Modulation of the CD4+ T cell response after acellular pertussis vaccination in the presence of TLR4 ligation

Whole cell pertussis (wP) vaccines are gradually being replaced by aluminum salt-adjuvanted acellular pertussis (aP) vaccines. These promote CD4⁺ T cell responses with a non-protective Th2 component, while protective immune mechanisms to B. pertussis may rather involve long-lived Th1/Th17 type CD4⁺ T cells. Here we asked whether addition of a non-toxic meningococcal LPS derivative, LpxL1, as adjuvant can favorably modulate the aP-induced pertussis-specific CD4⁺ T cell response in mice. To assess the effect of TLR4 ligation, Th type, quantity, and memory potential of pertussis-specific CD4⁺ T cells were determined at the single-cell level after aP and aP+LpxL1 vaccination using intracellular cytokine staining and MHC class II tetramers. Adding LpxL1 to the aP vaccine weakened the Th2 component and strengthened the Th1/Th17 component of the specific CD4⁺ T cell response. Notably, LpxL1 addition also induced higher frequencies of tetramer positive CD4⁺ T cells in draining lymph nodes or blood, depending on the phase after vaccination. Moreover, there was a net profit in the number of CD4⁺ T cells with a central memory phenotype, preferred for long-term immunity. Thus, adding a TLR4 ligand as adjuvant to a current aP vaccine was associated with a more favorable pertussis-specific CD4⁺ T cell response.     

TRANSVAC research infrastructure – Results and lessons learned from the European network of vaccine research and development

TRANSVAC was a collaborative infrastructure project aimed at enhancing European translational vaccine research and training. The objective of this four year project (2009–2013), funded under the European Commission's (EC) seventh framework programme (FP7), was to support European collaboration in the vaccine field, principally through the provision of transnational access (TNA) to critical vaccine research and development (R&D) infrastructures, as well as by improving and harmonising the services provided by these infrastructures through joint research activities (JRA). The project successfully provided all available services to advance 29 projects and, through engaging all vaccine stakeholders, successfully laid down the blueprint for the implementation of a permanent research infrastructure for early vaccine R&D in Europe.     

Targeting airway inflammation in asthma: current and future therapies

Asthma is a chronic inflammatory disease of the airway that requires long-term antiinflammatory therapy. Inhaled corticosteroids (ICSs) are recommended for first-line treatment of persistent disease, but not all patients achieve asthma control even when these agents are used in high doses and in combination with other medications, including a long-acting beta(2)-agonist or a leukotriene modifier. Such patients may require additional therapy. As information about asthma pathophysiology and inflammatory phenotypes continues to increase, and additional antiinflammatory options become available, it may be possible to target antiinflammatory therapy to various aspects of the disease and consequently to improve the treatment of patients with inadequate responses to standard ICS-based therapy. Several novel antiinflammatory therapies are in different stages of clinical development. The most clinically advanced of these is omalizumab, a recombinant humanized monoclonal antibody that specifically targets IgE and is indicated for patients with moderate-to-severe asthma caused by allergies. Omalizumab has demonstrated efficacy in patients with moderate-to-severe asthma and documented evidence of allergen sensitivity. Other key therapy options in clinical development either target proinflammatory cytokines (eg, interleukin-4 and tumor necrosis factor-alpha) or inflammatory cells (eg, T-helper type 2 cells and eosinophils). This review provides an overview of the current and future approaches targeting airway inflammation in patients with asthma.     

Safety of long-acting beta-agonists in stable COPD: a systematic review

BACKGROUND: Some studies have suggested that use of long-acting beta(2)-agonists (LABAs) leads to an increased risk for adverse events in patients with stable COPD. The purpose of this review was to assess the safety, and secondarily the efficacy of LABAs. METHODS: The authors conducted a systematic review with metaanalysis of randomized clinical trials (> or = 1 month in duration) in the published literature that have compared LABAs with placebo or anticholinergics in stable poorly reversible and reversible COPD. RESULTS: MEDLINE, EMBASE, CINAHL, and the Cochrane Controlled Trials Register were searched to identify 27 studies. LABAs reduced severe exacerbations compared with placebo (relative risk [RR], 0.78; 95% confidence interval [CI], 0.67 to 0.91). There was no significant difference between LABA and placebo groups in terms of respiratory deaths (RR, 1.09; 95% CI, 0.45 to 2.64). Use of LABAs with inhaled corticosteroids reduced the risk of respiratory death compared with LABAs alone (RR, 0.35; 95% CI, 0.14 to 0.93). Patients receiving LABAs showed significant benefits in airflow limitation measures, health-related quality of life, and use of rescue medication. Finally, tiotropium decreased the incidence of severe COPD exacerbations compared with LABAs (RR, 0.52; 95% CI, 0.31 to 0.87). CONCLUSION: This review supports the beneficial effects of the use of LABAs in patients with stable moderate-to-severe COPD, and did not confirm previous data about an increased risk for respiratory deaths. Also, our analysis suggests the superiority of tiotropium over LABAs for the treatment of stable COPD patients.     

Update on the management of COPD

COPD is highly prevalent and will continue to be an increasing cause of morbidity and mortality worldwide. COPD is now viewed under a new paradigm as preventable and treatable. In addition, it has become accepted that COPD is not solely a pulmonary disease but also one with important measurable systemic consequences. Patients with COPD have to be comprehensively evaluated to determine the extent of disease so that therapy can be adequately individualized. We now know that smoking cessation, oxygen for hypoxemic patients, lung reduction surgery for selected patients with emphysema, and noninvasive ventilation during severe exacerbations have an impact on mortality. The completion of well-planned pharmacologic trials have shown the importance of decreasing resting and dynamic hyperinflation on patient-centered outcomes and the possible impact on mortality and rate of decline of lung function. In addition, therapy with pulmonary rehabilitation and lung transplantation improve patient-centered outcomes such as health-related quality of life, dyspnea, and exercise capacity. Rational use of single or multiple therapeutic modalities in combination have an impact on exacerbations and hospitalizations. This monograph presents an integrated approach to patients with COPD and updates their management incorporating the recent advances in the field. The future for patients with COPD is bright as primary and secondary prevention of smoking becomes more effective and air quality improves. In addition, current research will unravel the pathogenesis, clinical, and phenotypic manifestations of COPD, thus providing exciting therapeutic targets. Ultimately, the advent of newer and more effective therapies will lead to a decline in the contribution of this disease to poor world health.     

Usefulness of serum biopterin as a predictive biomarker for childhood asthma control: A prospective cohort study

Background

Pteridines are metabolites of tetrahydrobiopterin, which serves as co-enzyme of nitric oxide synthase. We sought to investigate the usefulness of pteridines as biomarkers for childhood asthma control.

聚焦慢性阻塞性肺病治疗药物

慢性阻塞性肺病（COPD）是肺部进行性疾病,需长期治疗。预计到2020年,每年COPD将会导致全球600多万人死亡。尽管对新型药物开发投资不断增加,但该领域的治疗仍以缓解症状的支气管扩张吸入剂为主,而不是治愈性疗法,故应对COPD的创新药的研发仍困难重重。与乳腺癌等疾病领域相比,呼吸系统药物的研发成功率不到50％,但每种获批药物的研发成本却翻倍。因此,制药公司致力于药品生命周期的管理,在当前治疗的基础上进一步改进。其策略包括不同种类药物联用、开发新配方和各种剂量剂型．改善疗效,方便给药。其中以长效β受体激动剂（LABA）／长效毒蕈碱拮抗剂（LAMA）的定量复方药的需求增长最多。领导市场的GSK公司的LABA沙美特罗和吸入型皮质类固醇（ICS）氟替卡松的复方药Advair,就是应用以上方法的典型。虽已出现潜在新型靶标．但这些药物还处于早期开发阶段。吸入型LABA／ICS定量复方药短期内仍是COPD治疗领域的主力军。     

Humoral,T-cell and B-cell immune responses to seasonal influenza vaccine in solid organ transplant recipients receiving anti-T cell therapies

BackgroundWe analyzed the impact of the anti-T-cell agents basiliximab and antithymocyte globulins (ATG) on antibody and cell-mediated immune responses after influenza vaccination in solid-organ transplant recipients.Methods71 kidney and heart transplant recipients (basiliximab [n = 43] and ATG [n = 28]) received the trivalent influenza vaccine. Antibody responses were measured at baseline and 6 weeks post-vaccination by hemagglutination inhibition assay; T-cell responses were measured by IFN-γ ELISpot assays and intracellular cytokine staining (ICS); and influenza-specific memory B-cell (MBC) responses were evaluated using ELISpot.ResultsMedian time of vaccination from transplantation was 29 months (IQR 8–73). Post-vaccination seroconversion rates were 26.8% for H1N1, 34.1% for H3N2 and 4.9% for influenza B in the basiliximab group and 35.7% for H1N1, 42.9% for H3N2 and 14.3% for influenza B in the ATG group (p = 0.44, p = 0.61, and p = 0.21, respectively). The number of influenza-specific IFN-γ-producing cells increased significantly after vaccination (from 35 to 67.5 SFC/10⁶ PBMC, p = 0.0007), but no differences between treatment groups were observed (p = 0.88). Median number of IgG-MBC did not increase after vaccination (H1N1, p = 0.94; H3N2 p = 0.34; B, p = 0.79), irrespective of the type of anti-T-cell therapy.ConclusionsAfter influenza vaccination, a significant increase in antibody and T-cell immune responses but not in MBC responses was observed in transplant recipients. Immune responses were not significantly different between groups that received basiliximab or ATG.     

The efficacy and safety of three types of combination therapies in patients with moderate to very severe COPD: a systematic review and meta-analysis

Inhaled drugs, including long-acting muscarinic antagonists (LAMAs), long-acting β₂-agonists (LABAs) and inhaled corticosteroids (ICSs), are the main therapeutic options for patients with chronic obstructive pulmonary disease (COPD). We conducted a systematic review and meta-analysis to compare the efficacy and safety of LAMA+LABA+ICS, LAMA+LABA and LABA+ICS therapies. The Pubmed, Embase and Cochrane Library databases were searched for randomized controlled trials (RCTs) comparing the efficacy (moderate-to-severe exacerbations, lung function and quality of life) and safety (adverse events (AEs), severe adverse events (SAEs), withdrawals due to AEs, deaths and pneumonia) of LAMA+LABA+ICS, LAMA+LABA and LABA+ICS in COPD patients. Two investigators independently searched eligible studies and extracted relevant information. The data were analyzed using the Review Manager software, and the quality of included studies was assessed using the Cochrane risk of bias tool. A total of 27 studies were included, and majority of the studies showed low risk of bias. Moderate­to­severe exacerbations were lower after LAMA+LABA+ICS therapy compared with the LABA+ICS (RR = 0.66; 95% CI: 0.59–0.74) and LAMA+LABA therapies (RR = 0.88; 95% CI: 0.82–0.94). Lung function was significantly improved after LAMA+LABA+ICS compared with LAMA+ICS treatment. FEV1, peak FEV1 and trough FEV1 were significantly increased by 100 mL, 150 mL and 120 mL, respectively, in LAMA+LABA+ICS therapy compared with LAMA+ICS. In addition, LAMA+LABA therapy resulted in increased FEV1, peak FEV1 and trough FEV1 by 80 mL, 90 mL and 70 mL, respectively, compared with LAMA+ICS. SGRQ-total score was used to assess quality of life of COPD patients, which indicated that LAMA+LABA+ICS therapy was associated with slightly greater decrease compared with LABA+ICS (MD = –1.33; 95% CI: –2.35 to –0.30). No significant differences were found across all three treatment combinations in term of AEs, SAEs, withdrawals due to AEs and deaths. However, the risk of pneumonia was higher in the triple therapy group than that in the LABA+ICS (RR = 1.16; 95% CI: 1.01–1.33) or LAMA+LABA (RR = 1.31; 95% CI: 1.06–1.62) groups, and significantly lower in the LAMA+LABA group compared with LABA+ICS (RR = 0.64; 95% CI: 0.54–0.76). LAMA+LABA+ICS therapy offered greater efficacy and comparable safety compared with the LAMA+LABAor LABA+ICS therapies. However, triple therapy could increase the risk of pneumonia compared with LAMA+LABA or LABA+ICS therapies. People who have higher risk of pneumonia should carefully consider the use of triple therapy. LAMA+LABA therapy offered greater efficacy and lower risk of pneumonia to LABA+ICS therapy. Collectively, LAMA+LABA therapy might be a better choice than LABA+ICS.