Effect of CRTH2 antagonism on the response to experimental rhinovirus infection in asthma: a pilot randomised controlled trial

Background and aimsThe chemoattractant receptor-homologous molecule expressed on T helper type 2 cells (CRTH2) antagonist timapiprant improved lung function and asthma control in a phase 2 study, with evidence suggesting reduced exacerbations. We aimed to assess whether timapiprant attenuated or prevented asthma exacerbations induced by experimental rhinovirus (RV) infection. We furthermore hypothesised that timapiprant would dampen RV-induced type 2 inflammation and consequently improve antiviral immune responses.MethodsAtopic patients with partially controlled asthma on maintenance inhaled corticosteroids were randomised to timapiprant (n=22) or placebo (n=22) and challenged with RV-A16 3 weeks later. The primary endpoint was the cumulative lower respiratory symptom score over the 14 days post infection. Upper respiratory symptoms, spirometry, airway hyperresponsiveness, exhaled nitric oxide, RV-A16 virus load and soluble mediators in upper and lower airways samples, and CRTH2 staining in bronchial biopsies were additionally assessed before and during RV-A16 infection.ResultsSix subjects discontinued the study and eight were not infected; outcomes were assessed in 16 timapiprant-treated and 14 placebo-treated, successfully infected subjects. There were no differences between treatment groups in clinical exacerbation severity including cumulative lower respiratory symptom score day 0–14 (difference 3.0 (95% CI −29.0 to 17.0), p=0.78), virus load, antiviral immune responses, or RV-A16-induced airway inflammation other than in the bronchial biopsies, where CRTH2 staining was increased during RV-A16 infection in the placebo-treated but not the timapiprant-treated group. Timapiprant had a favourable safety profile, with no deaths, serious adverse events or drug-related withdrawals.ConclusionTimapiprant treatment had little impact on the clinicopathological changes induced by RV-A16 infection in partially controlled asthma.

Download Full-text

Type 2 immunity induced by bladder extracellular matrix enhances corneal wound healing

Science Advances ◽

10.1126/sciadv.abe2635 ◽

2021 ◽

Vol 7 (16) ◽

pp. eabe2635

Author(s):

Xiaokun Wang ◽

Liam Chung ◽

Joshua Hooks ◽

David R. Maestas ◽

Andriana Lebid ◽

...

Keyword(s):

Wound Healing ◽

Immune Responses ◽

Smooth Muscle Actin ◽

Treated Group ◽

Interleukin 4 ◽

Impaired Wound Healing ◽

Urinary Bladder Matrix ◽

Incomplete Healing ◽

Haze Formation

The avascular nature of cornea tissue limits its regenerative potential, which may lead to incomplete healing and formation of scars when damaged. Here, we applied micro- and ultrafine porcine urinary bladder matrix (UBM) particulate to promote type 2 immune responses in cornea wounds. Results demonstrated that UBM particulate substantially reduced corneal haze formation as compared to the saline-treated group. Flow cytometry and gene expression analysis showed that UBM particulate suppressed the differentiation of corneal stromal cells into α-smooth muscle actin–positive (αSMA+) myofibroblasts. UBM treatments up-regulated interleukin-4 (IL-4) produced primarily by eosinophils in the wounded corneas and CD4+ T cells in draining lymph nodes, suggesting a cross-talk between local and peripheral immunity. Gata1−/− mice lacking eosinophils did not respond to UBM treatment and had impaired wound healing. In summary, stimulating type 2 immune responses in the wounded cornea can promote proregenerative environments that lead to improved wound healing for vision restoration.

Download Full-text

Ceramides and phospholipids are downregulated with liraglutide treatment: results from the LiraFlame randomized controlled trial

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2021-002395 ◽

2021 ◽

Vol 9 (1) ◽

pp. e002395

Author(s):

Emilie H Zobel ◽

Asger Wretlind ◽

Rasmus S Ripa ◽

Viktor Rotbain Curovic ◽

Bernt J von Scholten ◽

...

Keyword(s):

Type 2 Diabetes ◽

Baseline Level ◽

Controlled Trial ◽

Treated Group ◽

Evidence Base ◽

Lipid Lowering ◽

Double Blind ◽

Mixed Effect ◽

Clinical Covariates

IntroductionTreatment with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) can reduce risk of cardiovascular disease (CVD) in persons living with type 2 diabetes, however the mechanisms explaining this cardiovascular benefit are still debated. We investigated changes in the plasma lipidome following treatment with the GLP-1 RA liraglutide.Research design and methodsIn a double-blind placebo-controlled trial, we randomized 102 persons with type 2 diabetes to liraglutide or placebo for 26 weeks. Fasting blood plasma was collected at baseline and at end-of-treatment. The lipidome was measured using liquid-chromatography-coupled mass-spectrometry as a secondary end point in the study. Treatment response of each lipid was tested with lipid-specific linear mixed-effect models comparing liraglutide with placebo. Bonferroni p<7.1e-03 was employed. The independence of the findings from clinical covariates was evaluated with adjustment for body mass index, HbA1c, fasting status, lipid-lowering treatment and change in lipid-lowering treatment during the trial.ResultsIn total, 260 lipids were identified covering 11 lipid families. We observed significant decreases following liraglutide treatment compared with placebo in 21 lipids (p<7.1e-03) from the following lipid families: ceramides, hexocyl-ceramides, phosphatidylcholines, phosphatidylethanolamines and triglycerides. We confirmed these findings in adjusted models (p≤0.01). In the liraglutide-treated group, the individual lipids were reduced in the range of 14%–61% from baseline level, compared with 19% decrease to 27% increase from baseline level in the placebo group.ConclusionsCompared with placebo, liraglutide treatment led to a significant downregulation in ceramides, phospholipids and triglycerides, which all are linked to higher risk of CVD. These findings were independent of relevant clinical covariates. Our findings are hypothesis generating and shed light on the biological mechanisms underlying the cardiovascular benefits observed with GLP-1 RAs in outcome studies, and further strengthen the evidence base for recommending GLP-1 RAs to prevent CVD in type 2 diabetes.Trial registration numberNCT03449654.

Download Full-text

Novel Type 2-high gene clusters associated with corticosteroid sensitivity in COPD

10.1101/2020.01.22.912022 ◽

2020 ◽

Author(s):

A. Faiz ◽

S. Pavlidis ◽

C.S. Kuo ◽

A. Rowe ◽

P. S. Hiemstra ◽

...

Keyword(s):

Mast Cell ◽

Inhaled Corticosteroids ◽

Gene Clusters ◽

Bronchial Biopsy ◽

Copd Patients ◽

High Signature ◽

Wide Range ◽

Bronchial Biopsies ◽

Long Acting

AbstractRationaleSevere asthma and COPD share common pathophysiologic traits such as relative corticosteroid insensitivity. We recently published three transcriptome-associated clusters (TACs) using hierarchical analysis of the sputum transcriptome in asthmatics from the U-BIOPRED cohort with one Type 2-high signature (TAC1) and 2 Type 2-low signatures.ObjectiveWe examined whether gene-expression signatures obtained in asthma can be used to identify the subgroup of COPD patients with steroid sensitivity.MethodsUsing gene set variation analysis (GSVA), we examined the distribution and enrichment scores (ES) of the 3 TACs in the transcriptome of bronchial biopsies from 46 patients who participated in the GLUCOLD COPD study that received 30 months of treatment with inhaled corticosteroids (ICS) with and without an added long-acting β-agonist (LABA). The identified signatures were then associated with longitudinal clinical variables after treatment.Measurements and main resultsBronchial biopsies in COPD patients at baseline showed a wide range of expression of the 3 TACs. After ICS±LABA treatment, the ES of TAC1 was significantly reduced at 30 months, but those of TAC2 and TAC3 were unaffected. A corticosteroid-sensitive TAC1 (sub)signature was developed from the TAC1 ICS-responsive genes. This signature consisted of mast cell-specific genes identified by single-cell RNA-seq and positively correlated with bronchial biopsy mast cell numbers following ICS±LABA. Baseline levels of gene transcription predicted change in FEV1 %predicted following 30-month ICS±LABA.ConclusionsSputum-derived transcriptomic signatures from an asthma cohort can be recapitulated in bronchial biopsies of COPD patients and identified airway wall mast cells as a predictor of those COPD patients who will benefit from inhaled corticosteroids.

Download Full-text

Effect of Alfacalcidol on multiple sclerosis-related fatigue: A randomized, double-blind placebo-controlled study

Multiple Sclerosis Journal ◽

10.1177/1352458514554053 ◽

2014 ◽

Vol 21 (6) ◽

pp. 767-775 ◽

Cited By ~ 43

Author(s):

Anat Achiron ◽

Uri Givon ◽

David Magalashvili ◽

Mark Dolev ◽

Sigal Liraz Zaltzman ◽

...

Keyword(s):

Multiple Sclerosis ◽

Medical Center ◽

Controlled Trial ◽

Treated Group ◽

Self Report ◽

Controlled Study ◽

Drug Discontinuation ◽

Serious Adverse Events ◽

Double Blind ◽

Mcdonald Criteria

Context: Fatigue is one of the most common and disabling symptoms of multiple sclerosis (MS); however, there is no medication that has been approved specifically to treat MS-related fatigue. Objective: We aimed to evaluate the effect of vitamin D analogue, Alfacalcidol, on MS-related fatigue. Design, settings, participants: This was a randomized, double-blind, parallel group, placebo-controlled trial in patients with clinically definite MS by McDonald criteria conducted in a single university-affiliated medical center in Israel. Randomly selected patients from the Sheba MS Registry computerized database ( N=600) were assessed using the self-report Fatigue Severity Scale (FSS). Patients with clinically meaningful fatigue ( N=259) were further assessed for trial eligibility, and MS patients with significant fatigue ( N=158; 61%, 118 females, mean age 41.1 ± 9.2 years and mean disease duration of 6.2 ± 5.5 years) were included in the study and randomized to receive treatment or placebo. Intervention: Alfacalcidol (1 mcg/d, N=80) or placebo ( N=78) was administered for six consecutive months. Main outcome measure: The primary endpoint of the study was the change between Alfacalcidol and placebo-treated patients in the Fatigue Impact Scale (FIS) score; the cut-off point for improvement was defined as 30% decrease. All analyses followed the intention-to-treat principle and were performed for all participants based on the group they were randomly allocated regardless of whether or not they dropped out. Results: Alfacalcidol decreased the mean relative FIS score as compared with placebo (–41.6% vs. –27.4%, p=0.007, respectively). This advantage was further emphasized when the modified FIS (MFIS) relative change was calculated. Quality of Life (QoL) improved in Alfacalcidol-treated patients as compared with placebo in the RAYS psychological ( p=0.033) and social ( p=0.043) sub-scales. The Alfacalcidol-treated group had reduced number of relapses ( p=0.006) and higher proportion of relapse-free patients ( p=0.007). Reduction of relapses by Alfacalcidol became significant at 4 months of treatment, was sustained at 6 months and decayed 2 months after drug discontinuation. Alfacalcidol treatment was safe and no serious adverse events were recorded. Conclusion: Alfacalcidol is a safe and effective treatment strategy to decrease fatigue and improve QoL in patients with MS.

Download Full-text