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Allergen-specific immunotherapy induces the suppressive secretoglobin 1A1 in cells of the lower airways

ABSTRACT: While several systemic immunomodulatory effects of allergen-specific immunotherapy (AIT) have been discovered, local anti-inflammatory mechanisms in the respiratory tract are largely unknown. We sought to elucidate local and epithelial mechanisms underlying allergen-specific immunotherapy in a genome-wide approach. We induced sputum in hay fever patients and healthy controls during the pollen peak season and stratified patients by effective allergen-immunotherapy or as untreated. Sputum was directly processed after induction and subjected to whole transcriptome RNA microarray analysis. Nasal secretions were analyzed for Secretoglobin1A1 (SCGB1A1) and IL-24 protein levels in an additional validation cohort at three defined time points during the three-year course of AIT. Subsequently, RNA was extracted and subjected to an array-based whole transcriptome analysis. AIT inhibited pro-inflammatory CXCL8, IL24 and CCL26 mRNA expression, while SCGB1A1, IL7, CCL5, CCL23 and WNT5B mRNAs were induced independently of the asthma status and allergen season. In our validation cohort, local increase of SCGB1A1 occurred concomitantly with the reduction of local IL-24 in upper airways during the course of AIT. Additionally, SCGB1A1 was identified as a suppressor of epithelial gene expression.AIT induces a yet unknown local gene expression footprint in the lower airways that on one hand appears to be a result of multiple regulatory pathways and on the other hand reveals SCGB1A1 as novel anti-inflammatory mediator of long-term allergen specific therapeutic intervention in the local environment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE167225 | GEO | 2021/02/24

REPOSITORIES: GEO

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Sputum microRNA‐screening reveals Prostaglandin EP3 receptor as selective target in allergen‐specific immunotherapy

Project description:Several microRNAs (miRs) have been described as potential biomarkers in liquid biopsies and in the context of allergic asthma, while therapeutic effects on the airway expression of miRs remain elusive. In this study, we investigated epigenetic miR-associated mechanisms in the sputum of grass pollen allergic patients with and without allergen specific immunotherapy (AIT). Induced sputum samples of healthy controls (HC), AIT treated and untreated grass pollen allergic rhinitis patients with (AA) and without asthma (AR) were profiled using miR microarray and transcriptome microarray analysis of the same samples. miR targets were predicted in silico and used to identify inverse regulation. Local PGE2 levels were measured using ELISA. Two Hundred and fifty nine miRs were upregulated in the sputum of AA patients compared with HC, while only one was downregulated. The inverse picture was observed in induced sputum of AIT-treated patients: while 21 miRs were downregulated, only 4 miRs were upregulated in asthmatics upon AIT. Of these 4 miRs, miR3935 stood out, as its predicted target PTGER3, the prostaglandin EP3 receptor, was downregulated in treated AA patients compared with untreated. The levels of its ligand PGE2 in the sputum supernatants of these samples were increased in allergic patients, especially asthmatics, and downregulated after AIT. Finally, local PGE2 levels correlated with ILC2 frequencies, secreted sputum IL13 levels, inflammatory cell load, sputum eosinophils and symptom burden.While profiling the sputum of allergic patients for novel miR expression patterns, we uncovered an association between miR3935 and its predicted target gene, the prostaglandin E3 receptor, which might mediate AIT effects through suppression of the PGE2-PTGER3 axis.

2022-05-31 | GSE184382 | GEO

Single cell transcriptomics reveal type-2 inflammatory gene regulation in airway epithelium driven by allergen-specific immunotherapy

Project description:Background: Airway epithelium in patients with allergic airway disease actively releases and is subjected to the influence of type-2 cytokines with observable changes in basal epithelial cells. Symptoms that grass pollen-allergic patients experience due to this priming can be controlled by allergen-specific immunotherapy (AIT). However, the impact of AIT on type-2 related mediators of airway epithelial cells is unknown. Methods: Protein levels of type-2 cytokines in nasal secretions of grass pollen-allergic patients were analyzed during 3-year AIT-regimen using multiplex-ELISA. Source and IL-4-dependence of type-2 cytokines were examined in IL-4-primed primary ALI cultures using single-cell transcriptomics. Results: Type-2 cytokines CCL-26 and POSTN oscillated seasonally, derived from basal epithelial cells and were induced by IL-4-priming. In contrast, TSLP and IL-33 derived from basal cells, albeit independently of IL-4. POSTN and IL-24 nasal levels changed corresponding to 3-year AIT progression. Four characteristic epithelial type-2 cytokines stood out: IL-33 changed independent of season, IL-4-exposure, or AIT; CCL-26 was triggered upon IL-4-priming and was induced during pollen season, but not influenced by AIT; IL-24 decreased following three years of AIT; and POSTN, which was increased in IL-4-primed basal epithelial cells and oscillated during pollen season, also responded to long-term AIT. Conclusions: Atopic reprogramming of type-2 epithelial cytokines seems to persist despite long-term AIT, which may be one mechanism explaining why AIT only restores allergen tolerance for seven to ten years. Type-2 related epithelial cytokines are differentially expressed which may relate to the distinct expression of basal as opposed to differentiated secretory or ciliated epithelial cells.

2023-03-31 | GSE203248 | GEO

Multiomics approaches disclose very-early molecular and cellular switches during insect-venom allergen-specific immunotherapy: an observational study

Project description:Allergen-specific immunotherapy (AIT) induces immune tolerance, showing the highest success rate (>95%) for insect venom while a much lower chance for pollen allergy. However, the molecular switches leading to successful durable tolerance restoration remain elusive. Here we applied a multilayer-omics approach to reveal dynamic peripheral immune landscapes during AIT-initiation phase in venom allergy patients (VAP) versus pollen-allergic and healthy controls. Already at baseline, VAP exhibited altered abundances of several cell types, including classical monocytes (cMono) and CD4/CD8 type 1-type 17 hybrids. At 8-24h following AIT launch in VAP, we identified a uniform AIT-elicited pulse of late-transitional/IL-10-producing B cells, IL-6 signaling within Th2 cells and non-inflammatory serum-IL-6 levels. Sequential induction of activation and survival protein markers also immediately occurred. A disequilibrium between serum IL-6 and cMono in VAP baseline was restored at day seven following AIT launch. Our longitudinal analysis discovers molecular switches during initiation-phase insect-venom AIT that secure long-term outcomes. Trial number: NCT02931955.

2024-10-30 | GSE240503 | GEO

scRNA-seq analysis of enriched CD4+ T cells from lung tissues after single or combined AIT treatment strategies with AhR agonist 10-Cl-BBQ in a murine model of OVA-induced allergic airway inflammation (AAI)

Project description:Allergen-specific immunotherapy (AIT) is able to restore immune tolerance to allergens in allergic patients. However, some patients do not or only poorly respond to current treatment protocols. Therefore, there is a need for deeper mechanistic insights and further improvement of treatment strategies. AIT was combined with the application of the high-affinity AhR agonist 10-chloro-7H-benzimidazo[2,1-a]benzo[de]iso-quinolin-7-one (10-Cl-BBQ) as an adjuvant to investigate the effects of AhR activation on therapeutic outcome in a murine model of OVA-induced AAI. To assess differences in Th cell populations CD4+ T cells from the lung tissue were enriched and subjected to sc-RNAseq analysis.

2024-05-06 | E-MTAB-14030 | biostudies-arrayexpress

Effect of Intradermal Immunotherapy (IDIT) injections on gene expression profiles of activated T cells derived from skin biopsy explants

Project description:A Randomized, Placebo-Controlled Trial of Intradermal Allergen Immunotherapy for Grass Pollen Allergy Background: Repeated intradermal injection of grass pollen (nanograms of allergen) suppresses allergen-induced cutaneous late phase responses, in keeping with effects of conventional high dose subcutaneous and sublingual immunotherapy. We evaluated the efficacy and safety of grass pollen intradermal immunotherapy for treatment of allergic rhinitis.Methods: We randomly assigned 93 adults with grass pollen allergic rhinitis to receive 7 pre-seasonal Intradermal allergen immunotherapy injections (containing 7 ng of Phl p 5 major allergen) or histamine control. The primary end point was daily combined symptom-medication scores during the 2013 pollen season. Skin biopsies were taken after the pollen season following an intradermal allergen challenge. Cutaneous late phase responses were measured 4 and either 7, 10 or 13 months post-treatment. Results No difference in the primary endpoint was observed between treatment arms (median difference, 14; 95% confidence interval [CI], -172.5 to 215.1; P=0.80). Amongst secondary endpoints, nasal symptoms measured with daily scores (median difference, 35; 95% CI, 4.0 to 67.5; P=0.03) and visual-analogue scales (median difference, 53; 95% CI, -11.6 to 125.2; P=0.05) were higher in the intradermal treatment group. Intradermal immunotherapy increased serum Phl p-specific IgE (P=0.001) compared to the control arm and T cells cultured from biopsies showed higher and lower surface of surface markers for Type 2 (P=0.04) and Type 1 (P=0.01) T-helper cells, respectively, Interleukin-5 was differentially expressed by microarray (P=0.03). Late phase responses were still inhibited 7 months after treatment (P=0.03) but not at 10-13 months. Conclusions Grass pollen intradermal allergen immunotherapy was not clinically effective but resulted in immunological priming and worsening of allergic rhinitis symptoms.

2017-06-23 | GSE72324 | GEO

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2018-10-29 | GSE118243 | GEO

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Induced Sputum Genes Associated With Spirometroc and Radiological Disease Severity in COPD Ex-smokers

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