Nasal and blood transcriptomic pathways underpinning the clinical response to grass pollen immunotherapy
File(s)
Accepted version
Supporting information
Author(s)
Type
Journal Article
Abstract
BACKGROUND: Allergen immunotherapy (AIT) is a well-established disease-modifying therapy for allergic rhinitis, yet the fundamental mechanisms underlying its clinical effect remain inadequately understood. OBJECTIVE: The GRASS study was a randomized, double-blind, placebo-controlled trial of timothy grass allergic individuals who received 2 years of placebo (n=30), subcutaneous (SCIT) (n=27), or sublingual immunotherapy (SLIT) (n=27) and were then followed for 1 additional year. Here we used yearly biospecimens from the GRASS study to identify molecular mechanisms of response. METHODS: We utilized longitudinal transcriptomic profiling of nasal brush and peripheral blood mononuclear cell (PBMC) samples after allergen provocation to uncover airway and systemic expression pathways mediating responsiveness to AIT. RESULTS: SCIT and SLIT demonstrated similar changes in gene module expression over time. In nasal samples, alterations included downregulation of pathways of mucus hypersecretion, leukocyte migration/activation, and endoplasmic reticulum stress (log2 fold changes (logFC) -0.133 to -0.640, FDRs <0.05). Interestingly, we observed upregulation of modules related to epithelial development, junction formation, and lipid metabolism (logFC 0.104 to 0.393, FDRs <0.05). In PBMCs, modules related to cellular stress response and type 2 cytokine signaling were reduced by immunotherapy (logFC -0.611 to -0.828, FDRs <0.05). Expression of these modules was also significantly associated with both Total Nasal Symptom Score and Peak Nasal Inspiratory Flow responses, indicating important links among treatment, module expression, and allergen response. CONCLUSION: Our results identify specific molecular responses of the nasal airway impacting barrier function, leukocyte migration activation, and mucus secretion, that are affected by both SCIT and SLIT, offering potential targets to guide novel strategies for AIT.
Date Issued
2023-11-01
Date Acceptance
2023-06-01
Citation
Journal of Allergy and Clinical Immunology, 2023, 152 (5), pp.1247-1260
ISSN
0091-6749
Publisher
Elsevier
Start Page
1247
End Page
1260
Journal / Book Title
Journal of Allergy and Clinical Immunology
Volume
152
Issue
5
Copyright Statement
© 2023 Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology. This manuscript version is made available under the CC-BY-NC-ND 4.0 license https://creativecommons.org/licenses/by-nc-nd/4.0/
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/37460024
PII: S0091-6749(23)00890-4
Subjects
Allergen immunotherapy
allergic rhinitis
RNA sequencing
Subcutaneous immunotherapy
Sublingual immunotherapy
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2023-07-15