All-trans retinoic acid (ATRA) or mesenchymal stem cells (MSCs) have been shown to promote lung tissue regeneration in animal models of emphysema. However, the reparative effects of the combination of the two and the role of p70S6 kinase-1 (p70S6k1) activation in the repair process have not been defined. Twenty-one days after intratracheal instillation of porcine pancreatic elastase (PPE), MSC and/or 10 days of ATRA treatment was initiated. Thirty-two days later, static lung compliance (Cst), mean linear intercepts (MLIs), and alveolar surface area (S) were measured. After PPE, mice demonstrated increased values of Cst and MLI, and decreased S values. Both ATRA and MSC transfer were individually effective in improving these outcomes while the combination of ATRA and MSCs was even more effective. The combination of p70S6k1-/- MSCs transfer followed by ATRA demonstrated only modest effects, and rapamycin treatment of recipients with wild-type (WT) MSCs and ATRA failed to show any effect. However, transfer of p70S6k1 over-expressing-MSCs together with ATRA resulted in further improvements over those seen following WT MSCs together with ATRA. ATRA activated p70S6k1 in MSCs in vitro, which was completely inhibited by rapamycin. Tracking of transferred MSCs following ATRA revealed enhanced accumulation and extended survival of MSCs in recipient lungs following PPE but not vehicle instillation. These data suggest that in MSCs, p70S6k1 activation plays a critical role in ATRA-enhanced lung tissue repair, mediated in part by prolonged survival of transferred MSCs. p70S6k1-activated MSCs may represent a novel therapeutic approach to reverse the lung damage seen in emphysema. Stem Cells Translational Medicine 2018;7:551-558.

Le dupilumab, un anticorps monoclonal entièrement humain dirigé contre la sous-unité α du récepteur de l’IL-4, inhibe la voie de signalisation d’IL-4 et d’IL-13, les principales cytokines des voies de type 2/Th2 associées à la dermatite atopique (DA). la tolérance et l’efficacité de 300 mg par semaine de dupilumab chez des adultes atteints de DA modérée à sévère non contrôlée par des traitements topiques ont été évaluées via des données combinées de deux essais de phase 2, (NCT01548404 ; NCT01859988) de 12 ou 16 semaines, randomisés, en double aveugle, contrôlés versus placebo (PBO). Les patients ont reçu 1 injection sous-cutanée par semaine de PBO ou de dupilumab. Les analyses d’efficacité incluaient le pourcentage de variation moyenne (méthode des moindres carrés) sur l’échelle en 5 dimensions du prurit (5-D), l’échelle d’évaluation numérique du prurit (NRS), l’indice de surface et de sévérité de l’eczéma (EASI) et le score de sévérité de la dermatite atopique (SCORAD), et la proportion de patients atteignant une amélioration EASI ≥ 50 %, ≥ 75 %, ou ≥ 90 % (EASI-50/75/90) ou du SCORAD ≥ 50 %, ≥ 75 % ou ≥ 90 % (SCORAD-50/75/90). L’efficacité et la tolérance combinées ont été évaluées jusqu’à la semaine 12. Les caractéristiques démographiques et cliniques étaient similaires dans les groupes dupilumab (n = 118) et PBO (n = 115). À la semaine 12, le dupilumab, par rapport au PBO, a significativement amélioré le score EASI (−73,6 % [3,7 %] contre −23,2 % [3,7 %], p < 0,0001), SCORAD (−56,64 % [2,628] contre −15,72 % [2,651], p < 0,0001), échelle 5-D du prurit (−41,7 % [1,9 %] contre −9,8 % [1,9 %], p < 0,0001) et échelle NRS du prurit (−52,8 % [3,0 %] contre −8,0 % [3,1 %], p < 0,0001). Les améliorations sur les échelles du prurit 5-D et NRS étaient significatives à la semaine 2 (p < 0,0001). À la semaine 12, un plus grand nombre de patients sous dupilumab vs PBO ont atteint des réponses EASI-50 (85,6 % contre 32,2 % ; p < 0,0001), EASI-75 (61,0 % contre 13,9 % ; p < 0,0001), EASI-90 (34,7 % contre 6,1 % ; p < 0,0001), SCORAD-50 (62,7 % contre 15,7 % ; p < 0,0001), SCORAD-75 (26,3 % contre 2,6 % ; p < 0,0001) et SCORAD-90 (6,8 % contre 0 % ; p = 0,0045). L’incidence combinée des évènements indésirables (EI) pendant le traitement jusqu’à la semaine 12 était de 81,4 % pour le dupilumab et de 80,9 % pour le PBO. Les EILT les plus fréquents (terme préconisé par MedDRA) dans le groupe dupilumab étaient : rhinopharyngite (32,2 % dupilumab ; 22,6 % PBO), céphalées (14,4 % dupilumab ; 7,8 % PBO) et conjonctivite (9,3 % dupilumab ; 1,7 % PBO). Chez l’adulte atteint de DA modérée à sévère, le dupilumab a amélioré significativement et nettement les résultats cliniques et a montré une efficacité précoce sur le prurit par rapport au PBO, avec un profil de tolérance favorable.

Background Dupilumab, a fully human anti-interleukin-4 receptor a monoclonal antibody, inhibits interleukin-4 and interleukin-13 signalling, key drivers of type-2-mediated inflammation. Adults with uncontrolled persistent asthma who are receiving medium-to-high-dose inhaled corticosteroids plus a long-acting beta(2) agonist require additional treatment options as add-on therapy. We aimed to assess the efficacy and safety of dupilumab as add-on therapy in patients with uncontrolled persistent asthma on medium-to-high-dose inhaled corticosteroids plus a long-acting beta(2) agonist, irrespective of baseline eosinophil count.Methods We did this randomised, double-blind, placebo-controlled, parallel-group, pivotal phase 2b clinical trial at 174 study sites across 16 countries or regions. Adults (aged >= 18 years) with an asthma diagnosis for 12 months or more based on the Global Initiative for Asthma 2009 Guidelines receiving treatment with medium-to-high-dose inhaled corticosteroids plus a long-acting beta(2) agonist were eligible for participation. Patients were randomly assigned (1:1:1:1:1) to receive subcutaneous dupilumab 200 mg or 300 mg every 2 weeks or every 4 weeks, or placebo, over a 24-week period. The primary endpoint was change from baseline at week 12 in forced expiratory volume in 1 s (FEV1 in L) in patients with baseline blood eosinophil counts of at least 300 eosinophils per mu L assessed in the intention-to-treat population. Safety outcomes were assessed in all patients that received at least one dose or part of a dose of study drug. This trial is registered at ClinicalTrials.gov, number NCT01854047, and with the EU Clinical Trials Register, EudraCT number 2013-000856-16.Findings 769 patients (158 in the placebo group and 611 in the dupilumab groups) received at least one dose of study drug. In the subgroup with at least 300 eosinophils per mu L, the greatest increases (200 mg every 2 weeks, p=0.0008; 300 mg every 2 weeks, p=0.0063) in FEV 1 compared with placebo were observed at week 12 with doses every 2 weeks in the 300 mg group (mean change 0.39 L [SE 0.05]; mean difference 0.21 [95% CI 0.06-0.36; p=0.0063]) and in the 200 mg group (mean change 0.43 L [SE 0.05]; mean difference 0.26 [0.11-0.40; p=0.0008]) compared with placebo (0.18 L [SE 0.05]). Similar significant increases were observed in the overall population and in the fewer than 300 eosinophils per mu L subgroup (overall population: 200 mg every 2 weeks, p< 0.0001; 300 mg every 2 weeks, p< 0.0001; < 300 eosinophils per mu L: 200 mg every 2 weeks, p=0.0034; 300 mg every 2 weeks, p=0.0086), and were maintained to week 24. Likewise, dupilumab every 2 weeks produced the greatest reductions in annualised rates of exacerbation in the overall population (70-70.5%), the subgroup with at least 300 eosinophils per mu L (71.2-80.7%), and the subgroup with fewer than 300 eosinophils per mu L (59.9-67.6%). The most common adverse events with dupilumab compared with placebo were upper respiratory tract infections (33-41% vs 35%) and injection-site reactions (13-26% vs 13%).Interpretation Dupilumab increased lung function and reduced severe exacerbations in patients with uncontrolled persistent asthma irrespective of baseline eosinophil count and had a favourable safety profile, and hence in addition to inhaled corticosteroids plus long-acting beta(2)-agonist therapy could improve the lives of patients with uncontrolled persistent asthma compared with standard therapy alone.

Background Data from early-stage studies suggested that interleukin (IL)-4 and IL-13 are requisite drivers of atopic dermatitis, evidenced by marked improvement after treatment with dupilumab, a fully-human monoclonal antibody that blocks both pathways. We aimed to assess the efficacy and safety of several dose regimens of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments.Methods In this randomised, placebo-controlled, double-blind study, we enrolled patients aged 18 years or older who had an Eczema Area and Severity Index (EASI) score of 12 or higher at screening (>= 16 at baseline) and inadequate response to topical treatments from 91 study centres, including hospitals, clinics, and academic institutions, in Canada, Czech Republic, Germany, Hungary, Japan, Poland, and the USA. Patients were randomly assigned (1: 1: 1: 1: 1: 1), stratified by severity (moderate or severe, as assessed by Investigator's Global Assessment) and region (Japan vs rest of world) to receive subcutaneous dupilumab: 300 mg once a week, 300 mg every 2 weeks, 200 mg every 2 weeks, 300 mg every 4 weeks, 100 mg every 4 weeks, or placebo once a week for 16 weeks. We used a central randomisation scheme, provided by an interactive voice response system. Drug kits were coded, providing masking to treatment assignment, and allocation was concealed. Patients on treatment every 2 weeks and every 4 weeks received volume-matched placebo every week when dupilumab was not given to ensure double blinding. The primary outcome was efficacy of dupilumab dose regimens based on EASI score least-squares mean percentage change (SE) from baseline to week 16. Analyses included all randomly assigned patients who received one or more doses of study drug. This trial is registered with ClinicalTrials.gov, number NCT01859988.Findings Between May 15, 2013, and Jan 27, 2014, 452 patients were assessed for eligibility, and 380 patients were randomly assigned. 379 patients received one or more doses of study drug (300 mg once a week [n=63], 300 mg every 2 weeks [n=64], 200 mg every 2 weeks [n=61], 300 mg every 4 weeks [n=65], 100 mg every 4 weeks [n=65]; placebo [n=61]). EASI score improvements favoured all dupilumab regimens versus placebo (p<0.0001): 300 mg once a week (-74% [SE 5.16]), 300 mg every 2 weeks (-68% [5.12]), 200 mg every 2 weeks (-65% [5.19]), 300 mg every 4 weeks (-64% [4.94]), 100 mg every 4 weeks (-45% [4.99]); placebo (-18% [5.20]). 258 (81%) of 318 patients given dupilumab and 49 (80%) of 61 patients given placebo reported treatment-emergent adverse events; nasopharyngitis was the most frequent (28% and 26%, respectively).Interpretation Dupilumab improved clinical responses in adults with moderate-to-severe atopic dermatitis in a dose-dependent manner, without significant safety concerns. Our findings show that IL-4 and IL-13 are key drivers of atopic dermatitis.

Background: Moderate to severe atopic dermatitis (AD) is associated with substantial patient burden despite current therapies.Objective: We sought to evaluate dupilumab treatment on patient-reported outcomes in adults with moderate to severe AD.Methods: Adults (N = 380) with moderate to severe AD inadequately controlled by topical medications were randomized to 16 weeks of double-blind, subcutaneous treatment with dupilumab 100 mg every 4 weeks, 200 mg every 2 weeks, 300 mg every 2 weeks, 300 mg once weekly, or placebo. Patient-reported outcomes included pruritus numeric rating scale; patient-reported sleep item on Scoring AD scale; Patient-Oriented Eczema Measure; Hospital Anxiety and Depression Scale; Dermatology Life Quality Index; and 5-dimension 3-level EuroQol.Results: Dupilumab reduced peak itch at 16 weeks relative to placebo by 1.1 to 3.2 points on numeric rating scale (P < .0001 all doses, except 100 mg every 4 weeks P < .05); improved sleep and health-related quality of life on Dermatology Life Quality Index and 5-dimension 3-level EuroQol (P < .05 all doses, except 100 mg every 4 weeks); and reduced anxiety and depression symptoms (P < .05 all doses). Dupilumab's effects appeared early and achieved clinically relevant improvements without significant safety concerns.Limitations: There are potential cultural differences affecting patient-reported outcome responses. Outcomes were secondary or exploratory end points.Conclusion: Dupilumab produced early and sustained patient-reported and clinically relevant improvements in sleep, mental health, and health-related quality of life; the two 300-mg dose regimens resulted in greatest benefits.

IMPORTANCE:Dupilumab has demonstrated efficacy in patients with asthma and atopic dermatitis, which are both type 2 helper T-cell-mediated diseases.OBJECTIVE:To assess inhibition of interleukins 4 and 13 with dupilumab in patients with chronic sinusitis and nasal polyposis.DESIGN, SETTING, AND PARTICIPANTS:A randomized, double-blind, placebo-controlled parallel-group study conducted at 13 sites in the United States and Europe between August 2013 and August 2014 in 60 adults with chronic sinusitis and nasal polyposis refractory to intranasal corticosteroids with 16 weeks of follow-up.INTERVENTIONS:Subcutaneous dupilumab (a 600 mg loading dose followed by 300 mg weekly; n = 30) or placebo (n = 30) plus mometasone furoate nasal spray for 16 weeks.MAIN OUTCOMES AND MEASURES:Change in endoscopic nasal polyp score (range, 0-8; higher scores indicate worse status) at 16 weeks (primary end point). Secondary end points included Lund-Mackay computed tomography (CT) score (range, 0-24; higher scores indicate worse status), 22-item SinoNasal Outcome Test score (range, 0-110; higher scores indicating worse quality of life; minimal clinically important difference ≥8.90), sense of smell assessed using the University of Pennsylvania Smell Identification Test (UPSIT) score (range, 0-40; higher scores indicate better status), symptoms, and safety.RESULTS:Among the 60 patients who were randomized (mean [SD] age, 48.4 years [9.4 years]; 34 men [56.7%]; 35 with comorbid asthma), 51 completed the study. The least squares (LS) mean change in nasal polyp score was -0.3 (95% CI, -1.0 to 0.4) with placebo and -1.9 (95% CI, -2.5 to -1.2) with dupilumab (LS mean difference, -1.6 [95% CI, -2.4 to -0.7]; P < .001). The LS mean difference between the 2 groups for the Lund-Mackay CT total score was -8.8 (95% CI, -11.1 to -6.6; P < .001). Significant improvements with dupilumab were also observed for the 22-item SinoNasal Outcome Test (LS mean difference between groups, -18.1 [95% CI, -25.6 to -10.6]; P < .001) and sense of smell assessed by UPSIT (LS mean difference, 14.8 [95% CI, 10.9 to 18.7]; P < .001). The most common adverse events were nasopharyngitis (33% in the placebo group vs 47% in the dupilumab group), injection site reactions (7% vs 40%, respectively), and headache (17% vs 20%).CONCLUSIONS AND RELEVANCE:Among adults with symptomatic chronic sinusitis and nasal polyposis refractory to intranasal corticosteroids, the addition of subcutaneous dupilumab to mometasone furoate nasal spray compared with mometasone alone reduced endoscopic nasal polyp burden after 16 weeks. Further studies are needed to assess longer treatment duration, larger samples, and direct comparison with other medications.TRIAL REGISTRATION:clinicaltrials.gov Identifier: NCT01920893.

Introduction: Dupilumab, a fully human IL-4R-α monoclonal antibody, inhibits IL-4 and IL-13, key drivers of Type 2-mediated inflammation. Aim: To evaluate the efficacy and safety of dupilumab dose regimens for uncontrolled asthma. Methods: Multinational, double-blind, pivotal phase 2b study (NCT01854047). Adults with uncontrolled asthma despite medium-to-high dose ICS/LABA were randomized to add on therapy with dupilumab 200 or 300 mg every 2 weeks (q2w) or every 4 weeks (q4w), or placebo (PBO), for 24 weeks. The primary endpoint was change from baseline to Week 12 in FEV1 (L) in pts with high eosinophil (Eos) count (HEos; ≥300/µL). Secondary endpoints included change from baseline in FEV1 (%), annualized severe exacerbation rate, and safety. Data were reported for HEos, low Eos (LEos; <300/µL), and overall groups. Results: Of 776 randomized pts, 325 (42%) had HEos. Dupilumab q2w regimens showed significant improvements in FEV1 at Week 12, and reduced annualized severe exacerbation rates in HEos, LEos and overall groups vs PBO. The q4w regimens were less efficacious vs q2w regimens. The most common adverse event was injection-site reaction (13–26% vs 13% PBO). Conclusions: Dupilumab q2w plus ICS/LABA therapy improves FEV1 and reduces severe exacerbations in pts with uncontrolled asthma, irrespective of Eos count (≥300/µL or <300/µL).

The prostaglandin D2 (PGD2) receptor, CRTH2, plays a role in allergic airway inflammation. The efficacy of BI 671800, a CRTH2 antagonist, was assessed in 2 separate trials in patients with asthma, in either the absence or the presence of inhaled corticosteroid (ICS) therapy. In this study, BI 671800 (50, 200 or 400 mg) and fluticasone propionate (220 μg) all given twice daily (bid) were compared with bid placebo in symptomatic controller-naïve adults with asthma (Trial 1), and BI 671800 400 mg bid compared with montelukast 10 mg once daily (qd), and matching placebo bid, in patients with asthma receiving inhaled fluticasone (88 μg bid) (Trial 2). The primary endpoint in both trials was change from baseline in trough forced expiratory volume in 1 s (FEV1) percent predicted. After 6 weeks' treatment, adjusted mean treatment differences (SE) for the primary endpoint compared with placebo in Trial 1 were 3.08% (1.65%), 3.59% (1.60%) and 3.98% (1.64%) for BI 671800 50, 200 and 400 mg bid, respectively, and 8.62% (1.68%) for fluticasone 220 μg bid (p = 0.0311, p = 0.0126, p = 0.0078 and p < 0.0001, respectively). In Trial 2, adjusted mean FEV1 (SE) treatment differences compared with placebo were 3.87% (1.49%) for BI 671800 400 mg bid and 2.37% (1.57%) for montelukast (p = 0.0050 and p = 0.0657, respectively). These findings suggest that BI 671800 is associated with a small improvement in FEV1 in symptomatic controller-naïve asthma patients, and in patients on ICS.

Atopic dermatitis (AD) is associated with substantial patient burden. Dupilumab, a fully-human monoclonal antibody against the interleukin-4 receptor-α, has demonstrated symptomatic efficacy in AD. 380 adults with moderate-to-severe AD were randomized 1:1:1:1:1:1 to 16-week treatment with subcutaneous placebo or dupilumab 100mg every 4 weeks (q4w), 300mg-q4w, 200mg every 2 weeks (q2w), 300mg-q2w, or 300mg weekly (NCT01859988). Assessments included PROs of Pruritus Numeric Rating Scale (NRS), SCORing Atopic Dermatitis (SCORAD), Patient Oriented Eczema Measure (POEM), Hospital Anxiety and Depression Scale (HADS), Dermatology Life Quality Index (DLQI), and EuroQol-5D (EQ-5D). Mean age was 37 years; mean disease duration was 28 years. At 16 weeks, dupilumab significantly reduced itch on NRS (>3-point decrease) in 20% to 54% of patients vs. 8.2% in placebo group (P<0.0005 all doses except 100mg-q4w P<0.05), along with improvements in sleep on items of SCORAD and POEM measures (P<0.0005 all doses except 100mg-q4w). Dupilumab also significantly reduced symptoms of depression and anxiety on HADS; number of patients with scores >11 indicating probable cases of anxiety or depression decreased by 66.7% to 75% in dupilumab groups vs. 22.2% in placebo group (P<0.05 all doses). Quality of life (QOL) improved at all dupilumab doses except 100mg-q4w (DLQI, P<0.0001; and EQ-5D, P<0.05). The most common adverse events (dupilumab doses combined vs. placebo) were nasopharyngitis (20.6% vs. 21.3%), headache (11.1% vs. 3.3%), and injection site reaction (9.5% vs. 3.3%). In adults with moderate-to-severe AD, dupilumab significantly reduced patient-reported itch relative to placebo, with concomitant improvements on PROs that evaluated sleep, mood, and QOL.

RATIONALE:Severe asthma is characterized by airway inflammatory responses associated with aberrant metabolism of arachidonic acid. Lipoxins (LX) are arachidonate-derived pro-resolving mediators that are decreased in severe asthma, yet mechanisms for defective LX biosynthesis and a means to increase LXs in severe asthma remain to be established.OBJECTIVES:To determine if oxidative stress and soluble epoxide hydrolase (sEH) activity are linked to decreased LX biosynthesis in severe asthma.METHODS:Aliquots of blood, sputum, and bronchoalveolar lavage fluid were obtained from asthma subjects for mediator determination. Select samples were exposed to t-butyl-hydroperoxide or sEH inhibitor (sEHI) before activation. Peripheral blood leukocyte-platelet aggregates were monitored by flow cytometry, and bronchial contraction was determined with cytokine-treated human lung sections.MEASUREMENTS AND MAIN RESULTS:8-Isoprostane levels in sputum supernatants were inversely related to LXA4 in severe asthma (r = -0.55; P = 0.03) and t-butyl-hydroperoxide decreased LXA4 and 15-epi-LXA4 biosynthesis by peripheral blood leukocytes. LXA4 and 15-epi-LXA4 levels were inversely related to sEH activity in sputum supernatants and sEHIs significantly increased 14,15-epoxy-eicosatrienoic acid and 15-epi-LXA4 generation by severe asthma whole blood and bronchoalveolar lavage fluid cells. The abundance of peripheral blood leukocyte-platelet aggregates was related to asthma severity. In a concentration-dependent manner, LXs significantly inhibited platelet-activating factor-induced increases in leukocyte-platelet aggregates (70.8% inhibition [LXA4 100 nM], 78.3% inhibition [15-epi-LXA4 100 nM]) and 15-epi-LXA4 markedly inhibited tumor necrosis factor-α-induced increases in bronchial contraction.CONCLUSIONS:LX levels were decreased by oxidative stress and sEH activity. Inhibitors of sEH increased LXs that mediated antiphlogistic actions, suggesting a new therapeutic approach for severe asthma. Clinical trial registered with www.clinicaltrials.gov (NCT 00595114).

BACKGROUND COPD patients have a great burden of comorbidity. However, it is not well established whether this is due to shared risk factors such as smoking, if they impact patients exercise capacity and quality of life, or whether there are racial disparities in their impact on COPD. METHODS We analyzed data from 10,192 current and ex-smokers with (cases) and without COPD (controls) from the COPDGene® cohort to establish risk for COPD comorbidities adjusted for pertinent covariates. In adjusted models, we examined comorbidities prevalence and impact in African-Americans (AA) and Non-Hispanic Whites (NHW). RESULTS Comorbidities are more common in COPD compared to those with normal spirometry (controls), and the risk persists after adjustments for covariates including pack-years smoked. After adjustment for confounders, eight conditions were independently associated with worse exercise capacity, quality of life and dyspnea. There were racial disparities in the impact of comorbidities on exercise capacity, dyspnea and quality of life, presence of osteoarthritis and gastroesophageal reflux disease having a greater negative impact on all three outcomes in AAs than NHWs (p<0.05 for all interaction terms). CONCLUSIONS Individuals with COPD have a higher risk for comorbidities than controls, an important finding shown for the first time comprehensively after accounting for confounders. Individual comorbidities are associated with worse exercise capacity, quality of life, and dyspnea, in African-Americans compared to non-Hispanic Whites.

BACKGROUND:Numbers of CD8(+) T cells expressing the leukotriene B4 (LTB4) receptor, BLT1, have been correlated with asthma severity. OBJECTIVE:To examine the activation and numbers of BLT1-expressing peripheral blood CD4(+) and CD8(+) T cells from patients with steroid-sensitive (SS) and steroid-resistant (SR) asthma. METHODS:CD4(+) and CD8(+) T cells isolated from peripheral blood of healthy human subjects and patients with SS and SR asthma were stimulated in culture with anti-CD3/anti-CD28 followed by analysis of BLT1 surface expression and cytokine production. Activation of CD8(+) T cells after ligation of BLT1 by LTB4 was monitored by changes in intracellular Ca(2+) concentrations. RESULTS:The number of BLT1-expressing cells was larger in patients with asthma than in controls and larger on activated CD8(+) than on CD4(+) T cells. Addition of LTB4 to activated CD8(+) T cells resulted in increases in intracellular Ca(2+) concentrations. Expansion of activated CD4(+) T cells, unlike CD8(+) T cells, was significantly decreased in the presence of corticosteroid. In patients with SS asthma, numbers of BLT1-expressing CD8(+) T cells were lower in the presence of corticosteroid, unlike in those with SR asthma in whom cell expansion was maintained. Levels of interleukin-13 were highest in cultured CD8(+) T cells, whereas interleukin-10 levels were higher in CD4(+) T cells from controls and patients with SS asthma. Interferon-γ levels were lowest in patients with SR asthma. CONCLUSION:Differences in BLT1 expression, steroid sensitivity, and cytokine production were demonstrated in T lymphocytes from patients with SS and SR asthma. The LTB4-BLT1 pathway in CD8(+) cells may play an important role in asthma and serve as an important target in the treatment of patients with SR asthma.