Hironori Sagara

Mepolizumab for Eosinophilic Chronic Obstructive Pulmonary Disease

BACKGROUND Patients with chronic obstructive pulmonary disease (COPD) with an eosinophilic phenotype may benefit from treatment with mepolizumab, a monoclonal antibody directed against interleukin‐5. METHODS We performed two phase 3, randomized, placebo‐controlled, double‐blind, parallel‐group trials comparing mepolizumab (100 mg in METREX, 100 or 300 mg in METREO) with placebo, given as a subcutaneous injection every 4 weeks for 52 weeks in patients with COPD who had a history of moderate or severe exacerbations while taking inhaled glucocorticoid‐based triple maintenance therapy. In METREX, unselected patients in the modified intention‐to‐treat population with an eosinophilic phenotype were stratified according to blood eosinophil count (≥150 per cubic millimeter at screening or ≥300 per cubic millimeter during the previous year). In METREO, all patients had a blood eosinophil count of at least 150 per cubic millimeter at screening or at least 300 per cubic millimeter during the previous year. The primary end point was the annual rate of moderate or severe exacerbations. Safety was also assessed. RESULTS In METREX, the mean annual rate of moderate or severe exacerbations in the modified intention‐to‐treat population with an eosinophilic phenotype (462 patients) was 1.40 per year in the mepolizumab group versus 1.71 per year in the placebo group (rate ratio, 0.82; 95% confidence interval [CI], 0.68 to 0.98; adjusted P=0.04); no significant between‐group differences were found in the overall modified intention‐to‐treat population (836 patients) (rate ratio, 0.98; 95% CI, 0.85 to 1.12; adjusted P>0.99). In METREO, the mean annual rate of moderate or severe exacerbations was 1.19 per year in the 100‐mg mepolizumab group, 1.27 per year in the 300‐mg mepolizumab group, and 1.49 per year in the placebo group. The rate ratios for exacerbations in the 100‐mg and 300‐mg mepolizumab groups versus the placebo group were 0.80 (95% CI, 0.65 to 0.98; adjusted P=0.07) and 0.86 (95% CI, 0.70 to 1.05; adjusted P=0.14), respectively. A greater effect of mepolizumab, as compared with placebo, on the annual rate of moderate or severe exacerbations was found among patients with higher blood eosinophil counts at screening. The safety profile of mepolizumab was similar to that of placebo. CONCLUSIONS Mepolizumab at a dose of 100 mg was associated with a lower annual rate of moderate or severe exacerbations than placebo among patients with COPD and an eosinophilic phenotype. This finding suggests that eosinophilic airway inflammation contributes to COPD exacerbations. (Funded by GlaxoSmithKline; METREX and METREO ClinicalTrials.gov numbers, NCT02105948 and NCT02105961.)

LAT1 Is a Critical Transporter of Essential Amino Acids for Immune Reactions in Activated Human T Cells

Activation of T cells accompanies remarkable enhancement of metabolism. Sufficient and continuous nutrient supply is therefore important to support immune reaction in T cells. However, the mechanism of the promotion of nutrient incorporation in activated T cells has not been elucidated. In this study, we show that L-type amino acid transporter 1 (LAT1) is a major transporter for essential amino acids into activated human T cells. CD3/CD28 stimulation in primary human T cells triggered dramatic induction of LAT1 expression mediated by NF-κB and AP-1. Functional disturbance of LAT1 by a specific inhibitor and by small interfering RNA in human T cells suppressed essential amino acid uptake and induced a stress response mediated by DNA damage–inducible transcript 3 to attenuate cytokine production via inhibition of NF-κB and NFAT activities. These results uncover the previously unknown mechanism by which T cells accelerate essential amino acid uptake upon activation and adapt to essential amino acid starvation. Our results also raise the possibility for application of an LAT1 inhibitor as a new drug for therapy of disease caused by exaggerated immune response.

Japanese guidelines for adult asthma 2017

Adult bronchial asthma is characterized by chronic airway inflammation, and presents clinically with variable airway narrowing (wheezes and dyspnea) and cough. Long-standing asthma induces airway remodeling, leading to intractable asthma. The number of patients with asthma has increased; however, the number of patients who die of asthma has decreased (1.2 per 100,000 patients in 2015). The goal of asthma treatment is to enable patients with asthma to attain normal pulmonary function and lead a normal life, without any symptoms. A good relationship between physicians and patients is indispensable for appropriate treatment. Long-term management by therapeutic agents and elimination of the causes and risk factors of asthma are fundamental to its treatment. Four steps in pharmacotherapy differentiate between mild and intensive treatments; each step includes an appropriate daily dose of an inhaled corticosteroid, varying from low to high levels. Long-acting β2-agonists, leukotriene receptor antagonists, sustained-release theophylline, and long-acting muscarinic antagonist are recommended as add-on drugs, while anti-immunoglobulin E antibody and oral steroids are considered for the most severe and persistent asthma related to allergic reactions. Bronchial thermoplasty has recently been developed for severe, persistent asthma, but its long-term efficacy is not known. Inhaled β2-agonists, aminophylline, corticosteroids, adrenaline, oxygen therapy, and other approaches are used as needed during acute exacerbations, by choosing treatment steps for asthma in accordance with the severity of exacerbations. Allergic rhinitis, eosinophilic chronic rhinosinusitis, eosinophilic otitis, chronic obstructive pulmonary disease, aspirin-induced asthma, and pregnancy are also important issues that need to be considered in asthma therapy.

Longitudinal increase in total IgE levels in patients with adult asthma: an association with poor asthma control

BackgroundImmunoglobulin (Ig) E is well-known to play a critical role in allergic diseases. We investigated the association between longitudinal change in total IgE level and the asthma control in patients with adult asthma.MethodsFor this retrospective study, 154 patients with asthma aged 21–82 years were recruited from the allergy and pulmonary units of the Showa University Hospital. Data on longitudinal changes in IgE over the preceding 10 years were collected and logarithmically transformed. Associations between longitudinal change in IgE and clinical characteristics including asthma control test (ACT) score, asthma control, pulmonary function test, and antigen specific IgE, were assessed.ResultsPatients with increased IgE tended to have significantly higher mean age, more episodes of acute exacerbation within a year, lower ACT scores, and used oral corticosteroids more frequently than those with decreased or unchanged IgE. The prevalence of uncontrolled asthma was higher in patients with increased IgE than in those with decreased or unchanged IgE. Mean %FEV1 and FEV1% were lower in patients with increased IgE than in those with decreased or unchanged IgE. Moreover, the prevalence of Aspergillus-specific IgE was higher in patients with increased IgE than in those with decreased or unchanged IgE.ConclusionsThese data suggest that a longitudinal increase in total IgE is associated with both poor asthma control and Aspergillus-specific IgE in patients with adult asthma.

Predicting future risk of exacerbations in Japanese patients with adult asthma: A prospective 1-year follow up study

BACKGROUND To avoid future risk is a definitive goal of long-term asthma management. Exacerbations are considered to be the most relevant future risk in real life asthma management. Few comparative studies have evaluated the risk factors associated with exacerbations in Japanese patients with asthma. METHODS We performed the prospective 1-year follow up study in Japanese patients with adult asthma. A total of 189 patients with asthma were enrolled and followed up for 1 year. Finally, 181 patients completed the study protocol. RESULTS Of 181 patients, 43 patients (23.8%) had exacerbations during the follow-up period. Among the 45 patients who had exacerbations during the preceding year, 32 patients (71.1%) had exacerbations. Prevalence of patients with previous exacerbations and those with previous admissions were significantly higher in patients with exacerbations than those with no exacerbation. Logistic regression analysis also identified a significant association between exacerbations during the follow-up period and exacerbations during the preceding year, admissions during the preceding 3 years, ACT score below 20, low %FVC (<80%), or low FEV1 (<70%), respectively. Of the 55 patients with severe asthma, 29 patients (52.7%) had exacerbations. Among the 36 patients with severe asthma with previous exacerbations, 26 patients (72.2%) had exacerbations. The history of exacerbations during the preceding year was associated with a significantly increased risk of exacerbations both among the patients with severe asthma and those with non-severe asthma. CONCLUSIONS This study implicated that exacerbations during the preceding year reliably predict future risk of exacerbations in Japanese patients with asthma.

Bacterial and Fungal Infections in Rheumatoid Arthritis

The advent of novel therapeutics for rheumatoid arthritis (RA) has transformed articular improvement and systemic outcomes, but the number of respiratory infections has been increasing in the past decade. Important causes for the elevated susceptibility to bacterial and fungal respiratory infections are mainly due to immune dysregulation of RA, pulmonary comorbidities, and immunosuppressive treatments such as corticosteroids, methotrexate, and biological agents. Pneumonia is the most common infection, and fungal infection is also frequently seen in patients with RA. Respiratory infections in patients with RA are considered important factors that affect not only patient survival but also the development of RA itself. Thus, it is essential for clinicians to have sufficient knowledge of the characteristics of respiratory infections in these settings of RA. Because controlling respiratory infections improves the survival of patients with RA, proper diagnosis and prompt treatment of respiratory infections in these patients are necessary throughout their treatment period.

Abstract 2277: TNF transactivation of EGFR protects EGFR-TKI, gefitinib induced pulmonary epithelial cell apoptosis and injury in TNF transgenic mice

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Background: TNF is a cytokine with many biological properties including both anti- and pro-apoptotic signaling pathways. However, the molecular switch, which determines TNF regulation of these two different functions, is not well characterized. EGFR and other ErbB family members could be activated by direct interaction with EGF-like ligands initiating formation of homo- and/or hetero-dimers and increased kinase activity. In addition to direct EGFR ligands, EGFR can be transactivated by various extracellular stimuli, such as agonists for GPCR and cytokine receptors. Previously, we have reported that EGFR and ErbB2 were transactivated via Src kinase family activation with TNF exposure and blockade of EGFR enhanced intestinal epithelial cells apoptosis. Furthermore, TNF administration enhanced apoptotic cells in colonic grand of EGFRwa2 mice. Hypothesis: The induction of pulmonary epithelial cell apoptosis is a persistent finding in lung tissue from patients with emphysema and pulmonary fibrosis. We hypothesized that EGFR tyrosine kinase activity is required for protection from pulmonary cell apoptosis in TNF-rich condition. Methods: We employed C57BL/6 mice as a control and surfactant protein-C (SP-C)/TNF transgenic (TG) mice (6-8 weeks old), which showed over-expression of TNF in lung tissue by induction of SP-C production. The lung tissue sections were stained by H&E and trichrome stain. Apoptosis and signal transduction was determined by TUNEL assay and Western-blot analysis, respectively. The accumulation of collagen was measured by Sircol assay. Results: Control mice and TG mice was administrated gefitinib 100mg/kg for 14days. Gefitinib increased lymphocyte infiltration into interstitial spaces of the TG mice lung, significantly. Although TG mice lung was severely injured by gefitinib, fibroblast proliferation was not observed and the accumulation of collagen was not detected. In TG mice, gefitinib increased apoptotic response 10-fold compared to 1% tween80 treated TG mice in interstitial spaces. To test the role of EGFR in apoptosis induction in TG mice, the protein was isolated from whole lung tissue. The tyrosine kinase activity of EGFR was increased and the downstream of AKT and ERK were activated in TG mice. Conversely, treating with gefitinib on TG mice, EGFR phosphorylation was inhibited and, AKT and ERK were inactivated. One of the pro-apoptotic signals, p38 MAPK was activated via MKK3/6 by gefitinib treatment in TG mice, suggesting activation of ASK1/p38 MAPK signals leading to pulmonary epithelial cell apoptosis. Conclusions: The dysregulated production of TNF is a mediator of inflammation and tumor growth. Therefore, the mechanisms of TNF-regulated anti-/pro- apoptotic responses are important in understanding the role of TNF in the pathogenesis of pulmonary disorders, such as inflammation and cancer. Citation Format: Toshimitsu Yamaoka, Yasunari Oki, Yasunori Murata, Sojiro Kusumoto, Hiroo Ishida, Takao Shirai, Etsuko Toya, Motoi Ohba, Ken-ichi Fujita, Satoru Arata, Tohru Ohmori, Tsukasa Ohnishi, Hironori Sagara, Yasutsuna Sasaki. TNF transactivation of EGFR protects EGFR-TKI, gefitinib induced pulmonary epithelial cell apoptosis and injury in TNF transgenic mice. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2277. doi:10.1158/1538-7445.AM2014-2277