Clinical and Experimental Allergy最新文献

Background: Non-steroidal anti-inflammatory drug-exacerbated respiratory disease (N-ERD) is characterised by the clinical triad of hypersensitivity to NSAIDs, nasal polyposis, and asthma. The cells and mediators causing acute symptoms when driving the hypersensitivity reaction to acetylsalicylic acid (ASA) ingestion, remain poorly defined.

Objective: To investigate the dynamics of nasal mediators during ASA provocation in N-ERD patients before and 24 weeks after therapy with the IL-4 receptor alpha-blocking antibody dupilumab (EudraCT (2019-004889-18) and ClinicalTrials.gov (NCT04442256)).

Methods: Nasal mucosal lining fluids of patients with N-ERD, chronic rhinosinusitis patients with nasal polyp (CRSwNP) and healthy disease controls were collected at selected time points up to 2 h after ASA provocation. Analysis of thirty-three different inflammatory mediators as well as transcriptomic profiling was performed. In N-ERD patients, provocation was repeated after 24 weeks of dupilumab therapy.

Results: Sixty minutes after provocation with ASA, N-ERD patients showed a significant increase in type 2 associated cytokines (i.e., TSLP, IL-5 and eotaxin-3) as compared to the other patient groups. This effect was diminished after 24 weeks of dupilumab therapy and was independent of the development of ASA tolerance. Transcriptomics revealed dampened upregulation of type 2 associated pathway genes (i.e., AREG) as well as enhanced downregulation of lipid (i.e., ALOX15) and peroxisome metabolisms (i.e., NOS2) at ASA provocation after dupilumab therapy.

Conclusion and clinical relevance: Treatment with dupilumab leads to reduced nasal type 2 cytokine secretion and distinct changes in transcriptomic profile during ASA provocation, but changes in type 2 mediators show no association with tolerance development.

Trial registration: EudraCT (2019-004889-18) and ClinicalTrials.gov (NCT04442256).

Introduction: Subcutaneous immunotherapy (SCIT) is a well-established treatment for inducing immune tolerance in patients with allergic rhinitis (AR). However, the precise molecular mechanisms by which SCIT induces immune tolerance, particularly at the transcriptomic level over the treatment course, have not been fully elucidated. This study aimed to investigate the molecular mechanisms of SCIT by analysing changes in peripheral blood gene expression profiles in AR patients over time.

Methods: Whole blood samples were prospectively collected from 30 AR patients (16 paediatric, 14 adult) and 10 healthy controls. RNA sequencing was performed at baseline and at 3, 6 and 12 months of SCIT. Differentially expressed genes (DEGs) were identified, and pathway enrichment, immune cell deconvolution and weighted gene co-expression network analysis were conducted to explore immune regulation and tolerance mechanisms.

Results: AR patients showed 1180 DEGs compared to healthy controls, with upregulated genes related to B-cell activation and downregulated genes linked to Th1 differentiation. Both paediatric and adult cohorts exhibited consistent transcriptomic changes, characterised by progressive normalisation of gene expression, with the number of DEGs decreasing over time and significant convergence towards healthy control profiles by 12 months. SCIT enhanced type I interferon responses and antiviral pathways while reducing B-cell activation and inflammatory responses. Immune cell analysis revealed increased regulatory T cells and dendritic cells by 6 months and reduced Th2 cells and eosinophils by 12 months. Key immune-related hub genes, including CD19, CD79A, CD79B, CD22, IFIH1, STAT1, DHX58, TLR4, IL1B and TLR1, were identified as central to SCIT efficacy.

Conclusion: SCIT dynamically modulates blood gene expression profiles in AR patients, inducing immune tolerance and reducing inflammatory responses. These findings enhance understanding of the molecular mechanisms of SCIT and highlight potential biomarkers for predicting and monitoring treatment efficacy.