Searching for predictive biomarkers of allergen-specific immunotherapy efficacy based on modern concepts of its mechanisms
- Authors: Timoshenko D.O.1, Pavlova K.S.1, Kurbacheva O.M.1,2
-
Affiliations:
- National Research Center ― Institute of Immunology Federal Medical-Biological Agency of Russia
- Moscow State University of Medicine and Dentistry named after A.I. Evdokimov
- Issue: Vol 20, No 2 (2023)
- Pages: 187-200
- Section: Reviews
- URL: https://journals.rcsi.science/raj/article/view/253521
- DOI: https://doi.org/10.36691/RJA7526
- ID: 253521
Cite item
Abstract
Allergen-specific immunotherapy is the primary pathogenetically substantiated method for treating allergic diseases.
This treatment decreases the severity of clinical symptoms, has disease-modifying effects, and prevents disease progression, asthma development, and the spread of sensitization. A complex interaction between various cells of innate and adaptive immunity mediates immunological tolerance driven by allergen-specific immunotherapy. Although the primary mechanisms of allergen-specific immunotherapy have been described to date, the understanding of these processes becomes more detailed at the cellular, molecular, and epigenetic levels each year. As a result, deep insights into the mechanisms underlying the development and maintenance of tolerance to allergens during allergen-specific immunotherapy can help reveal the predictive biomarkers of efficacy. These biomarkers can streamline the selection of patients via the identification of responders to allergen-specific immunotherapy.
This review presents the current concepts of allergen-specific immunotherapy mechanisms at various stages of the allergic process. Furthermore, the predictive biomarkers of the efficacy are described, with consideration of promising directions of research in this area.
Full Text
##article.viewOnOriginalSite##About the authors
Daria O. Timoshenko
National Research Center ― Institute of Immunology Federal Medical-Biological Agency of Russia
Author for correspondence.
Email: d.o.timoshenko@gmail.com
ORCID iD: 0000-0002-7585-1390
SPIN-code: 2714-0906
Post graduate student, MD
Russian Federation, 24 Kashirskoe shosse, 115522 MoscowKsenia S. Pavlova
National Research Center ― Institute of Immunology Federal Medical-Biological Agency of Russia
Email: ksenimedical@gmail.com
ORCID iD: 0000-0002-4164-4094
SPIN-code: 7593-0838
Scopus Author ID: 7004658159
ResearcherId: P-9255-2017
MD, Cand. Sci. (Med.)
Russian Federation, 24 Kashirskoe shosse, 115522 MoscowOksana M. Kurbacheva
National Research Center ― Institute of Immunology Federal Medical-Biological Agency of Russia; Moscow State University of Medicine and Dentistry named after A.I. Evdokimov
Email: kurbacheva@gmail.com
ORCID iD: 0000-0003-3250-0694
SPIN-code: 5698-6436
MD, Dr. Sci. (Med.), Professor
Russian Federation, 24 Kashirskoe shosse, 115522 Moscow; MoscowReferences
- Federal clinical guidelines for allergen-specific immunotherapy. Russian Association of Allergology and Clinical Immunology; 2013. (In Russ). Available from: https://raaci.ru/dat/pdf/7asit.pdf. Accessed: 15.02.2023.
- Muraro A, Roberts G. Translating knowledge into clinical practice Allergen Immunotherapy Guidelines Part 1: Systematic reviews. European Academy of Allergy and Clinical Immunology (EAACI), 2017. 192 р.
- Gushchin IS, Kurbacheva OM. Allergy and allergen-specific immunotherapy. Moscow: Farmus Print Media; 2010. (In Russ).
- Shamji MH, Kappen JH, Akdis M, et al. Biomarkers for monitoring clinical efficacy of allergen immunotherapy for allergic rhinoconjunctivitis and allergic asthma: An EAACI Position Paper. Allergy. 2017;72(8):1156–1173. doi: 10.1111/ALL.13138
- Sözener ZC, Mungan D, Cevhertas L. Tolerance mechanisms in allergen immunotherapy. Curr Opin Allergy Clin Immunol. 2020;20(6):591–601. doi: 10.1097/ACI.0000000000000693
- Kanagaratham C, Ansari Y, Lewis O, et al. IgE and IgG antibodies as regulators of mast cell and basophil functions in food allergy. Front Immunol. 2020;(11):603050. doi: 10.3389/fimmu.2020.603050
- Schmid J, Würtzen P, Siddhuraj P, et al. Basophil sensitivity reflects long-term clinical outcome of subcutaneous immunotherapy in grass pollen-allergic patients. Allergy. 2021;76(5):1528–1538. doi: 10.1111/ALL.14264
- Eljaszewicz A, Ruchti F, Radzikowska U, et al. Trained immunity and tolerance in innate lymphoid cells, monocytes, and dendritic cells during allergen-specific immunotherapy. J Allergy Clin Immunol. 2021;147(5):1865–1877. doi: 10.1016/J.JACI.2020.08.042
- Wen H, Qu L, Zhang Y, et al. A dendritic cells-targeting nano-vaccine by coupling polylactic-co-glycolic acid-encapsulated allergen with mannan induces regulatory T cells. Int Arch Allergy Immunol. 2021;182(9):777–787. doi: 10.1159/000512872
- Sirvent S, Soria I, Cirauqui C, et al. Novel vaccines targeting dendritic cells by coupling allergoids to nonoxidized mannan enhance allergen uptake and induce functional regulatory T cells through programmed death ligand 1. J Allergy Clin Immunol. 2016; 138(2):558–567.e11. doi: 10.1016/J.JACI.2016.02.029
- Soria I, López-Relaño J, Viñuela M, et al. Oral myeloid cells uptake allergoids coupled to mannan driving Th1/Treg responses upon sublingual delivery in mice. Allergy. 2018;73(4):875–884. doi: 10.1111/ALL.13396
- Benito-Villalvilla C, Pérez-Diego M, Angelina A, et al. Allergoid-mannan conjugates imprint tolerogenic features in human macrophages. Allergy. 2022;77(1):320–323. doi: 10.1016/J.JACI.2021.06.012
- Zimmer A, Bouley J, Le Mignon M, et al. A regulatory dendritic cell signature correlates with the clinical efficacy of allergen-specific sublingual immunotherapy. J Allergy Clin Immunol. 2012; 129(4):1020–1030. doi: 10.1016/J.JACI.2012.02.014
- Starchenka S, Heath M, Lineberry A, et al. Transcriptome analysis and safety profile of the early-phase clinical response to an adjuvanted grass allergoid immunotherapy. World Allergy Organ. 2019;12(11):100087. doi: 10.1016/J.WAOJOU.2019.100087
- López J, Imam M, Satitsuksanoa P, et al. Mechanisms and biomarkers of successful allergen-specific immunotherapy. Asia Pac Allergy. 2022;12(4):e45. doi: 10.5415/apallergy.2022.12.e45
- Wambre E, Delong J, James E, et al. Differentiation stage determines pathologic and protective allergen-specific CD4+ T-cell outcomes during specific immunotherapy. J Allergy Clin Immunol. 2012;129(2):544–551,551.e1-7. doi: 10.1016/J.JACI.2011.08.034
- Wambre E, Delong J, James E, et al. Specific immunotherapy modifies allergen-specific CD4(+) T-cell responses in an epitope-dependent manner. J Allergy Clin Immunol. 2014;133(3):872–879.e7. doi: 10.1016/J.JACI.2013.10.054
- Wambre E. Effect of allergen-specific immunotherapy on CD4+ T cells. Curr Opin Allergy Clin Immunol. 2015;15(6):581–587. doi: 10.1097/ACI.0000000000000216
- Dolch A, Kunz S, Dorn B, et al. IL-10 signaling in dendritic cells is required for tolerance induction in a murine model of allergic airway inflammation. Eur J Immunol. 2019;49(2):302–312. doi: 10.1002/EJI.201847883
- Scadding G, Calderon M, Shamji M, et al. Effect of 2 years of treatment with sublingual grass pollen immunotherapy on nasal response to allergen challenge at 3 years among patients with moderate to severe seasonal allergic rhinitis: The GRASS randomized clinical trial. JAMA. 2017;317(6):615–625. doi: 10.1001/JAMA.2016.21040
- Renand A, Shamji M, Harris K, et al. Synchronous immune alterations mirror clinical response during allergen immunotherapy. J Allergy Clin Immunol. 2018;141(5):1750–1760.e1. doi: 10.1016/J.JACI.2017.09.041
- Shamji MH, Durham SR. Mechanisms of allergen immunotherapy for inhaled allergens and predictive biomarkers. J Allergy Clin Immunol. 2017;140(6):1485–1498. doi: 10.1016/j.jaci.2017.10.010
- Zemmour D, Zilionis R, Kiner E, et al. Single-cell gene expression reveals a landscape of regulatory T cell phenotypes shaped by the TCR. Nat Immunol. 2018;19(3):291–301. doi: 10.1038/S41590-018-0051-0
- Scadding G, Shamji M, Jacobson M, et al. Sublingual grass pollen immunotherapy is associated with increases in sublingual Foxp3-expressing cells and elevated allergen-specific immunoglobulin G4, immunoglobulin A and serum inhibitory activity for immunoglobulin E-facilitated allergen binding to B cells. Clin Exp Allergy. 2010; 40(4):598–606. doi: 10.1111/J.1365-2222.2010.03462.X
- Van de Veen W, Akdis M. Tolerance mechanisms of allergen immunotherapy. Allergy. 2020;75(5):1017–1018. doi: 10.1111/ALL.14126
- Boonpiyathad T, van de Veen W, Wirz O, et al. Role of Der p 1-specific B cells in immune tolerance during 2 years of house dust mite-specific immunotherapy. J Allergy Clin Immunol. 2019;143(3):1077–1086.e10. doi: 10.1016/J.JACI.2018.10.061
- Wang CM, Chang CB, Wu SF. Differential DNA methylation in allergen-specific immunotherapy of asthma. Cell Mol Immunol. 2020;17(9):1017–1018. doi: 10.1038/s41423-020-0476-x
- Timoshenko DO, Kofiadi IA, Gudima GO, Kurbacheva OM. Epigenetics of bronchial asthma. Immunologiya. 2021;42(2):93–101. (In Russ). doi: 10.33029/0206-4952-2021-42-2-93-101
- Swamy R, Reshamwala N, Hunter T, et al. Epigenetic modifications and improved regulatory T-cell function in subjects undergoing dual sublingual immunotherapy. J Allergy Clin Immunol. 2012;130(1):215–224.e7. doi: 10.1016/j.jaci.2012.04.021
- Syed A, Garcia M, Lyu S, et al. Peanut oral immunotherapy results in increased antigen-induced regulatory T-cell function and hypomethylation of forkhead box protein 3 (FOXP3). J Allergy Clin Immunol. 2014;133(2):500–510. doi: 10.1016/J.JACI.2013.12.1037
- Wang C, Chang C, Chan M, et al. Dust mite allergen-specific immunotherapy increases IL4 DNA methylation and induces Der p-specific T cell tolerance in children with allergic asthma. Cell Mol Immunol. 2018;15(11):963–972. doi: 10.1038/CMI.2017.26
- Shamji M, Layhadi J, Achkova D, et al. Role of IL-35 in sublingual allergen immunotherapy. J Allergy Clin Immunol. 2019;143(3): 1131–1142.e4. doi: 10.1016/J.JACI.2018.06.041
- Rigas D, Lewis G, Aron J, et al. Type 2 innate lymphoid cell suppression by regulatory T cells attenuates airway hyperreactivity and requires inducible T-cell costimulator-inducible T-cell costimulator ligand interaction. J Allergy Clin Immunol. 2017;139(5): 1468–1477.e2. doi: 10.1016/J.JACI.2016.08.034
- Shamji M, Larson D, Eifan A, et al. Differential induction of allergen-specific IgA responses following timothy grass subcutaneous and sublingual immunotherapy. J Allergy Clin Immunol. 2021;148(4):1061–1071.e11. doi: 10.1016/j.jaci.2021.03.030
- Shamji M, Valenta R, Jardetzky T, et al. The role of allergen-specific IgE, IgG and IgA in allergic disease. Allergy. 2021;76(12): 3627–3641. doi: 10.1111/ALL.14908
- Van de Veen W, Akdis M. Role of IgG4 in IgE-mediated allergic responses. J Allergy Clin Immunol. 2016;138(5):1434–1435. doi: 10.1016/J.JACI.2016.07.022
- Orengo J, Radin A, Kamat V, et al. Treating cat allergy with monoclonal IgG antibodies that bind allergen and prevent IgE engagement. Nat Commun. 2018;9(1):1421. doi: 10.1038/S41467-018-03636-8
- Kolfschoten M, Schuurman J, Losen M, et al. Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange. Science. 2007;317(5844):1554–1557. doi: 10.1126/SCIENCE.1144603
- Heeringa J, McKenzie C, Varese N, et al. Induction of IgG2 and IgG4 B-cell memory following sublingual immunotherapy for ryegrass pollen allergy. Allergy. 2020;75(5):1121–1132. doi: 10.1111/ALL.14073
- Boonpiyathad T, Pradubpongsa P, Mitthamsiri W, et al. Allergen-specific immunotherapy boosts allergen-specific IgD production in house dust mite-sensitized asthmatic patients. Allergy. 2020;75(6):1457–1460. doi: 10.1111/ALL.14133
- Satitsuksanoa P, Daanje M, Akdis M, et al. Biology and dynamics of B cells in the context of IgE-mediated food allergy. Allergy. 2021;76(6):1707–1717. doi: 10.1111/ALL.14684
- Jansen K, Cevhertas L, Ma S, et al. Regulatory B cells, A to Z. Allergy. 2021;76(9):2699–2715. doi: 10.1111/ALL.14763
- Ma S, Satitsuksanoa P, Jansen K, et al. B regulatory cells in allergy. Immunol Rev. 2021;299(1):10–30. doi: 10.1111/IMR.12937
- Van de Veen W, Stanic B, Yaman G, et al. IgG4 production is confined to human IL-10-producing regulatory B cells that suppress antigen-specific immune responses. J Allergy Clin Immunol. 2013;131(4):1204–1212. doi: 10.1016/J.JACI.2013.01.014
- Boonpiyathad T, Meyer N, Moniuszko M, et al. High-dose bee venom exposure induces similar tolerogenic B-cell responses in allergic patients and healthy beekeepers. Allergy. 2017;72(3): 407–415. doi: 10.1111/ALL.12966
- Wang S, Xia P, Chen Y, et al. Regulatory innate lymphoid cells control innate intestinal inflammation. Cell. 2017;171(1):201–216.e18. doi: 10.1016/J.CELL.2017.07.027
- Morita H, Kubo T, Rückert B, et al. Induction of human regulatory innate lymphoid cells from group 2 innate lymphoid cells by retinoic acid. J Allergy Clin Immunol. 2019;143(6):2190–2201.e9. doi: 10.1016/J.JACI.2018.12.1018
- Golebski K, Layhadi J, Sahiner U, et al. Induction of IL-10-producing type 2 innate lymphoid cells by allergen immunotherapy is associated with clinical response. Immunity. 2021;54(2): 291–307.e7. doi: 10.1016/J.IMMUNI.2020.12.013
- Federal clinical guidelines for allergic rhinitis diagnosis and management. 2020. (In Russ). Available from: https://cr.minzdrav.gov.ru/recomend/261_1. Accessed: 15.02.2023.
- Federal clinical guidelines for bronchial asthma diagnosis and management. 2021. (In Russ). Available from: https://cr.minzdrav.gov.ru/recomend/359_2. Accessed: 15.02.2023.
- Shamji MH, Ljørring C, Würtzen PA. Predictive biomarkers of clinical efficacy of allergen-specific immunotherapy: How to proceed. Immunotherapy. 2013;5(3):203–206. doi: 10.2217/imt.13.6
- Muraro A., Roberts G. Translating knowledge into clinical practice Allergen Immunotherapy Guidelines Part 2: Systematic reviews. European Academy of Allergy and Clinical Immunology (EAACI), 2017. 190 р.
- Timoshenko DO, Pavlova KS, Kurbacheva OM, Ilina NI. Molecular allergology place in allergen-specific immunotherapy. Russ J Allergy. 2022;19(3):336–345. (In Russ). doi: 10.36691/RJA1572
- Shamji M, Ljørring C, Francis J, et al. Functional rather than immunoreactive levels of IgG4 correlate closely with clinical response to grass pollen immunotherapy. Allergy. 2012;67(2): 217–226. doi: 10.1111/J.1398-9995.2011.02745.X
- Dahl R, Kapp A, Colombo G, et al. Sublingual grass allergen tablet immunotherapy provides sustained clinical benefit with progressive immunologic changes over 2 years. J Allergy Clin Immunol. 2008;121(2):512–518.e2. doi: 10.1016/J.JACI.2007.10.039
- Gleich G, Zimmermann E, Henderson L, et al. Effect of immunotherapy on immunoglobulin E and immunoglobulin G antibodies to ragweed antigens: A six-year prospective study. J Allergy Clin Immunol. 1982;70(4):261–271. doi: 10.1016/0091-6749(82)90062-8
- Pilette C, Nouri-Aria K, Jacobson M, et al. Grass pollen immunotherapy induces an allergen-specific IgA2 antibody response associated with mucosal TGF-β expression. J Immunol. 2007;178(7):4658–4666. doi: 10.4049/JIMMUNOL.178.7.4658
- Nouri-Aria K, Wachholz P, Francis J, et al. Grass pollen immunotherapy induces mucosal and peripheral IL-10 responses and blocking IgG activity. J Immunol. 2004;172(5):3252–3259. doi: 10.4049/JIMMUNOL.172.5.3252
- Di Lorenzo G, Mansueto P, Pacor M, et al. Evaluation of serum s-IgE/total IgE ratio in predicting clinical response to allergen-specific immunotherapy. J Allergy Clin Immunol. 2009;123(5): 1103–1110,1110.e1-4. doi: 10.1016/J.JACI.2009.02.012
- Fujimura T, Yonekura S, Horiguchi S, et al. Increase of regulatory T cells and the ratio of specific IgE to total IgE are candidates for response monitoring or prognostic biomarkers in 2-year sublingual immunotherapy (SLIT) for Japanese cedar pollinosis. Clin Immunol. 2011;139(1):65–74. doi: 10.1016/J.CLIM.2010.12.022
- Würtzen P, Lund G, Lund K, et al. A double-blind placebo-controlled birch allergy vaccination study II: Correlation between inhibition of IgE binding, histamine release and facilitated allergen presentation. Clin Exp Allergy. 2008;38(8):1290–1301. doi: 10.1111/J.1365-2222.2008.03020.X
- Bohle B, Kinaciyan T, Gerstmayr M, et al. Sublingual immunotherapy induces IL-10-producing T regulatory cells, allergen-specific T-cell tolerance, and immune deviation. J Allergy Clin Immunol. 2007;120(3):707–713. doi: 10.1016/J.JACI.2007.06.013
- Ciepiela O, Zawadzka-Krajewska A, Kotuła I, et al. sublingual immunotherapy for asthma: Affects T-cells but does not impact basophil activation. Pediatric Allergy Immunol Pulmonol. 2014;27(1):17–23. doi: 10.1089/PED.2014.0328
- Schulten V, Tripple V, Seumois G, et al. Allergen-specific immunotherapy modulates the balance of circulating Tfh and Tfr cells. J Allergy Clin Immunol. 2018;141(2):775–777.e6. doi: 10.1016/j.jaci.2017.04.032
- Atkinson A, Colburn W, DeGruttola V, et al. Biomarkers and surrogate endpoints: Preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001;69(3):89–95. doi: 10.1067/MCP.2001.113989
- Shamji M, Wilcock L, Wachholz P, et al. The IgE-facilitated allergen binding (FAB) assay: Validation of a novel flow-cytometric based method for the detection of inhibitory antibody responses. J Immunol Methods. 2006;317(1-2):71–79. doi: 10.1016/J.JIM.2006.09.004
- Shamji M, Francis J, Würtzen P, et al. Cell-free detection of allergen-IgE cross-linking with immobilized phase CD23: Inhibition by blocking antibody responses after immunotherapy. J Allergy Clin Immunol. 2013;132(4):1003–1005.e1-4. doi: 10.1016/J.JACI.2013.05.025
- Liu J, Hu M, Tao X, et al. Salivary IgG4 levels contribute to assessing the efficacy of dermatophagoides pteronyssinus subcutaneous immunotherapy in children with asthma or allergic rhinitis. J Clin Med. 2023;12(4):1665. doi: 10.3390/JCM12041665
- Knol E, Mul F, Jansen H, et al. Monitoring human basophil activation via CD63 monoclonal antibody 435. J Allergy Clin Immunol. 1991;88(3):328–338. doi: 10.1016/0091-6749(91)90094-5
- Ebo D, Bridts C, Mertens C, et al. Analyzing histamine release by flow cytometry (HistaFlow): A novel instrument to study the degranulation patterns of basophils. J Immunol Methods. 2012; 375(1-2):30–38. doi: 10.1016/j.jim.2011.09.003
- Nullens S, Sabato V, Faber M, et al. Basophilic histamine content and release during venom immunotherapy: Insights by flow cytometry. Cytometry B Clin Cytom. 2013;84B(3):173–178. doi: 10.1002/CYTO.B.21084
- Jutel M, Akdis M, Budak F, et al. IL-10 and TGF-beta cooperate in the regulatory T cell response to mucosal allergens in normal immunity and specific immunotherapy. Eur J Immunol. 2003;33(5):1205–1214. doi: 10.1002/EJI.200322919
- Faith A, Richards D, Verhoef A, et al. Impaired secretion of interleukin-4 and interleukin-13 by allergen-specific T cells correlates with defective nuclear expression of NF-AT2 and jun B: relevance to immunotherapy. Clin Exp Allergy. 2003;33(9):1209–1215. doi: 10.1046/J.1365-2222.2003.01748.X
- Ebner C, Siemann U, Bohle B, et al. Immunological changes during specific immunotherapy of grass pollen allergy: Reduced lymphoproliferative responses to allergen and shift from TH2 to TH1 in T-cell clones specific for Phl p 1, a major grass pollen allergen. Clin Exp Allergy. 1997;27(9):1007–1015. doi: 10.1111/J.1365-2222.1997.TB01252.X
- Fanta C, Bohle B, Hirt W, et al. Systemic immunological changes induced by administration of grass pollen allergens via the oral mucosa during sublingual immunotherapy. Int Arch Allergy Immunol. 1999;120(3):218–224. doi: 10.1159/000024270
- Cosmi L, Santarlasci V, Angeli R, et al. Sublingual immunotherapy with Dermatophagoides monomeric allergoid down-regulates allergen-specific immunoglobulin E and increases both interferon-gamma- and interleukin-10-production. Clin Exp Allergy. 2006; 36(3):261–272. doi: 10.1111/J.1365-2222.2006.02429.X
- Wachholz P, Nouri-Aria K, Wilson D, et al. Grass pollen immunotherapy for hayfever is associated with increases in local nasal but not peripheral Th1:Th2 cytokine ratios. Immunology. 2002;105(1):56–62. doi: 10.1046/J.1365-2567.2002.01338.X
- Francis JN, Till SJ, Durham SR. Induction of IL-10+CD4+CD25+T cells by grass pollen immunotherapy. J Allergy Clin Immunol. 2003; 111(6):1255–1261. doi: 10.1067/mai.2003.1570
- Plewako H, Holmberg K, Oancea I, et al. A follow-up study of immunotherapy-treated birch-allergic patients: Effect on the expression of chemokines in the nasal mucosa. Clin Exp Allergy. 2008;38(7):1124–1131. doi: 10.1111/J.1365-2222.2008.03005.X
- Makino Y, Noguchi E, Takahashi N, et al. Apolipoprotein A-IV is a candidate target molecule for the treatment of seasonal allergic rhinitis. J Allergy Clin Immunol. 2010;126(6):1163–1169.e5. doi: 10.1016/J.JACI.2010.06.031
- Li H, Xu E, He M. Cytokine responses to specific immunotherapy in house dust mite-induced allergic rhinitis patients. Inflammation. 2015;38(6):2216–2223. doi: 10.1007/S10753-015-0204-3
- Sakashita M, Yamada T, Imoto Y, et al. Long-term sublingual immunotherapy for Japanese cedar pollinosis and the levels of IL-17A and complement components 3a and 5a. Cytokine. 2015; 75(1):181–185. doi: 10.1016/J.CYTO.2015.03.019
- Scadding G, Eifan A, Lao-Araya M, et al. Effect of grass pollen immunotherapy on clinical and local immune response to nasal allergen challenge. Allergy. 2015;70(6): 689–696. doi: 10.1111/ALL.12608
- Ciprandi G, De Amici M, Murdaca G, et al. Adipokines and sublingual immunotherapy: Preliminary report. Hum Immunol. 2009;70(1):73–78. doi: 10.1016/J.HUMIMM.2008.10.001
- Kirmaz C, Kirgiz O, Bayrak P, et al. Effects of allergen-specific immunotherapy on functions of helper and regulatory T cells in patients with seasonal allergic rhinitis. Eur Cytokine Netw. 2011;22(1):15–23. doi: 10.1684/ECN.2011.0277
- Xie S, Jiang S, Zhang H, et al. Prediction of sublingual immunotherapy efficacy in allergic rhinitis by serum metabolomics analysis. Int Immunopharmacol. 2021;(90):107211. doi: 10.1016/J.INTIMP.2020.107211
- Zheng P, Yan G, Zhang Y, et al. Metabolomics reveals process of allergic rhinitis patients with single- and double-species mite subcutaneous immunotherapy. Metabolites. 2021;11(9):613. doi: 10.3390/METABO11090613
- Shamji M, Layhadi J, Perera-web A, et al. IL-35+ Regulatory T Cells suppress grass pollen-driven Th2 responses and are induced following grass pollen-specific sublingual immunotherapy. J Allergy Clin Immunol. 2013;131(2):AB146. doi: 10.1016/J.JACI.2012.12.1182
- Gueguen C, Bouley J, Moussu H, et al. Changes in markers associated with dendritic cells driving the differentiation of either TH2 cells or regulatory T cells correlate with clinical benefit during allergen immunotherapy. J Allergy Clin Immunol. 2016;137(2): 545–558. doi: 10.1016/j.jaci.2015.09.015
- O’Mahony L, Akdis CA, Eiwegger T. Innate mechanisms can predict successful allergy immunotherapy. J Allergy Clin Immunol. 2016;137(2):559–561. doi: 10.1016/J.JACI.2015.10.047
- Wang C, Chang C, Lee S, et al. Differential DNA methylation profiles of peripheral blood mononuclear cells in allergic asthmatic children following dust mite immunotherapy. J Microbiol Immunol Inf. 2020;53(6):986–995. doi: 10.1016/j.jmii.2020.06.004
- Jakwerth C, Chaker A, Guerth F, et al. Sputum microRNA-screening reveals Prostaglandin EP3 receptor as selective target in allergen-specific immunotherapy. Clin Exp Allergy. 2021;51(12): 1577–1591. doi: 10.1111/CEA.14013