Metoprolol for the Prevention of Acute Exacerbations of COPD.

BACKGROUND: Observational studies suggest that beta-blockers may reduce the risk of exacerbations and death in patients with moderate or severe chronic obstructive pulmonary disease (COPD), but these findings have not been confirmed in randomized trials. METHODS: In this prospective, randomized trial, we assigned patients between the ages of 40 and 85 years who had COPD to receive either a beta-blocker (extended-release metoprolol) or placebo. All the patients had a clinical history of COPD, along with moderate airflow limitation and an increased risk of exacerbations, as evidenced by a history of exacerbations during the previous year or the prescribed use of supplemental oxygen. We excluded patients who were already taking a beta-blocker or who had an established indication for the use of such drugs. The primary end point was the time until the first exacerbation of COPD during the treatment period, which ranged from 336 to 350 days, depending on the adjusted dose of metoprolol. RESULTS: A total of 532 patients underwent randomization. The mean (±SD) age of the patients was 65.0±7.8 years; the mean forced expiratory volume in 1 second (FEV1) was 41.1±16.3% of the predicted value. The trial was stopped early because of futility with respect to the primary end point and safety concerns. There was no significant between-group difference in the median time until the first exacerbation, which was 202 days in the metoprolol group and 222 days in the placebo group (hazard ratio for metoprolol vs. placebo, 1.05; 95% confidence interval [CI], 0.84 to 1.32; P = 0.66). Metoprolol was associated with a higher risk of exacerbation leading to hospitalization (hazard ratio, 1.91; 95% CI, 1.29 to 2.83). The frequency of side effects that were possibly related to metoprolol was similar in the two groups, as was the overall rate of nonrespiratory serious adverse events. During the treatment period, there were 11 deaths in the metoprolol group and 5 in the placebo group. CONCLUSIONS: Among patients with moderate or severe COPD who did not have an established indication for beta-blocker use, the time until the first COPD exacerbation was similar in the metoprolol group and the placebo group. Hospitalization for exacerbation was more common among the patients treated with metoprolol. (Funded by the Department of Defense; BLOCK COPD ClinicalTrials.gov number, NCT02587351.).

Ability of Exhaled Nitric Oxide to Discriminate for Airflow Obstruction Among Frequent Exacerbators of Clinically Diagnosed Asthma.

OBJECTIVE: Fraction of exhaled nitric oxide (FENO) has been proposed as a non-invasive biomarker for allergic inflammation seen in asthma. Many asthmatics in clinical practice have never had spirometry and recent data report misdiagnoses in patients with physician diagnosed (PD) asthma. The aim of this study was to assess the ability of FENO to discriminate between those with and without airflow obstruction (AO) among patients with PD-asthma. METHODS: Frequent exacerbators of PD-asthma (with 2 or more asthma exacerbations leading to emergency room visit or hospitalization within last 12 months) were enrolled. All patients underwent diagnostic evaluations including spirometry, FENO testing and serum immunoglobulin (IgE) and eosinophils. Serial spirometry and methacholine challenge testing (MCT) were performed as indicated. AO was defined by a decreased FEV1/FVC ratio (< 70% and/or < LLN), or a positive MCT. RESULTS: Of the 222 patients with PD-asthma, AO was found in 136 (vs. 86 without AO). 81.6% of patients with AO and 66.2% without AO completed FENO testing. There was no significant difference in the mean FENO levels among patients with or without AO (40.8 vs. 30.4 ppb, P = 0.10). Likewise, there was no difference in the serum IgE levels and serum eosinophils. CONCLUSIONS: Our analyses suggest that FENO levels do not help discriminate between those with and without AO in patients with PD-asthma. Patients who experience symptoms of asthma may have elevated FENO levels above the suggested cut points of 20-25 ppb. Objective confirmation of AO should be considered in all patients with PD-asthma, irrespective of FENO levels.

Misdiagnosis Among Frequent Exacerbators of Clinically Diagnosed Asthma and COPD in Absence of Confirmation of Airflow Obstruction.

PURPOSE: Clinical diagnosis of severe asthma and chronic obstructive lung disease (COPD) remains a challenge and often flawed with lack of objective confirmation of airflow obstruction (AO). Misdiagnosis of asthma and COPD has been reported in stable disease, data are non-existent in frequent exacerbators. We investigated misdiagnosis and its predictors in frequent exacerbators. METHODS: The cohort comprised of frequent severe exacerbators (requiring ≥2 emergency room (ER) visits or hospitalizations) of physician diagnosed (PD)-asthma and PD-COPD. All patients underwent a rigorous diagnostic algorithm over a follow-up period of 10 ± 6 months. Two board-certified pulmonologists ascertained final diagnosis. Patients with persistent absence of AO were identified to have misdiagnosis. Multivariate logistic regression analyses were used to identify predictors of misdiagnoses. RESULTS: Among 333 frequent exacerbators analyzed (171 patients with PD-asthma, 162 with PD-COPD, mean annual exacerbations 3.4 ± 2.8), 24 % of patients had a baseline post-bronchodilator spirometry. Misdiagnosis was found in 26 % (87 of 333) of patients. Another 12 % (41 of 333) of patients had obstructive lung diseases other than asthma and COPD. Independent risk factors for misdiagnosis were spirometry underutilization (PD-asthma: OR = 2.8, 95 % CI 1.16-6.78, p = 0.02 and PD-COPD: OR = 10.7, 95 % CI 2.05-56.27, p = 0.005) and pack years of smoking (PD-COPD: OR = 1.05, 95 % CI 1.01-1.11, p = 0.03). CONCLUSIONS: Objective confirmation of AO is essential in preventing misdiagnosis in frequent severe exacerbators of clinically diagnosed asthma and COPD, a third of whom have neither. Spirometry utilization is strongly associated with a reduced risk of misdiagnosis. Smoking is associated with increased risk of misdiagnosis in severe COPD, but not asthma.

Lung volume abnormalities and its correlation to spirometric and demographic variables in adult asthma.

BACKGROUND: Presence of airflow obstruction in asthma has been based on a fixed FEV1(forced expiratory volume at 1 second)/FVC (forced vital capacity) ratio abnormality. The accuracy of FEV1/FVC ratio in diagnosing airflow obstruction remains controversial. Lung volume abnormalities have been observed in severe asthma. We utilized simultaneously measured spirometry and lung volume to determine the utility of residual volume (RV)/total lung capacity (TLC) ratio in diagnosing airflow obstruction and to identify predictors of abnormal RV in asthmatic subjects. METHODS: Data from physician-diagnosed asthmatics referred for lung function tests were collected retrospectively. Patient demographics and lung function data were analyzed using general linear modeling. RESULTS: Of the 321 subjects, 221 were female (69%). The ethnicity was Caucasian in 157 (49%), Hispanic in 131 (41%), and African-American in 33 (10%). The percentage of subjects with FEV(1)/FVC ratio <70%, FEV(1)-predicted <80%, and FEF25-75% <65% were 25%, 25%, and 38%, respectively. Fifty-two and fifty-seven percent of the patients had abnormal residual volume and abnormal RV/TLC ratio, respectively. A significant bronchodilator response was observed in 32% of the patients. A positive correlation was observed between RV to age (r = 0.4) and height (r = 0.3). A negative correlation was observed between RV to FEF25-75% (r = 0.5) and body weight (r = 0.07). There was no significant correlation between FEV1 reversibility and residual volume (r = 0.1). RV correlated significantly better with FEF25-75% (r(2) = 0.25) than FEV(1) (r(2) = 0.16). CONCLUSION: A significant proportion of asthmatic patients have elevated residual volume and abnormal RV/TLC ratio in the presence of normal FEV1/FVC ratio and absence of significant bronchodilator response. The clinical significance of these findings in asthma needs further prospective study.

Residual Volume Responsiveness Testing May Improve the Detection of Reversible Airway Obstruction in Asthma.

BACKGROUND: Residual volume responsiveness to bronchodilator administration has been observed in subjects with chronic obstructive pulmonary disease. However, the prevalence of residual volume (RV) responsiveness has not been formally studied in asthma. OBJECTIVE: To identify the prevalence and magnitude of RV responsiveness in asthma. METHODS: Physician-diagnosed adult subjects with asthma on treatment for >12 months were prospectively recruited to perform spirometry and measurement of lung volumes using body plethysmography before and after administration of 360 µg of albuterol. RESULTS: Among 120 subjects, 76% were women. The ethnic composition was 64% Caucasian, 32% Hispanic, and 13% African American. The mean age was 52 ± 15 years. The mean duration of asthma was 16 ± 15 years. The mean RV% responsiveness was -7.74 ± 14. Whereas patients with the lowest baseline forced expiratory volume in 1 second (FEV1) value showed the highest mean responsiveness (P = .001), the baseline RV value had minimal influence on RV responsiveness. Using -7.74% to define significant RV responsiveness, and ≥12% and ≥200 mL to define significant FEV1 responsiveness, more subjects showed isolated RV responsiveness (37%) compared with 6% with isolated FEV1 responsiveness and 14% with both FEV1 and RV responsiveness (P = .04). There was a minimal correlation between FEV1 responsiveness and RV responsiveness (r = 0.17, P = .06). The RV responsiveness was significantly associated with the wheeze score (P = .006) and dyspnea score (P = .029). CONCLUSION: The addition of RV responsiveness testing to spirometry based responsiveness testing can improve the identification of reversible airway obstruction in asthma. RV responsiveness may be useful in monitoring symptoms associated with air trapping in asthma.

Air Trapping Correlates With Increased Frequency of Albuterol Use and Severity of Wheeze in Persistent Asthma.

BACKGROUND: Symptoms of asthma have been shown to correlate poorly with spirometric variables of obstruction. We hypothesized that lung volume measurements might correlate with symptoms and frequency of rescue inhaler use in asthma. METHODS: Patients with persistent asthma on treatment for ≥12 months were enrolled from university-based clinics. The association between lung volumes, spirometry, asthma symptoms, and rescue inhaler use were explored by using linear modeling. RESULTS: Among the 120 subjects, 76% were women. The mean age ± SD was 52 ± 15 y. With regard to ethnicity, 64% of the subjects were caucasian, 23% were Hispanic, and 13% were African-American. Twenty-one percent of the subjects reported chest pain. There was no significant correlation between asthma symptoms or rescue inhaler use to spirometry indices of obstruction. The residual volume percent of predicted showed a significant association with the wheeze score (r = 0.32, P = .001) and frequency of rescue inhaler use (r = 0.35, P ≤ .001). Linear contrast analysis showed that the mean wheeze score (P = .003) and frequency of rescue inhaler (P = .007) use increased linearly from the lowest to the highest quartiles of residual volume. Furthermore, multiple regression analysis showed an association only to the residual volume percent predicted value to the pressurized metered-dose inhaler score and the wheeze score. CONCLUSIONS: Frequent albuterol use and wheezing may be a sign of unrelieved air trapping. Chest pain is a unique symptom in persistent asthma, and the pathogenesis requires further studies. Lung volume measurement added to routine spirometry can help identify patients with asthma and with air trapping.

Costimulation and allergic responses: immune and bioinformatic analyses.

Asthma is a complex polygenic disease, the prevalence of which has been on the rise for last few decades. Defining the underpinnings of allergic immune responses and the factors predisposing to asthma are fundamental investigative challenges. T cell costimulatory pathways play critical roles in the pathogenesis of asthma. In this review, we analyze the current state of the art of T cell costimulation in allergic airway inflammation. Also, we discuss both immune and bioinformatic approaches as potential strategies for analyzing multiple costimulatory pathways relevant to asthma.

Hubs in biological interaction networks exhibit low changes in expression in experimental asthma.

Asthma is a complex polygenic disease involving the interaction of many genes. In this study, we investigated the allergic response in experimental asthma. First, we constructed a biological interaction network using the BOND (Biomolecular Object Network Databank) database of literature curated molecular interactions. Second, we mapped differentially expressed genes from microarray data onto the network. Third, we analyzed the topological characteristics of the modulated genes. Fourth, we analyzed the correlation between the topology and biological function using the Gene Ontology classifications. Our results demonstrate that nodes with high connectivity (hubs and superhubs) tend to have low levels of change in gene expression. The significance of our observations was confirmed by permutation testing. Furthermore, our analysis indicates that hubs and superhubs have significantly different biological functions compared with peripheral nodes based on Gene Ontology classification. Our observations have important ramifications for interpreting gene expression data and understanding biological responses. Thus, our analysis suggests that a combination of differential gene expression plus topological characteristics of the interaction network provides enhanced understanding of the biology in our model of experimental asthma.

Longer duration of asthma is significantly associated with increased RV/TLC ratio.

BACKGROUND: Although FEV1/FVC ratio has been shown to be negatively associated with longer duration of asthma; an association between RV/TLC ratio and longer duration of asthma has not been explored. MATERIAL AND METHODS: Patients with established asthma for more than a year and met inclusion and exclusion criteria were recruited. Data obtained by questionnaire after informed consent was obtained, Pulmonary function tests and laboratory results were collected through chart review. Correlation and multiple linear regressions were used to analyze the data. RESULTS: Among the 93 subjects, 61 were women. The mean age of patients was 58 ± 15 years, and the mean duration of asthma was 21 ± 18 years. The ethnic composition included: Caucasians 64%, Hispanics 28% and other groups 8%. The FEV1/FVC ratio was not significantly associated with duration of asthma (R2 = 0.15, p = 0.05). However, the RV/TLC ratio was significantly associated with duration of asthma (R2 = 0.46, p < 0.001). CONCLUSION: RV/TLC ratio may be a better indicator than FEV1/FVC ratio to detect airway obstruction related to longer duration of asthma. Lung volume measurements should be done in addition to spirometry to detect changes related to airway obstruction in patients with longer duration of asthma.

Office spirometry correlates with laboratory spirometry in patients with symptomatic asthma and COPD.

OBJECTIVES: Spirometry remains underutilized in the evaluation of obstructive lung disease. While office spirometry (OS) has been compared to formal laboratory-based spirometry (LS) in healthy subjects, the correlation has never been formally assessed in patients with symptomatic obstructive lung disease. The aim of this study was to investigate the correlation in this population. METHODS: We used a retrospective study design to analyze spirometry data from patients that underwent both OS and LS. Two flow sensing office (portable) spirometers were used and compared with laboratory-based (body plethymosgraph) spirometer. Accuracy and reliability were assessed using Bland Altman analysis. RESULTS: Among 185 patients with symptomatic obstructive lung disease, 129 had undergone both OS and LS. Of these, 107 patients had both tests performed less than 90 days apart and were included in final analyses. Mean age was 54 years with mean FEV1 of 1.97 L (65% predicted). Ninety-two patients had airflow obstruction, as determined by a FEV1/FVC ratio of <70%. We found significant correlation in the values between OS and LS for both FEV1 and FVC (r = 0.937 and 0.90, respectively, P < 0.001). Eighty-seven percent of patients had a concordant spirometry in terms of airflow obstruction. Correlation was independent of the office spirometer (and hence the Flow-sensing mechanism) used. CONCLUSIONS: In patients with known asthma and chronic obstructive pulmonary disease (COPD), OS is accurate and reliable when compared to formal laboratory-based spirometry. Routine use of OS should be encouraged to improve spirometry utilization and healthcare outcomes in patients with Asthma and COPD.

Immunomodulation of allergic responses by targeting costimulatory molecules.

PURPOSE OF REVIEW: This review focuses on putative targets, including costimulatory and additional pathways involving T regulatory cells, that may be critical for modifying allergic responses. RECENT FINDINGS: Multiple costimulatory signals including CD28/CTLA4: CD80/CD86, ICOS: ICOSL, OX40:OX40L and PD-1: PD-L1/PD-L2 have been identified and implicated in the regulation of immune disorders. Recent studies indicate that T regulatory cells may also suppress T cell costimulation by the secretion of TGF-beta and IL-10, suggesting an important role of T regulatory cells in the regulation of allergic disorders. SUMMARY: Immune-mediated disorders, including allergic diseases, have been increasing in prevalence. Unravelling these immune pathways may suggest new targets for immunomodulation.

Reactivation histoplasmosis after treatment with anti-tumor necrosis factor alpha in a patient from a nonendemic area.

Histoplasma capsulatum (HC) is a thermally dimorphic ascomycete that is a significant cause of respiratory infections (>80%) in endemic areas (Midwest and southeast USA), but infections are rare in non-endemic areas. Most primary HC infections are subclinical or self-limited. While reactivation Histoplasmosis has been reported in the setting of immunosuppression, it remains unclear whether remote primary latent infection represents risk of endogenous reactivation after anti-tumor necrosis factor (TNF)-alpha therapy. We report a case of a patient who developed reactivation Histoplasmosis after receiving anti-TNF-alpha. To our knowledge, this is the first clear report of reactivation of "latent" Histoplasmosis after anti-TNF-alpha therapy.

Action plans for COPD: strategies to manage exacerbations and improve outcomes.

COPD is the third-largest killer in the world, and certainly takes a toll on the health care system. Recurrent COPD exacerbations accelerate lung-function decline, worsen mortality, and consume over US$50 billion in health care spending annually. This has led to a tide of payment reforms eliciting interest in strategies reducing preventable COPD exacerbations. In this review, we analyze and discuss the evidence for COPD action plan-based self-management strategies. Although action plans may provide stabilization of acute symptomatology, there are several limitations. These include patient-centered attributes, such as comprehension and adherence, and nonadherence of health care providers to established guidelines. While no single intervention can be expected independently to translate into improved outcomes, structured together within a comprehensive integrated disease-management program, they may provide a robust paradigm.

Effect of nitrogen dioxide exposure on allergic asthma in a murine model.

STUDY OBJECTIVES: The purpose of this study was to examine the effects of NO(2), a major component of air pollution, on airway eosinophilic inflammation and bronchial hyperreactivity, using a mouse model of asthma. SETTING AND SUBJECTS: BALB/c mice (eight mice per experimental group) were studied in a basic research laboratory at the University of Iowa. INTERVENTIONS: Using a standard murine model of asthma, BALB/c mice were sensitized to ovalbumin (OVA) by intraperitoneal (IP) injections (days 1 and 7) and were challenged with aerosolized OVA (days 13 and 14). Some mice were exposed to NO(2) (2 ppm) in an exposure chamber for 24 h before undergoing OVA aerosol challenge. A control group was exposed to OVA alone. MEASUREMENTS AND RESULTS: The outcomes assessed included airway inflammation, bronchial hyperreactivity to inhaled methacholine, and goblet cell hyperplasia. We found that NO(2) exposure modestly increased airway neutrophilia but not airway eosinophilia in OVA-exposed mice. These mice exhibited epithelial damage and loss of epithelial mucin. Surprisingly, nonspecific bronchial hyperreactivity (ie, enhanced pause index) was not increased, although baseline smooth muscle tone was increased (p < 0.05) in the mice exposed to NO(2). CONCLUSIONS: These data indicate that relatively short-term (24 h) exposure to NO(2) causes epithelial damage, reduced mucin expression, and increased tone of respiratory smooth muscle. Reduced mucin production may be a mechanism of injury following long-term exposure to inhaled NO(2). Despite enhancing epithelial damage in OVA-exposed mice, NO(2) exposure does not otherwise alter the expression of allergen-induced airway responses.

Modulation of murine allergic rhinosinusitis by CpG oligodeoxynucleotides.

BACKGROUND: Allergic rhinosinusitis is characterized by eosinophilic inflammation of the upper airway, which is induced by TH-2 cytokines. CpG oligodeoxynucleotides (ODN) are known to induce TH-1 and to suppress TH-2 cytokines in a variety of settings, including murine models of asthma. OBJECTIVE: To examine the effect of CpG ODN in a murine model of upper airway allergic inflammation and to correlate with reduction of its manifestations of sneezing and nasal scratching. METHODS: BALB/c mice were sensitized using Ovalbumin (Ova) intraperitoneally and challenged with aerosolized Ova. CpG ODN were administered at the time of Ova sensitization. Outcomes measured included nasal symptoms, submucosal eosinophilia in the areas lined by respiratory or olfactory epithelium, and bone marrow eosinophilia. To delineate the mechanism of CpG ODN-induced suppression of eosinophilic inflammation, in vitro experiments were carried out to examine the effect of stimulation with Ova on splenocytes obtained from mice that were treated with CpG or control ODN (or no ODN) in vivo. Supernatant was collected after 72 hours of incubation and cytokines were measured by enzyme linked immunosorbent assay. RESULTS: CpG ODN administered at the time of Ova sensitization effectively abrogated nasal symptoms and eosinophilic upper airway inflammation compared with mice treated with control ODN or with no ODN. Cytokine data revealed that Ova sensitization suppressed IFN-gamma and induced IL-4 and IL-5 compared with non-sensitized mice. CpG ODN treatment reversed these effects. CONCLUSION: CpG ODN prevents the development of TH-2-mediated eosinophilic inflammation and symptoms in a murine model of allergic rhinosinusitis.

Impact of an integrated disease management program in reducing exacerbations in patients with severe asthma and COPD.

BACKGROUND: Conflicting data exists on the effectiveness of integrated programs in reducing recurrent exacerbations and hospitalizations in patients with Asthma and chronic obstructive lung disease (COPD). We developed a Pulmonologist-led Chronic Lung Disease Program (CLDP) for patients with severe asthma and COPD and analyzed its impact on healthcare utilization and predictors of its effectiveness. METHODS: CLDP elements included clinical evaluation, onsite pulmonary function testing, health education, and self-management action plan along with close scheduled and on-demand follow-up. Patients with ≥2 asthma or COPD exacerbations requiring emergency room visit or hospitalization within the prior year were enrolled, and followed for respiratory related ER visits (RER) and hospitalizations (RHA) over the year (357 ± 43 days) after CLDP interventions. RESULTS: A total of 106 patients were enrolled, and 104 patients were subject to analyses. During the year of follow-up after CLDP enrollment, there was a significant decrease in mean RER (0.56 ± 1.48 versus 2.62 ± 2.81, p < 0.0001), mean RHA (0.39 ± 0.08 versus 1.1 ± 1.62, p < 0.0001), and 30 day rehospitalizations (0.05 ± 0.02 versus 0.28 ± 0.07, p < 0.0001). Reduction of healthcare utilization was strongly associated with GERD and sinusitis therapy, and was independent of pulmonary rehabilitation. Direct variable cost analyses estimated annual savings at $1.17 million. Multivariate logistic regression analysis revealed lack of spirometry utilization as an independent risk factor for severe exacerbations. CONCLUSIONS: A Pulmonologist-led disease management program integrating key elements of care is cost effective and significantly decreases severe exacerbations. Integrated programs should be encouraged for care of frequent exacerbators of asthma and COPD.

CpG DNA: immunomodulation and remodelling of the asthmatic airway.

Asthma is a disorder of increasing severity and prevalence. Present understanding of the pathogenesis of asthma emphasises its inflammatory nature. Unbridled inflammation appears to induce irreversible changes, collectively known as airway remodelling. CpG oligonucleotides are a class of compounds that have been developed from studies of prokaryotic DNA. Bacterial DNA, for example, contains sequence motifs based on the dinucleotides cytosine-guanine (CpG); these motifs are suppressed in mammalian DNA and induce (as part of the innate immune system) inflammation, characterised by the induction of T helper type 1 and regulatory responses. The pattern of inflammation promoted by CpG DNA tends to suppress the cytokine and cellular responses characteristic of asthma and atopic disorders. This has led to the investigation and development of CpG DNA as a novel therapeutic approach for the treatment and prevention of these disorders. In addition to suppressing acute and persistent airway inflammation, CpG DNA also reduces the development of subepithelial collagen deposition, goblet cell hyperplasia/metaplasia, and other aspects of airway remodelling. In this paper, the effects of CpG DNA on asthma inflammation and remodelling are reviewed.

Treatment of established asthma in a murine model using CpG oligodeoxynucleotides.

Allergen immunotherapy is an effective but underutilized treatment for atopic asthma. We have previously demonstrated that CpG oligodeoxynucleotides (CpG ODN) can prevent the development of a murine model of asthma. In the current study, we evaluated the role of CpG ODN in the treatment of established eosinophilic airway inflammation and bronchial hyperreactivity in a murine model of asthma. In this model, mice with established ovalbumin (OVA)-induced airway disease were given a course of immunotherapy (using low doses of OVA) in the presence or absence of CpG ODN. All mice then were rechallenged with experimental allergen. Untreated mice developed marked airway eosinophilia and bronchial hyperresponsiveness, which were significantly reduced by treatment with OVA and CpG. CpG ODN leads to induction of antigen-induced Th1 cytokine responses; successful therapy was associated with induction of the chemokines interferon-gamma-inducible protein-10 and RANTES and suppression of eotaxin. Unlike previous studies, these data demonstrate that the combination of CpG ODN and allergen can effectively reverse established atopic eosinophilic airway disease, at least partially through redirecting a Th2 to a Th1 response.

Immunomodulatory effects of CpG oligodeoxynucleotides on established th2 responses.

CpG oligodeoxynucleotides (CpG ODNs) are known to induce type 1 T-helper-cell (Th1) responses. We have previously demonstrated that CpG ODNs administered during sensitization prevent Th2-mediated eosinophilic airway inflammation in vivo. We also reported that key Th1 cytokines, gamma interferon (IFN-gamma) and interleukin 12 (IL-12), are not necessary for this protection. Recent in vivo data suggest that CpG ODNs might also reverse established pulmonary eosinophilia. In order to clarify how CpG ODNs can inhibit established Th2 responses, we evaluated the cytokine production from splenocytes from antigen- and alum-immunized mice. Restimulation with antigen induced IL-5, which was clearly inhibited by coculture with CpG ODNs in a concentration-dependent manner. CpG ODNs also induced IFN-gamma, but in a concentration-independent manner. The inhibition of IL-5 production was not mediated through natural killer cells or via CD8(+) T lymphocytes. Although IFN-gamma plays an important role in inhibition of antigen-induced IL-5 production by CpG ODNs, IFN-gamma was not the sole factor in IL-5 inhibition. CpG ODNs also induced IL-10, and this induction correlated well with IL-5 inhibition. Elimination of IL-10 reduced the anti-IL-5 effect of CpG ODNs, although incompletely. This may be because IFN-gamma, induced by CpG ODNs, is also inhibited by IL-10, serving as a homeostatic mechanism for the Th1-Th2 balance. Overproduction of IFN-gamma was downregulated by CpG ODN-induced IL-10 via modulation of IL-12 production. These data suggest that CpG ODNs may inhibit established Th2 immune responses through IFN-gamma and IL-10 production, the latter serving to regulate excessive Th1 bias. These properties of CpG ODNs might be a useful feature in the development of immunotherapy adjuvants against allergic diseases such as asthma.