Single-cell immunoprofiling after immunotherapy for allergic rhinitis reveals functional suppression of pathogenic TH2 cells and clonal conversion

Iinuma, Tomohisa; Kiuchi, Masahiro; Hirahara, Kiyoshi; Kurita, Junya; Kokubo, Kota; Yagyu, Hitomi; Yoneda, Riyo; Arai, Toshiyasu; Sonobe, Yuri; Fukuyo, Masaki; Kaneda, Atsushi; Yonekura, Syuji; Nakayama, Toshinori; Okamoto, Yoshitaka; Hanazawa, Toyoyuki

doi:10.1016/j.jaci.2022.06.024

Cited by 23 publications

(9 citation statements)

References 38 publications

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“…This interaction stimulates generation of Th1 cells and Tregs while downregulating Th2 and Th2A cells, analogous to the mechanisms observed in SCIT [ 18 ]. Single-cell immunoprofiling implicated increased expression of musculin (MSC), a transcription factor that represses the activity of Th2 cells, in pathogenic Th2 cells among SLIT-treated patients one year into therapy [ 55 ]. Patients who had a favorable response to SLIT exhibited increases in MSC levels, raising its candidacy as a potential biomarker for clinical efficacy.…”

Section: Immunology Of Subcutaneous and Sublingual Immunotherapymentioning

confidence: 99%

Immunology of allergen immunotherapy

Rahman

Wesemann

2022

Immunotherapy Advances

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Summary Allergen immunotherapy (AIT) is the only disease-modifying therapy for allergic disease. Through repeated inoculations of low doses of allergen—either as whole proteins or peptides—patients can achieve a homeostatic balance between inflammatory effectors induced and/or associated with allergen contact, and mediators of immunologic non-responsiveness, potentially leading to sustained clinical improvements. AIT for airborne/respiratory tract allergens and insect venoms have traditionally been supplied subcutaneously, but other routes and modalities of administration can also be effective. Despite differences of allergen administration, there are some similarities of immunologic responses across platforms, with a general theme involving the restructuring and polarization of adaptive and innate immune effector cells. Here we review the immunology of AIT across various delivery platforms, including subcutaneous, sublingual, epicutaneous, intradermal, and intralymphatic approaches, emphasizing shared mechanisms associated with achieving immunologic non-responsiveness to allergen.

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Section: Immunology Of Subcutaneous and Sublingual Immunotherapymentioning

confidence: 99%

Immunology of allergen immunotherapy

Rahman

Wesemann

2022

Immunotherapy Advances

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“…All of the data were freely available online. In addition, we selected the AR patients of the GSE200107[ 39 ] datasets for further study. The datasets included 14 PBMC samples collected from 7 patients suffering from Japanese cedar pollinosis before and 1 year after SLIT treatment.…”

Section: Methodsmentioning

confidence: 99%

Identification of key genes and the pathophysiology associated with allergen-specific immunotherapy for allergic rhinitis

et al. 2023

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Background Allergen-specific immunotherapy (AIT) is a causative treatment in allergic rhinitis (AR), comprising long-term allergen administration and over three years of treatment. This study is carried out for revealing the mechanisms and key genes of AIT in AR. Methods The present study utilized online Gene Expression Omnibus (GEO) microarray expression profiling dataset GSE37157 and GSE29521 to analyze the hub genes changes related to AIT in AR. Based on limma package, differential expression analysis for the two groups (samples of allergic patients prior to AIT and samples of allergic patients undergoing AIT) was performed to obtain differentially expressed genes (DEGs). Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of DEGs were conducted using DAVID database. A Protein-Protein Interaction network (PPI) was built and a significant network module was acquired by using Cytoscape software (Cytoscape, 3.7.2). Utilizing the miRWalk database, we identified potential gene biomarkers, constructed interaction networks of target genes and microRNAs (miRNAs) using Cytoscape software, and explore the cell type-specific expression patterns of these genes in peripheral blood using publicly available single-cell RNA sequencing data (GSE200107). Finally, we are using PCR to detect changes in the hub genes that are screened using the above method in peripheral blood before and after AIT treatment. Results GSE37157 and GSE29521 included 28 and 13 samples, respectively. A total of 119 significantly co-upregulated DEGs and 33 co-downregulated DEGs were obtained from two datasets. The GO and KEGG analyses demonstrated that protein transport, positive regulation of apoptotic process, Natural killer cell mediated cytotoxicity, T cell receptor signaling pathway, TNF signaling pathway, B cell receptor signaling pathway and Apoptosis may be potential candidate therapeutic targets for AIT of AR. From the PPI network, 20 hub genes were obtained. Among them, the PPI sub-networks of CASP3, FOXO3, PIK3R1, PIK3R3, ATF4, and POLD3 screened out from our study have been identified as reliable predictors of AIT in AR, especially the PIK3R1. Conclusion Our analysis has identified novel gene signatures, thereby contributing to a more comprehensive understanding of the molecular mechanisms underlying AIT in the treatment of AR.

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“…However, it is unclear how Tr1 cells are induced during allergen immunotherapy [ 53 ]. A recent single-cell analysis study using allergen-specific T cell clones obtained from patients with allergic rhinitis suggested that allergen-specific Treg cells differentiate from allergen-specific Th2 cells during sublingual immunotherapy [ 54 ].…”

Section: Immunomodulatory Strategies Activating Regulatory T Cells Fo...mentioning

confidence: 99%

Regulatory T Cell-Targeted Immunomodulatory Therapy for Long-Term Clinical Improvement of Atopic Dermatitis: Hypotheses and Perspectives

Nahm

2023

Life

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Atopic dermatitis (AD) is a chronically relapsing inflammatory skin disorder characterized by itching and eczematous lesions. It is often associated with a personal or familial history of allergic diseases. Allergic inflammation induced by immunoglobulin E and T-helper type 2 (Th2) cell responses to common environmental agents has been suggested to play an essential role in AD pathogenesis. The standard therapies for AD, including topical or systemic agents, focus on controlling skin inflammation. Recently developed monoclonal antibody to interleukin-4 receptor alpha or Janus kinase inhibitors can provide significant clinical improvements in patients with AD by inhibiting Th2 cell-mediated skin inflammation. However, the clinical efficacy of the Th2 cell-targeted therapy is transient and incomplete in patients with AD. Patients with AD are seeking a permanent cure. Therefore, the development of novel immunomodulatory strategies that can improve a long-term clinical outcome and provide a long-term treatment-free clinical remission of AD (disease-modifying therapy) is needed. Regulatory T (Treg) cells play a critical role in the maintenance of immune tolerance and suppress the development of autoimmune and allergic diseases. This review provides three working hypotheses and perspectives for the treatment of AD by Treg cell activation. (1) A decreased number or function of Treg cells is a critical event that causes the activation of Th2 cells, leading to the development and maintenance of AD. (2) Activation of Treg cells is an effective therapeutic approach for AD. (3) Many different immunomodulatory strategies activating Treg cells can provide a long-term clinical improvement of AD by induction of immune tolerance. The Treg cell-targeted immunomodulatory therapies for AD include allergen immunotherapy, microbiota, vitamin D, polyvalent human immunoglobulin G, monoclonal antibodies to the surface antigens of T cell or antigen-presenting cell, and adoptive transfer of autologous Treg cells or genetically engineered Treg cells expanded in vitro.

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Single-cell immunoprofiling after immunotherapy for allergic rhinitis reveals functional suppression of pathogenic TH2 cells and clonal conversion

Cited by 23 publications

References 38 publications

Immunology of allergen immunotherapy

Immunology of allergen immunotherapy

Identification of key genes and the pathophysiology associated with allergen-specific immunotherapy for allergic rhinitis

Regulatory T Cell-Targeted Immunomodulatory Therapy for Long-Term Clinical Improvement of Atopic Dermatitis: Hypotheses and Perspectives

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