Advances in Allergen Immunotherapy for Asthma

Ioana Agache; Alexandru Laculiceanu; Catalina Cojanu; Daniela Spanu; Liliana Rogoze

Curr Opin Allergy Clin Immunol. 2020;20(6):602-608.

Abstract and Introduction

Abstract

Purpose of Review: Allergen immunotherapy (AIT) is a well-known disease-modifying intervention for allergic diseases. Its benefit in allergic asthma, ranging from prevention to facilitating asthma control, is yet to be clarified.

Recent Findings: In 2017, following several well-designed randomised controlled trials (RCTs) with house-dust mites (HDM) sublingual (SLIT) tablets in asthma, global initiative for asthma (GINA) guidelines highlighted the need to treat the allergic component of asthma. In 2019, the European Academy of Allergy and Clinical Immunology published the first comprehensive guidelines for HDM AIT in allergic asthma, formulating separate recommendations for subcutaneous, SLIT drops, and SLIT tablets. Significant steps were undertaken in understanding the mechanisms of allergic asthma, facilitating the stratified approach for selecting responders and in translating the immune-modulation effect in achieving long-term control of the chronic inflammation in asthma.

Summary: Currently existing guidelines recommend AIT as a therapeutic option in controlled or partially controlled HDM allergic asthma. Limited data are available for pollen, molds and pets, as well as for the severe allergic asthma population. The challenge for the future research will be to clarify the subendotypes of allergic asthma responding to AIT, the mechanisms facilitating its' preventive and disease-modifying effect, the optimal duration of the treatment, and route of administration.

Introduction

Allergic asthma is a high-prevalence chronic disease, especially in the pediatric population where it can account for up to 90% of cases with asthma.^[1–3] It is often persistent although there is a wide variation in disease severity.

Targeted immune modulation of a specific sensitization with allergen immunotherapy (AIT) is the only disease-modifying intervention in allergic diseases, with proven efficacy in allergic rhinitis where it prevents the occurrence of asthma and/or of new sensitizations (primary prevention) and decreases the need for antiinflammatory and rescue medication.^[4–6]

The last years brought a specific focus on asthma primary and secondary prevention and on the potential role of immune modulation as a disease-modifying treatment approach.^[7–9] The introduction of high-quality standardized extracts for AIT together with clinical trials with a specific focus on AIT in asthma has renewed the interest for this immune-modulatory approach in asthma.^[10,11] Newer approaches to AIT are currently being tested including modified allergens, second-generation adjuvants/carriers, and routes of administration, all aiming to increased efficacy with no compromise on safety.^[12–15]

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Next Section

Table 1. Summary of novel developments in AIT mechanisms 2019–2020
AIT mechanism	Key findings	References
Dynamics of the immune response during HDM-SCIT using gene coexpression networks	2-stage 'rewiring': early symptom reduction (during up-dosing) is associated with initial merging of Th2-effector and IL-2/T-regulatory network modules, without major quantitative changes in gene expression The 2nd phase (end of 2nd year) involves fusion with an upregulated type 1 interferon signaling module, potentially stabilizing Th2-antagonistic treatment effects	Jones AC, Anderson D, Troy NM, et al. Rewiring of gene networks underlying mite allergen-induced CD4+ Th-cell responses during immunotherapy [published online ahead of print, 2020 Mar 17]. Allergy. 2020;10.1111/all.14265
T-follicular helper cells	Specialized subset of CD4+ T cells that regulate B-cell responses within the germinal center Enhanced frequency and function in the tonsils of HDM-sensitized children making them specifically amenable to SLIT	Foster WS, Grime CJ, Tan HL, et al. Enhanced frequency and function of follicular T cells in the tonsils of house dust mite-sensitized children. Allergy. 2020;75(5):1240–43
Functional evaluation of Tregs induced by peptide AIT	Tregs induced by peptide AIT express GARP and SATB1 GARP expression is as an activation marker of parasitic infection induced Tregs that strongly suppress allergic inflammation, thus is a novel potential mechanistic pathway for AIT SATB1 is a genome organizer protein expressed in a lineage-specific manner in CD4+ T-cells. SATB1-dependent Treg-cell-specific superenhancers activation is crucial for Treg-cell lineage specification in the thymus During the early Th2-cell differentiation, IL-5 expression is repressed through direct binding of SATB1 to the IL-5 promoter. Thus, SATB1 modulation might expand the impact of AIT on eosinophilic inflammation of particular interest for AIT in asthma	Sharif H, Singh I, Kouser L, et al. Immunologic mechanisms of a short-course of Lolium perenne peptide immunotherapy: a randomized, double-blind, placebo-controlled trial. J Allergy Clin Immunol. 2019;144(3):738–49
Inducible iTR35 cells	iTR35 promote production of IL-10 from CD19+ B cells, Breg subsets and Tfr cells	Sharif H, Singh I, Kouser L, et al. Immunologic mechanisms of a short-course of Lolium perenne peptide immunotherapy: a randomized, double-blind, placebo-controlled trial. J Allergy Clin Immunol 2019;144(3):738–49
Circulating memory-like Tfr cells induced by peptide AIT	Circulating memory-like Tfr share properties of memory cells and persist for long periods Distinct from their lymph nodes counterpart they strongly suppress B and Tfh cells	Sharif H, Singh I, Kouser L, et al. Immunologic mechanisms of a short-course of Lolium perenne peptide immunotherapy: a randomized, double-blind, placebo-controlled trial. J Allergy Clin Immunol 2019;144(3):738–49
The cellular and clonal origin of IgE-memory responses	Following mucosal allergen exposure via SLIT, human IgE memory resides in allergen-specific IgG+ memory B cells. These cells rapidly switch isotype, expand into short-lived IgE+ plasmablasts, and serve as a potential target for therapeutic intervention	Hoof I, Schulten V, Layhadi JA, et al. Allergen-specific IgG+ memory B cells are temporally linked to IgE memory responses. J Allergy Clin Immunol 2020;146(1):180–91
Formation and maintenance of T-memory cells	Specific epigenetic drivers and pathways, highly context-dependent and varying with each subpopulation and location The epigenetic signature has the potential to be modified, which is relevant from a therapeutic perspective	Mikami N, Kawakami R, Chen KY, Sugimoto A, Ohkura N, Sakaguchi S. Epigenetic conversion of conventional T cells into regulatory T cells by CD28 signal deprivation. Proc Natl Acad Sci USA 2020;117(22):12258–68 Hayward SL, Scharer CD, Cartwright EK, et al. Environmental cues regulate epigenetic reprogramming of airway-resident memory CD8+ T cells. Nat Immunol 2020;21(3):309–20
Evaluation of switched memory B cells following AIT	Frequencies and absolute numbers of circulating memory B cells are increased in allergic rhinitis patients. CD23 expression on CD19+ CD20+ CD27+ IgD− switched memory B cells was significantly enhanced and positively correlated with antigen-specific IgE levels, symptom scores, and Tfh2/Tfr cell ratio in allergic rhinitis patients Tfh2 cells from allergic rhinitis patients had a greater capacity to induce CD23 expression on switched memory B cells via IL-4 CD23 expression on switched memory B cells was downregulated after 12-month AIT, which positively associated with disease remission in allergic rhinitis patients	Yao Y, Wang N, Chen CL, et al. CD23 expression on switched memory B cells bridges T-B-cell interaction in allergic rhinitis [published online ahead of print, 2020 Mar 21]. Allergy 2020;10.1111/all.14288
New simpler methods for measuring allergen-specific inhibitory antibody (IgG4) activity	The IgE-FAB utilizes flow cytometry to measure the binding of allergen-IgE complexes to EBV-transformed B cells The ELI-FAB assay uses standard ELISA-based techniques to measure allergen-IgE binding to plate-bound CD23, the low-affinity IgE receptor expressed on B cells	Shamji MH, Francis JN. Measurement of allergen-specific inhibitory antibody activity. Methods Mol Biol 2019;2020:33–43
AIT biomarkers	Nasal IgG4-associated inhibitory activity correlates closely with the clinical response to SCIT in patients with allergic rhinitis with or without asthma	Shamji MH, Kappen J, Abubakar-Waziri H, et al. Nasal allergen-neutralizing IgG4 antibodies block IgE-mediated responses: novel biomarker of subcutaneous grass pollen immunotherapy. J Allergy Clin Immunol. 2019;143(3):1067–76
	IgD producing B cells expansion following HDM-SCIT for asthma correlated with the ability to control asthma	Boonpiyathad T, Pradubpongsa P, Mitthamsiri W, Satitsuksanoa P, Jacquet A, Sangasapaviliya A. Allergen-specific immunotherapy boosts allergen-specific IgD production in house dust mite-sensitized asthmatic patients. Allergy 2020;75(6):1457–60

AIT, Allergen immunotherapy; EBV, Ebstein-Barr virus; ELI-FAB, enzyme-linked immunosorbent-facilitated antigen binding; GARP, glycoprotein A repetitions predominant; HDM, house-dust mites; IgE-FAB, IgE-facilitated allergen binding assay; iTR35, T-regulatory cells secreting IL-35; SATB1, special AT-rich sequence binding protein 1; SLIT, sublingual immunotherapy; Tfh, T follicular helper; Tfr, T-follicular regulatory.

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Advances in Allergen Immunotherapy for Asthma

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