Astegolimab or Efmarodocokin Alfa in Patients With Severe COVID-19 Pneumonia: A Randomized, Phase 2 Trial.

OBJECTIVES: Severe cases of COVID-19 pneumonia can lead to acute respiratory distress syndrome (ARDS). Release of interleukin (IL)-33, an epithelial-derived alarmin, and IL-33/ST2 pathway activation are linked with ARDS development in other viral infections. IL-22, a cytokine that modulates innate immunity through multiple regenerative and protective mechanisms in lung epithelial cells, is reduced in patients with ARDS. This study aimed to evaluate safety and efficacy of astegolimab, a human immunoglobulin G2 monoclonal antibody that selectively inhibits the IL-33 receptor, ST2, or efmarodocokin alfa, a human IL-22 fusion protein that activates IL-22 signaling, for treatment of severe COVID-19 pneumonia. DESIGN: Phase 2, double-blind, placebo-controlled study (COVID-astegolimab-IL). SETTING: Hospitals. PATIENTS: Hospitalized adults with severe COVID-19 pneumonia. INTERVENTIONS: Patients were randomized to receive IV astegolimab, efmarodocokin alfa, or placebo, plus standard of care. The primary endpoint was time to recovery, defined as time to a score of 1 or 2 on a 7-category ordinal scale by day 28. MEASUREMENTS AND MAIN RESULTS: The study randomized 396 patients. Median time to recovery was 11 days (hazard ratio [HR], 1.01 d; p = 0.93) and 10 days (HR, 1.15 d; p = 0.38) for astegolimab and efmarodocokin alfa, respectively, versus 10 days for placebo. Key secondary endpoints (improved recovery, mortality, or prevention of worsening) showed no treatment benefits. No new safety signals were observed and adverse events were similar across treatment arms. Biomarkers demonstrated that both drugs were pharmacologically active. CONCLUSIONS: Treatment with astegolimab or efmarodocokin alfa did not improve time to recovery in patients with severe COVID-19 pneumonia.

Phase 2 randomized clinical trial of astegolimab in patients with moderate to severe atopic dermatitis.

BACKGROUND: The binding of IL-33 to its receptor ST2 (alias of IL1RL1) leads to the release of inflammatory mediators and may play a role in the pathogenesis of atopic dermatitis. Astegolimab is a fully human, IgG2 mAb that binds to ST2 and inhibits IL-33 signaling. OBJECTIVES: This study sought to assess the efficacy, safety, and pharmacokinetics of astegolimab in patients with atopic dermatitis. METHODS: This was a randomized, placebo-controlled, phase 2 study in which adults with chronic atopic dermatitis were randomized 1:1 to receive astegolimab 490 mg every 4 weeks or placebo, for 16 weeks. The primary outcome was the percentage of change from baseline to week 16 of the Eczema Area and Severity Index score. RESULTS: A total of 65 patients were enrolled in the study (placebo, n = 32; astegolimab, n = 33). The adjusted mean percentage of change from baseline to week 16 in the Eczema Area and Severity Index score was -51.47% for astegolimab compared with -58.24% for placebo, with a nonsignificant treatment difference of 6.77% (95% CI: -16.57-30.11; P = .5624). No differences were observed between treatment groups for secondary efficacy outcomes and in exploratory biomarkers (blood eosinophils, serum IL-5, serum CCL13). With the use of loading dose, pharmacokinetic exposure was sufficient from week 1. Astegolimab was well-tolerated, with a safety profile consistent with that observed in previous clinical trials. CONCLUSIONS: In patients with atopic dermatitis, astegolimab did not show a significant difference compared to placebo for the primary or secondary outcomes.

Astegolimab (anti-ST2) efficacy and safety in adults with severe asthma: A randomized clinical trial.

BACKGROUND: The IL-33/ST2 pathway is linked with asthma susceptibility. Inhaled allergens, pollutants, and respiratory viruses, which trigger asthma exacerbations, induce release of IL-33, an epithelial-derived "alarmin." Astegolimab, a human IgG2 mAb, selectively inhibits the IL-33 receptor, ST2. Approved biologic therapies for severe asthma mainly benefit patients with elevated blood eosinophils (type 2-high), but limited options are available for patients with low blood eosinophils (type 2-low). Inhibiting IL-33 signaling may target pathogenic pathways in a wider spectrum of asthmatics. OBJECTIVES: This study evaluated astegolimab efficacy and safety in patients with severe asthma. METHODS: This double-blind, placebo-controlled, dose-ranging study (ZENYATTA [A Study to Assess the Efficacy and Safety of MSTT1041A in Participants With Uncontrolled Severe Asthma]) randomized 502 adults with severe asthma to subcutaneous placebo or 70-mg, 210-mg, or 490-mg doses of astegolimab every 4 weeks. The primary endpoint was the annualized asthma exacerbation rate (AER) at week 54. Enrollment caps ensured ∼30 patients who were eosinophil-high (≥300 cells/µL) and ∼95 patients who were eosinophil-low (<300 cells/µL) per arm. RESULTS: Overall, adjusted AER reductions relative to placebo were 43% (P = .005), 22% (P = .18), and 37% (P = .01) for 490-mg, 210-mg, and 70-mg doses of astegolimab, respectively. Adjusted AER reductions for patients who were eosinophil-low were comparable to reductions in the overall population: 54% (P = .002), 14% (P = .48), and 35% (P = .05) for 490-mg, 210-mg, and 70-mg doses of astegolimab. Adverse events were similar in astegolimab- and placebo-treated groups. CONCLUSIONS: Astegolimab reduced AER in a broad population of patients, including those who were eosinophil-low, with inadequately controlled, severe asthma. Astegolimab was safe and well tolerated.

A phase 1, randomized study to evaluate safety, tolerability, and pharmacokinetics of GDC-3280, a potential novel anti-fibrotic small molecule, in healthy subjects.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease. Although anti-fibrotic treatments, such as pirfenidone, are available that reduce the rate of disease progression, these medications have limitations in tolerability, and IPF patients still have poor prognoses. GDC-3280, an orally available small molecule that was designed to improve upon pirfenidone's activity, has anti-fibrotic activity in animal models. This first-in-human, phase 1 trial evaluated GDC-3280 to determine its safety, tolerability, and pharmacokinetics (PK). METHODS: Single and multiple ascending-doses of GDC-3280 were administered to healthy volunteers in two parts. Part A consisted of 6 treatment groups, each receiving a single, oral dose of GDC-3280 (25-1600 mg) or placebo in the fasted state. Part A also assessed the effect of food and coadministration of a proton pump inhibitor (rabeprazole) on the tolerability and PK of single doses of 400- and 800-mg GDC-3280. Part B consisted of 3 treatment groups who received either 200- or 275-mg GDC-3280 twice daily or 525-mg once daily after a low-fat meal for 7 days. The trial monitored treatment-emergent adverse events (TEAEs) and assessed the pharmacokinetics of GDC-3280 in blood and urine samples. RESULTS: Fifty-six subjects (42 GDC-3280, 14 placebo) in Part A and 24 subjects (18 GDC-3280, 6 placebo) in Part B received treatment. No deaths, serious adverse events, or dose-limiting adverse events occurred, and no subjects withdrew due to a TEAE. In both Parts A and B, most TEAEs were mild. The most frequent TEAEs in Part A were headache and nausea. TEAEs occurred more often when GDC-3280 was administered with food. Pretreatment and coadministration with rabeprazole had no effect on GDC-3280 tolerability. In Part B, the most frequent TEAEs were nausea, dizziness, nasal congestion, and cough. Transient, treatment-related increases in serum creatinine occurred at doses greater than 400 mg in Part A (12%-18% from baseline) and after multiple doses in each group in Part B (20%-34% from baseline). GDC-3280 was generally readily absorbed with a median tmax < 4.0 h following single- or repeat-dose oral administration. In Part A, less-than-dose-proportional increases in systemic exposure occurred, and in Part B, dose-proportional increases occurred within the dose range tested. At doses of 200 mg or lower, more than 50%-70% of orally administered doses were recovered in urine as unchanged GDC-3280 when subjects received a single dose of GDC-3280, suggesting renal excretion is one of the major routes of elimination. Administration of single doses of 400- and 800-mg GDC-3280 after a meal caused statistically significant increases in exposure due to increased rates of absorption compared to the fasted state. Pretreatment and coadministration of rabeprazole dosing led to decreases in exposure compared to GDC-3280 alone, indicating a weak drug-drug interaction. Following repeat dose administration, steady-state plasma concentrations of GDC-3280 were achieved within 2 days with an apparent terminal half-life (t1/2) between 5 and 6 h. CONCLUSIONS: Single and multiple doses of GDC-3280 were generally well tolerated, with acceptable safety and pharmacokinetic profiles that support twice-daily, oral administration with food in future clinical trials.

Determination of a novel antifibrotic small molecule GDC-3280 in human plasma and urine by liquid chromatography tandem mass spectrometry to support its first-in-human clinical trial.

A specific and robust LC-MS/MS method was developed and validated for the quantitative determination of GDC-3280 in human plasma and urine. The nonspecific binding associated with urine samples was overcome by the addition of CHAPS. The sample volume was 25 µL for either matrix, and supported liquid extraction was employed for analyte extraction. d6-GDC-3280 was used as the internal standard. Linear standard curves (R2 > 0.9956) were established from 5.00 to 5000 ng/mL in both matrices with quantitation extended to 50,000 ng/mL through dilution. In plasma matrix, the precision (RSD) ranged from 1.5 to 9.9% (intra-run) and from 2.4 to 7.2% (inter-run); the accuracy (RE) ranged from 96.1 to 107% (intra-run) and from 96.7 to 104% (inter-run). Similarly, in urine the precision was 1.5-6.2% (intra-run) and 1.9-6.1% (inter-run); the accuracy was 83.1-99.3% (intra-run) and 87.1-98.3% (inter-run). Good recovery (>94%) and negligible matrix effect were achieved in both matrices. Long-term matrix stability was established for at least 703 days in plasma and 477 days in urine. Bench-top stability of 25 h and five freeze-thaw cycles were also confirmed in both matrices. The method was successfully implemented in GDC-3280's first-in-human trial for assessing its pharmacokinetic profiles.

Cysteinyl leukotriene receptor 1 expression identifies a subset of neutrophils during the antiviral response that contributes to postviral atopic airway disease.

BACKGROUND: Viral respiratory tract infections increase the risk of development and exacerbation of atopic disease. Previously, we demonstrated the requirement for a neutrophil (PMN) subset expressing CD49d to drive development of postviral atopic airway disease in mice. OBJECTIVE: We sought to determine whether human CD49d+ PMNs are present in the nasal mucosa during acute viral respiratory tract infections and further characterize this PMN subset in human subjects and mice. METHODS: Sixty subjects (5-50 years old) were enrolled within 4 days of acute onset of upper respiratory symptoms. Nasal lavage for flow cytometry and nasal swabs for viral PCR were performed at enrollment and during convalescence. The Sendai virus mouse model was used to investigate the phenotype and functional relevance of CD49d+ PMNs. RESULTS: CD49d+ PMN frequency was significantly higher in nasal lavage fluid during acute respiratory symptoms in all subjects (2.9% vs 1.0%, n = 42, P < .001). In mice CD49d+ PMNs represented a "proatopic" neutrophil subset that expressed cysteinyl leukotriene receptor 1 (CysLTR1) and produced TNF, CCL2, and CCL5. Inhibition of CysLTR1 signaling in the first days of a viral respiratory tract infection was sufficient to reduce accumulation of CD49d+ PMNs in the lungs and development of postviral atopic airway disease. Similar to the mouse, human CD49d+ PMNs isolated from nasal lavage fluid during a viral respiratory tract infection expressed CysLTR1. CONCLUSION: CD49d and CysLTR1-coexpressing PMNs are present during symptoms of an acute viral respiratory tract infection in human subjects. Further study is needed to examine selective targeting of proatopic neutrophils as a potential therapeutic strategy to prevent development of postviral atopic airway disease.

The effectiveness of video-based exercise training program for people with intellectual disability: a multicenter study.

Objective: To examine the effectiveness of a specially designed video-based exercise program in promoting physical and balance performance in people with intellectual disability. Methods: This study was a multicenter controlled trial. Participants with intellectual disability were divided into exercise group and control group by cluster sampling. The participants in the exercise group received 1 h exercise training sessions twice a week for 8 weeks, and the controls continued their usual care without exercise training. The exercises were specially designed to match the physical ability level of the participants classified as high and low, and a third group called "special" was designed for those wheelchair-bound persons with limited mobility. Elements of light-tempo music and animation were introduced in the videos to motivate the participants. Recording the exercises in video format makes it easier for the class instructors and participants to perform the exercises together, and ensure consistency across different exercise groups conducted in different centers. Each participant underwent the pre- and post-intervention assessment including 30-s chair stand repetitions, five-time chair stand duration, 4-m comfortable walk time, standing static balance level, 6-min walk test, and short physical performance battery score. These variables were compared within each group at pre- and post-intervention stages, and they were also compared between the two groups. Results: A total of 180 participants were enrolled in 16 subcenters, including 160 participants in the exercise group and 20 participants in the control group. After 8 weeks of exercise training, there were significant improvements in their physical performance including 30-s chair stand repetitions and five-time chair stand duration, 4-m comfortable walk time and also 6-min walk test, within the exercise group (all P < 0.05). Approximately 39% of the participants in the exercise group also showed significant improvement in standing static balance level. No significant differences were found when compared with the control group participants who did not have any regular exercise participation. Conclusion: A specially designed video-based exercise program has demonstrated some positive effects on physical and balance performance after 8 weeks of training among adults with intellectual disability.

Weak to no correlation between quantitative high-resolution computed tomography metrics and lung function change in fibrotic diseases.

Background: Identifying systemic sclerosis (SSc) and idiopathic pulmonary fibrosis (IPF) patients at risk of more rapid forced vital capacity (FVC) decline could improve trial design. The purpose of the present study was to explore the prognostic value of quantitative high-resolution computed tomography (HRCT) metrics derived by Imbio lung texture analysis (LTA) tool in predicting FVC slope. Methods: This retrospective study used data from patients who were not treated with investigational drugs with and without background antifibrotic therapies in tocilizumab phase 3 SSc, lebrikizumab phase 2 IPF, and zinpentraxin alfa phase 2 IPF studies conducted from 2015 to 2021. Controlled HRCT axial volumetric multidetector computed tomography scans were evaluated using the Imbio LTA tool. Associations between HRCT metrics and FVC slope were assessed through the Spearman correlation coefficient and adjusted R2 in a linear regression model adjusted by demographics and baseline clinical characteristics. Results: A total of 271 SSc and IPF patients were analysed. Correlation coefficients of highest magnitude were observed in the SSc study between the extent of ground glass, normal volume, quantification of interstitial lung disease, reticular pattern, and FVC slope (-0.25, 0.28, -0.28, and -0.33, respectively), while the correlation coefficients observed in IPF studies were in general <0.2. The incremental prognostic value of the baseline HRCT metrics was marginal after adjusting baseline characteristics and was inconsistent across study arms. Conclusion: Data from the SSc and IPF studies suggested weak to no and inconsistent correlation between quantitative HRCT metrics derived by the Imbio LTA tool and FVC slope in the studied SSc and IPF population.

Role of viruses in the development of atopic disease in pediatric patients.

The prevalence of atopic diseases continues to rise in modernized countries, without a clear explanation for this increase. One potential cause identified from epidemiologic studies of children is respiratory RNA viral infections leading to development of recurrent wheezing, asthma, and allergic sensitization. We review human epidemiologic data that both support and refute the role of viruses in this process. Exploring recent murine models, we document possible immunologic mechanisms that could translate a viral infection into atopic disease. We further discuss evidence for a post-viral "atopic cycle" that could explain the development of multiple allergen sensitization, and we explore available data to suggest a connection between viral infections of the gastrointestinal tract with the development of food allergy. Taken together, this review documents evidence to support the "viral hypothesis", and, in particular, the role of RNA viruses in the development of atopic disease.

Cutting edge: CD49d+ neutrophils induce FcepsilonRI expression on lung dendritic cells in a mouse model of postviral asthma.

The increasing prevalence of atopy and asthma remains unexplained but may be due to infection with respiratory viruses. In support of this hypothesis, we showed that experimental asthma after viral infection in mice depended on type I IFN-driven upregulation of FcεRI on conventional dendritic cells (cDCs) in the lung. In this article, we demonstrate that FcεRI expression on lung cDCs depends on an unexpected activity of a CD49d(+) subset of polymorphonuclear neutrophils (PMNs) that are found in the lungs of wild-type C57BL6 but not mice deficient in type I IFNR. Expression of FcεRI depends in part on a CD11b-dependent interaction between PMNs and cDCs. This study demonstrates a PMN-cDC interaction in the lung that is necessary for the ability of viral infection to induce atopic disease.

Population Pharmacokinetics and Exposure-Response Relationships of Astegolimab in Patients With Severe Asthma.

Astegolimab is a fully human immunoglobulin G2 monoclonal antibody that binds to the ST2 receptor and blocks the interleukin-33 signaling. It was evaluated in patients with uncontrolled severe asthma in the phase 2b study (Zenyatta) at doses of 70, 210, and 490 mg subcutaneously every 4 weeks for 52 weeks. This work aimed to characterize astegolimab pharmacokinetics, identify influential covariates contributing to its interindividual variability, and make a descriptive assessment of the exposure-response relationships. A population pharmacokinetic model was developed using data from 368 patients in the Zenyatta study. Predicted average steady-state concentration was used in the subsequent exposure-response analyses, which evaluated efficacy (asthma exacerbation rate) and biomarker end points including forced expiratory volume in 1 second, fraction exhaled nitric oxide, blood eosinophils, and soluble ST2. A 2-compartment disposition model with first-order elimination and first-order absorption best described the astegolimab pharmacokinetics. The relative bioavailability for the 70-mg dose was 15.3% lower. Baseline body weight, estimated glomerular filtration rate, and eosinophils were statistically correlated with pharmacokinetic parameters, but only body weight had a clinically meaningful influence on the steady-state exposure (ratios exceeding 0.8-1.25). The exposure-response of efficacy and biomarkers were generally flat with a weak trend in favor of the highest dose/exposure. This study characterized astegolimab pharmacokinetics in patients with asthma and showed typical pharmacokinetic behavior as a monoclonal antibody-based drug. The exposure-response analyses suggested the highest dose tested in the Zenyatta study (490 mg every 4 weeks) performed close to the maximum effect, and no additional response may be expected above it.

Astegolimab, an anti-ST2, in chronic obstructive pulmonary disease (COPD-ST2OP): a phase 2a, placebo-controlled trial.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a heterogeneous inflammatory airway disease. The epithelial-derived IL-33 and its receptor ST2 have been implicated in airway inflammation and infection. We aimed to determine whether astegolimab, a selective ST2 IgG2 monoclonal antibody, reduces exacerbations in COPD. METHODS: COPD-ST2OP was a single-centre, randomised, double-blinded, placebo-controlled phase 2a trial in moderate-to-very severe COPD. Participants were randomly assigned (1:1) with a web-based system to received 490 mg subcutaneous astegolimab or subcutaneous placebo, every 4 weeks for 44 weeks. The primary endpoint was exacerbation rate assessed for 48 weeks assessed with a negative binomial count model in the intention-to-treat population, with prespecified subgroup analysis by baseline blood eosinophil count. The model was the number of exacerbations over the 48-week treatment period, with treatment group as a covariate. Safety was assessed in the whole study population until week 60. Secondary endpoints included Saint George's Respiratory Questionnaire for COPD (SGRQ-C), FEV1, and blood and sputum cell counts. The trial was registered with ClinicalTrials.gov, NCT03615040. FINDINGS: The exacerbation rate at 48 weeks in the intention-to-treat analysis was not significantly different between the astegolimab group (2·18 [95% CI 1·59 to 2·78]) and the placebo group (2·81 [2·05 to 3·58]; rate ratio 0·78 [95% CI 0·53 to 1·14]; p=0·19]). In the prespecified analysis stratifying patients by blood eosinophil count, patients with 170 or fewer cells per µL had 0·69 exacerbations (0·39 to 1·21), whereas those with more than 170 cells per µL had 0·83 exacerbations (0·49 to 1·40). For the secondary outcomes, the mean difference between the SGRQ-C in the astegolimab group versus placebo group was -3·3 (95% CI -6·4 to -0·2; p=0·039), and mean difference in FEV1 between the two groups was 40 mL (-10 to 90; p=0·094). The difference in geometric mean ratios between the two groups for blood eosinophil counts was 0·59 (95% CI 0·51 to 0·69; p<0·001) and 0·25 (0·19 to 0·33; p<0·001) for sputum eosinophil counts. Incidence of treatment-emergent adverse events was similar between groups. INTERPRETATION: In patients with moderate-to-very severe COPD, astegolimab did not significantly reduce exacerbation rate, but did improve health status compared with placebo. FUNDING: Funded by Genentech and National Institute for Health Research Biomedical Research Centres.

A whole genome sequencing study of moderate to severe asthma identifies a lung function locus associated with asthma risk.

Genome-wide association studies (GWAS) have identified many common variant loci associated with asthma susceptibility, but few studies investigate the genetics underlying moderate-to-severe asthma risk. Here, we present a whole-genome sequencing study comparing 3181 moderate-to-severe asthma patients to 3590 non-asthma controls. We demonstrate that asthma risk is genetically correlated with lung function measures and that this component of asthma risk is orthogonal to the eosinophil genetics that also contribute to disease susceptibility. We find that polygenic scores for reduced lung function are associated with younger asthma age of onset. Genome-wide, seven previously reported common asthma variant loci and one previously reported lung function locus, near THSD4, reach significance. We replicate association of the lung function locus in a recently published GWAS of moderate-to-severe asthma patients. We additionally replicate the association of a previously reported rare (minor allele frequency < 1%) coding variant in IL33 and show significant enrichment of rare variant burden in genes from common variant allergic disease loci. Our findings highlight the contribution of lung function genetics to moderate-to-severe asthma risk, and provide initial rare variant support for associations with moderate-to-severe asthma risk at several candidate genes from common variant loci.

High resolution analysis of follicular lymphoma genomes reveals somatic recurrent sites of copy-neutral loss of heterozygosity and copy number alterations that target single genes.

A multiplatform approach, including conventional cytogenetic techniques, BAC array comparative genomic hybridization, and Affymetrix 500K SNP arrays, was applied to the study of the tumor genomes of 25 follicular lymphoma biopsy samples with paired normal DNA samples to characterize balanced translocations, copy number imbalances, and copy-neutral loss of heterozygosity (cnLOH). In addition to the t(14;18), eight unique balanced translocations were found. Commonly reported FL-associated copy number regions were revealed including losses of 1p32-36, 6q, and 10q, and gains of 1q, 6p, 7, 12, 18, and X. The most frequent regions affected by copy-neutral loss of heterozygosity were 1p36.33 (28%), 6p21.3 (20%), 12q21.2-q24.33 (16%), and 16p13.3 (24%). We also identified by SNP analysis, 45 aberrant regions that each affected one gene, including CDKN2A, CDKN2B, FHIT, KIT, PEX14, and PTPRD, which were associated with canonical pathways involved in tumor development. This study illustrates the power of using complementary high-resolution platforms on paired tumor/normal specimens and computational analysis to provide potential insights into the significance of single-gene somatic aberrations in FL tumorigenesis.

Population repeated time-to-event analysis of exacerbations in asthma patients: A novel approach for predicting asthma exacerbations based on biomarkers, spirometry, and diaries/questionnaires.

Identification of covariates, including biomarkers, spirometry, and diaries/questionnaires, that predict asthma exacerbations would allow better clinical predictions, shorter phase II trials and inform decisions on phase III design, and/or initiation (go/no-go). The objective of this work was to characterize asthma-exacerbation hazard as a function of baseline and time-varying covariates. A repeated time-to-event (RTTE) model for exacerbations was developed using data from a 52-week phase IIb trial, including 502 patients with asthma randomized to placebo or 70 mg, 210 mg, or 490 mg astegolimab every 4 weeks. Covariate analysis was performed for 20 baseline covariates using the full random effects modeling approach, followed by time-varying covariate analysis of nine covariates using the stepwise covariate model (SCM) building procedure. Following the SCM, an astegolimab treatment effect was explored. Diary-based symptom score (difference in objective function value [dOFV] of -83.7) and rescue medication use (dOFV = -33.5), and forced expiratory volume in 1 s (dOFV = -14.9) were identified as significant time-varying covariates. Of note, time-varying covariates become more useful with more frequent measurements, which should favor the daily diary scores over others. The most influential baseline covariates were exacerbation history and diary-based symptom score (i.e., symptom score was important as both time-varying and baseline covariate). A (nonsignificant) astegolimab treatment effect was included in the final model because the limited data set did not allow concluding the remaining effect size as irrelevant. Without time-varying covariates, the treatment effect was statistically significant (p < 0.01). This work demonstrated the utility of a population RTTE approach to characterize exacerbation hazard in patients with severe asthma.

Mechanisms of immunotherapy: a historical perspective.

OBJECTIVE: To provide a historical review of mechanisms proposed during the last century to explain the efficacy of immunotherapy. DATA SOURCES: We retrieved review articles and original research from MEDLINE, OVID, and PubMed that addressed our topic of interest. STUDY SELECTION: Articles were selected for their relevance to immunotherapy and mechanisms. RESULTS: Early studies focused on the production of blocking antibodies induced by immunotherapy, with mechanistic explanations aimed at understanding a relationship between blocking antibodies and clinical response. This was followed by a period when the effects of immunotherapy on levels and function of effector cells in the allergic response were studied. Aiding in characterization of this response was the discovery of IgE and its role in allergic sensitization, which brought a renewed focus on the antibody-mediated effects of immunotherapy. In an attempt to create a unifying hypothesis to explain humoral and cellular mechanisms of immunotherapy, recent approaches have been focused on the role of the T cell and, specifically, regulatory T cells. CONCLUSIONS: Although the clinical practice of immunotherapy has been refined since its introduction 100 years ago, our understanding of the mechanisms that underlie this success has awaited discoveries in basic immunology.

Development of atopy by severe paramyxoviral infection in a mouse model.

BACKGROUND: Atopic diseases have been increasing in prevalence, yet the initial inciting events that lead to atopy are not understood. Paramyxoviral infections have been suggested to play a role; however, much of these data are correlative. OBJECTIVE: To determine whether exposure to a nonviral antigen during a paramyxoviral infection is sufficient to drive IgE production against the bystander antigen and whether clinical disease against this antigen would result. METHODS: Wild-type C57BL6 mice or mice deficient in FcεRIα (FcεRIα(-/-)) or IgE (IgE(-/-)) were inoculated with Sendai virus (SeV) or UV-inactivated SeV (UV-SeV) and subsequently exposed to ovalbumin (OVA) intranasally. Mice were further challenged 3 times with intranasal OVA on days 20 to 22 after inoculation with SeV, and airway hyperreactivity and mucous cell metaplasia were determined. RESULTS: Exposure to OVA during SeV infection led to significant OVA specific IgE production (median, 548 vs 0 ng/mL; P = .03; SeV vs UV-SeV). This induction of OVA specific IgE production depended on FcεRI because FcεRIα(-/-) mice produced significantly less IgE (112 ng/mL; P = .03; vs wild-type mice). Furthermore, in wild-type mice OVA exposure and challenge significantly enhanced SeV-induced airway hyperreactivity and mucous cell metaplasia, but this failed to occur in either FcεRIα(-/-) or IgE(-/-) mice. CONCLUSION: A single exposure to a bystander allergen during a paramyxoviral infection is sufficient to drive allergen specific IgE production in a partial FcεRI-dependent mechanism. These data begin to provide mechanistic insight into how viral infections might drive development of atopic disease.

Epigenomic programming in early fetal brain development.

Aim: To provide a comprehensive understanding of gene regulatory networks in the developing human brain and a foundation for interpreting pathogenic deregulation. Materials & methods: We generated reference epigenomes and transcriptomes of dissected brain regions and primary neural progenitor cells (NPCs) derived from cortical and ganglionic eminence tissues of four normal human fetuses. Results: Integration of these data across developmental stages revealed a directional increase in active regulatory states, transcription factor activities and gene transcription with developmental stage. Consistent with differences in their biology, NPCs derived from cortical and ganglionic eminence regions contained common, region specific, and gestational week specific regulatory states. Conclusion: We provide a high-resolution regulatory network for NPCs from different brain regions as a comprehensive reference for future studies.