (1) investigate effects of aerobic walking on motor function, cognition, and quality of life in Parkinson disease (PD), and (2) compare safety, tolerability, and fitness benefits of different forms of exercise intervention: continuous/moderate intensity vs interval/alternating between low and vigorous intensity, and individual/neighborhood vs group/facility setting. METHODS: Initial design was a 6-month, 2 × 2 randomized trial of different exercise regimens in independently ambulatory patients with PD. All arms were required to exercise 3 times per week, 45 minutes per session. RESULTS: Randomization to group/facility setting was not feasible because of logistical factors. Over the first 2 years, we randomized 43 participants to continuous or interval training. Because preliminary analyses suggested higher musculoskeletal adverse events in the interval group and lack of difference between training methods in improving fitness, the next 17 participants were allocated only to continuous training. Eighty-one percent of 60 participants completed the study with a mean attendance of 83.3% (95% confidence interval: 77.5%-89.0%), exercising at 46.8% (44.0%-49.7%) of their heart rate reserve. There were no serious adverse events. Across all completers, we observed improvements in maximum oxygen consumption, gait speed, Unified Parkinson's Disease Rating Scale sections I and III scores (particularly axial functions and rigidity), fatigue, depression, quality of life (e.g., psychological outlook), and flanker task scores (p < 0.05 to p < 0.001). Increase in maximum oxygen consumption correlated with improvements on the flanker task and quality of life (p < 0.05). CONCLUSIONS: Our preliminary study suggests that aerobic walking in a community setting is safe, well tolerated, and improves aerobic fitness, motor function, fatigue, mood, executive control, and quality of life in mild to moderate PD. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that in patients with PD, an aerobic exercise program improves aerobic fitness, motor function, fatigue, mood, and cognition.

Central nervous system influences in asthma.

Asthma is a biomedical disorder whose presentation can be markedly influenced by neurological and psychological factors. This chapter describes several approaches that provide insight into the role of psychological factors and brain function in asthma. These include the study of placebo responses and recent explorations using functional neuroimaging during the onset of asthma symptoms. Although the specific mechanisms involved remain uncertain, we are gaining an appreciation for some of the neurocircuitry that is involved. The insula and ACC may modulate inflammatory processes by their influence on neuroendocrine responses to stress, including highly studied effects on the HPA axis and its physiologic responses. However much we have recently learned, it is clear that further study of this topic is critical to fully explicate the role of the brain in asthma.

Bronchial thermoplasty: Long-term safety and effectiveness in patients with severe persistent asthma.

BACKGROUND: Bronchial thermoplasty (BT) has previously been shown to improve asthma control out to 2 years in patients with severe persistent asthma. OBJECTIVE: We sought to assess the effectiveness and safety of BT in asthmatic patients 5 years after therapy. METHODS: BT-treated subjects from the Asthma Intervention Research 2 trial (ClinicalTrials.govNCT01350414) were evaluated annually for 5 years to assess the long-term safety of BT and the durability of its treatment effect. Outcomes assessed after BT included severe exacerbations, adverse events, health care use, spirometric data, and high-resolution computed tomographic scans. RESULTS: One hundred sixty-two (85.3%) of 190 BT-treated subjects from the Asthma Intervention Research 2 trial completed 5 years of follow-up. The proportion of subjects experiencing severe exacerbations and emergency department (ED) visits and the rates of events in each of years 1 to 5 remained low and were less than those observed in the 12 months before BT treatment (average 5-year reduction in proportions: 44% for exacerbations and 78% for ED visits). Respiratory adverse events and respiratory-related hospitalizations remained unchanged in years 2 through 5 compared with the first year after BT. Prebronchodilator FEV1 values remained stable between years 1 and 5 after BT, despite a 18% reduction in average daily inhaled corticosteroid dose. High-resolution computed tomographic scans from baseline to 5 years after BT showed no structural abnormalities that could be attributed to BT. CONCLUSIONS: These data demonstrate the 5-year durability of the benefits of BT with regard to both asthma control (based on maintained reduction in severe exacerbations and ED visits for respiratory symptoms) and safety. BT has become an important addition to our treatment armamentarium and should be considered for patients with severe persistent asthma who remain symptomatic despite taking inhaled corticosteroids and long-acting ß2-agonists.

CaMKII is essential for the proasthmatic effects of oxidation.

Increased reactive oxygen species (ROS) contribute to asthma, but little is known about the molecular mechanisms connecting increased ROS with characteristic features of asthma. We show that enhanced oxidative activation of the Ca(2+)/calmodulin-dependent protein kinase (ox-CaMKII) in bronchial epithelium positively correlates with asthma severity and that epithelial ox-CaMKII increases in response to inhaled allergens in patients. We used mouse models of allergic airway disease induced by ovalbumin (OVA) or Aspergillus fumigatus (Asp) and found that bronchial epithelial ox-CaMKII was required to increase a ROS- and picrotoxin-sensitive Cl(-) current (ICl) and MUC5AC expression, upstream events in asthma progression. Allergen challenge increased epithelial ROS by activating NADPH oxidases. Mice lacking functional NADPH oxidases due to knockout of p47 and mice with epithelial-targeted transgenic expression of a CaMKII inhibitory peptide or wild-type mice treated with inhaled KN-93, an experimental small-molecule CaMKII antagonist, were protected against increases in ICl, MUC5AC expression, and airway hyperreactivity to inhaled methacholine. Our findings support the view that CaMKII is a ROS-responsive, pluripotent proasthmatic signal and provide proof-of-concept evidence that CaMKII is a therapeutic target in asthma.

Endotoxin inhalation alters lung development in neonatal mice.

BACKGROUND: Childhood asthma is a significant public health problem. Epidemiologic evidence suggests an association between childhood asthma exacerbations and early life exposure to environmental endotoxin. Although the pathogenesis of endotoxin-induced adult asthma is well studied, questions remain about the impact of environmental endotoxin on pulmonary responsiveness in early life. METHODS: We developed a murine model of neonatal/juvenile endotoxin exposures approximating those in young children and evaluated the lungs inflammatory and remodeling responses. RESULTS: Persistent lung inflammation induced by the inhalation of endotoxin in early life was demonstrated by the influx of inflammatory cells and pro-inflammatory mediators to the airways and resulted in abnormal alveolarization. CONCLUSIONS: Results of this study advance the understanding of the impact early life endotoxin inhalation has on the lower airways, and demonstrates the importance of an experimental design that approximates environmental exposures as they occur in young children.

Tim-1 regulates Th2 responses in an airway hypersensitivity model.

T-cell immunoglobulin mucin-1 (Tim-1) is a transmembrane protein postulated to be a key regulator of Th2-type immune responses. This hypothesis is based in part upon genetic studies associating Tim-1 polymorphisms in mice with a bias toward airway hyperrespon-siveness (AHR) and the development of Th2-type CD4(+) T cells. Tim-1 expressed by Th2 CD4(+) T cells has been proposed to function as a co-stimulatory molecule. Tim-1 is also expressed by B cells, macrophages, and dendritic cells, but its role in responses by these cell types has not been firmly established. Here, we generated Tim-1-deficient mice to determine the role of Tim-1 in a murine model of allergic airway disease that depends on the development and function of Th2 effector cells and results in the generation of AHR. We found antigen-driven recruitment of inflammatory cells into airways is increased in Tim-1-deficient mice relative to WT mice. In addition, we observed increased antigen-specific cytokine production by splenocytes from antigen-sensitized Tim-1-deficient mice relative to those from controls. These data support the conclusion that Tim-1 functions in pathways that suppress recruitment of inflammatory cells into the airways and the generation or activity of CD4(+) T cells.

Silicotuberculosis and silicosis as occupational diseases: report of two cases.

INTRODUCTION: Silicosis, the most prevalent of the pneumoconioses, is caused by inhalation of crystalline silica particles. Silica-exposed workers are at increased risk for tuberculosis and other mycobacterium-related diseases. The risk of a patient with silicosis developing tuberculosis is higher (2.8 to 39 fold higher, depending on the severity of silicosis) than that found in healthy controls. OUTLINE OF CASES: The first patient was a 52-year-old male who was admitted in 2002 for the second time with dyspnoea, wheezing and fatigue over the last 11 years. He had worked in an iron smelting factory and was exposed to silica dust for 20 years. First hospitalization chest radiography showed bilateral pleural adhesions, diffuse lung fibrosis with signs of a specific lung process. Second hospitalization chest radiography showed bilateral massive irregular, non-homogenous calcified changes in the upper and middle parts of lungs. The patient died due to respiratory failure and chronic pulmonary heart in 2007. The main causes of his death were silicotuberculosis and chronic obstructive pulmonary disease. The second patient was a 50-year-old male who was admitted in 2005 for the second time with chest tightness, dyspnoea, wheezing and fatigue over the last 10 years. He had worked in an iron smelting factory and was exposed to silica dust for 30 years. First hospitalization chest radiography showed diffuse lung fibrosis and small nodular opacities. The patient was diagnosed with silicosis, small opacities sized level p/q, and profusion level 2/3. Second hospitalization chest radiography and CT showed diffuse lung fibrosis and small nodular opacities predominantly in the upper lobes. The patient was recognized as having an occupational disease, and received early retirement due to disability. CONCLUSION: In low-income countries, new cases of silicosis and associated lung cancer, chronic obstructive pulmonary disease and tuberculosis are likely to be seen for decades because necessary reduction of silica use will take time to be achieved.

Anti-inflammatory effects of the neurotransmitter agonist Honokiol in a mouse model of allergic asthma.

Chronic airway inflammation is a hallmark of asthma, an immune-based disease with great societal impact. Honokiol (HNK), a phenolic neurotransmitter receptor (γ-aminobutyric acid type A) agonist purified from magnolia, has anti-inflammatory properties, including stabilization of inflammation in experimentally induced arthritis. The present study tested the prediction that HNK could inhibit the chronic inflammatory component of allergic asthma. C57BL/6 mice sensitized to and challenged with OVA had increased airway hyperresponsiveness to methacholine challenge and eosinophilia compared with naive controls. HNK-treated mice showed a reduction in airway hyperresponsiveness as well as a significant decrease in lung eosinophilia. Histopathology studies revealed a marked drop in lung inflammation, goblet cell hyperplasia, and collagen deposition with HNK treatment. Ag recall responses from HNK-treated mice showed decreased proinflammatory cytokines in response to OVA, including TNF-α-, IL-6-, Th1-, and Th17-type cytokines, despite an increase in Th2-type cytokines. Regulatory cytokines IL-10 and TGF-ß were also increased. Assessment of lung homogenates revealed a similar pattern of cytokines, with a noted increase in the number of FoxP3(+) cells in the lung. HNK was able to alter B and T lymphocyte cytokine secretion in a γ-aminobutyric acid type A-dependent manner. These results indicate that symptoms and pathology of asthma can be alleviated even in the presence of increased Th2 cytokines and that neurotransmitter agonists such as HNK have promise as a novel class of anti-inflammatory agents in the treatment of chronic asthma.

Motile cilia of human airway epithelia are chemosensory.

Cilia are microscopic projections that extend from eukaryotic cells. There are two general types of cilia; primary cilia serve as sensory organelles, whereas motile cilia exert mechanical force. The motile cilia emerging from human airway epithelial cells propel harmful inhaled material out of the lung. We found that these cells express sensory bitter taste receptors, which localized on motile cilia. Bitter compounds increased the intracellular calcium ion concentration and stimulated ciliary beat frequency. Thus, airway epithelia contain a cell-autonomous system in which motile cilia both sense noxious substances entering airways and initiate a defensive mechanical mechanism to eliminate the offending compound. Hence, like primary cilia, classical motile cilia also contain sensors to detect the external environment.

MMP9 modulates tight junction integrity and cell viability in human airway epithelia.

The family of zinc- and calcium-dependent matrix metalloproteases (MMPs) play an important role in remodeling of the airways in disease. Transcriptional regulation by proinflammatory cytokines increases lymphocyte-derived MMP9 levels in the airway lumen of asthmatics. Moreover, the levels of the MMP9 inhibitor, tissue inhibitor of metalloprotease (TIMP1), are decreased leading to increased protease activity. The mechanism by which MMP9 activity leads to asthma pathogenesis and remodeling remains unclear. Using a model of well-differentiated human airway epithelia, we found that apical MMP9 significantly increases transepithelial conductance. Moreover, apical MMP9 treatment decreased immunostaining of tight junction proteins suggesting disruption of barrier function. Consistent with this, viruses gained access to the epithelial basolateral surface after MMP9 treatment, which increased infection efficiency. All of these effects were blocked by TIMP1. In addition, loss of epithelial integrity correlated with increased epithelial cell death. Thus we hypothesized that MMP9 exerts its effects on the epithelium by cleaving one or more components of cell-cell junctions and triggering anoikis. Taken together, these data suggest that a component of airway remodeling associated with asthma may be directly regulated by MMP9.

Use of CpG oligonucleotides in treatment of asthma and allergic disease.

In the last several decades, there has been a marked increase in the prevalence of atopic disorders including asthma in "Western" societies; a relationship has been identified between lack of early-life exposure to microbes or microbial products and increased susceptibility to atopic disorders. The innate immune system is activated by early microbial exposures, many of which utilize one of the Toll-like receptors, and there has been significant interest in studying how ligation of TLRs may be therapeutically useful. CpG oligonucleotides (CpG-ODN, resembling bacterial DNA) engage TLR-9 on B-cells, dendritic cells and other cell types, resulting in a cascade that includes induction of Th1-type and T-regulatory-type immune responses. Preclinical models of asthma have demonstrated that CpG-ODN are potent inhibitors of atopic responses, suppressing Th2 cytokine and, reducing airway eosinophilia, systemic levels of IgE, and bronchial hyperreactivity-in short the critical attributes of the asthmatic phenotype. In models of chronic allergen exposure, CpG-ODN are also effective at preventing the development of airway remodeling. In established asthma, CpG-ODN can reverse manifestations of disease, both when used alone or in combination with allergen immunotherapy. Early clinical trials have had mixed results, including a significant benefit when CpG-ODN were conjugated to ragweed allergen in an allergic rhinitis immunotherapy study, but only limited efficacy seen when administered prior to allergen challenge in asthmatics. Further study of CpG-ODNs for the treatment of asthma and other atopic disorders is warranted by existing data.

Toll-like receptor 9 activation with CpG oligodeoxynucleotides for asthma therapy.

Prokaryotic DNA has long been recognized as immunostimulatory. In the last decade the role played by CpG motifs (nucleotide sequence motifs centered on a cytosine-guanine dinucleotide) in bacterial and viral DNA has been elucidated. CpG motifs are detected by the innate immune pattern recognition receptor Toll-like receptor (TLR) 9, the ligation of which activates multiple signal cascades in responding cells. A restricted pattern of TLR9 expression to certain dendritic cells and B cells appears to provide relative specificity in responses, especially in comparison to other TLR ligands. TLR9 activation induces a Th1-like pattern of cytokine release which led to interest in the use of synthetic CpG oligodeoxynucleotides (CpG ODN) for the prevention and treatment of Th2-associated atopic disorders such as asthma. Interestingly, Th1 cytokines do not appear to be necessary for a therapeutic response in preclinical models of atopic asthma. Additional potential mechanisms of action include induction of regulatory-type responses (involving interleukin-10 release), and expression of indoleamine 2,3-dioxygenase. CpG ODN have been shown to prevent and reverse antigen-induced eosinophilic airway inflammation in animal models; human trials are ongoing with encouraging early results when used as a ragweed vaccine adjuvant in allergic upper airway disease.