Mechanisms in AIT: Insights 2021

Background: Allergen-specific immunotherapy (AIT) is currently the only treatment with potential long-term disease-modifying effects for patients suffering from allergic diseases such as allergic rhinitis, allergic asthma, venom allergy, or IgE-mediated food allergy. A better understanding of the molecular mechanisms underlying immune responses during successful AIT is of utmost importance and it may help to develop more effective and safer treatments. Materials and methods: PubMed literature review was performed using keywords such as allergen-specific immunotherapy; regulatory T cells; regulatory B cells; regulatory innate lymphoid cells; and allergen-specific antibody from years 2018 to 2021. Results: The proposed mechanism of long-term tolerance induction in AIT, even upon treatment discontinuation, involves basophils, mast cells, innate lymphoid cells, dendritic cells, allergen-specific regulatory T and B cells, downregulation of effector type 2 responses, decrease in the production of IgE and increase in production of allergen-specific blocking antibodies, such as IgG2 and IgG4. Conclusion: We summarize the most recent advances related to mechanisms involved in the restoration of healthy immune responses to allergens during AIT. Our knowledge in this regard has significantly improved over the last years, which might well contribute to design novel and improved therapeutic approaches.

[1]  J. Subiza,et al.  Allergoid‐mannan conjugates imprint tolerogenic features in human macrophages , 2021, Allergy.

[2]  C. Akdis,et al.  Cannabinoids induce functional Tregs by promoting tolerogenic DCs via autophagy and metabolic reprograming , 2021, Mucosal immunology.

[3]  Da Huo,et al.  A Dendritic Cells-Targeting Nano-Vaccine by Coupling Polylactic-Co-Glycolic Acid-Encapsulated Allergen with Mannan Induces Regulatory T Cells , 2021, International Archives of Allergy and Immunology.

[4]  S. Sánchez-Ramón,et al.  Editorial: Trained Immunity-Based Vaccines , 2021, Frontiers in Immunology.

[5]  S. Durham,et al.  The role of allergen‐specific IgE, IgG and IgA in allergic disease , 2021, Allergy.

[6]  A. Togias,et al.  Differential Induction of Allergen-specific IgA Responses following Timothy Grass Subcutaneous and Sublingual Immunotherapy. , 2021, The Journal of allergy and clinical immunology.

[7]  M. Akdiş,et al.  Regulatory B cells, A to Z , 2021, Allergy.

[8]  Feng Q. He,et al.  Induction of IL-10-producing type 2 innate lymphoid cells by allergen immunotherapy is associated with clinical response. , 2021, Immunity.

[9]  I. Pali-Schöll,et al.  Allergens and Adjuvants in Allergen Immunotherapy for Immune Activation, Tolerance, and Resilience. , 2021, The journal of allergy and clinical immunology. In practice.

[10]  M. Akdiş,et al.  B regulatory cells in allergy , 2020, Immunological reviews.

[11]  H. Oettgen,et al.  IgE and IgG Antibodies as Regulators of Mast Cell and Basophil Functions in Food Allergy , 2020, Frontiers in Immunology.

[12]  S. Boyd,et al.  Biology and dynamics of B cells in the context of IgE‐mediated food allergy , 2020, Allergy.

[13]  U. Jappe,et al.  Trained immunity and allergy: State of the art and future perspectives , 2020, Allergy.

[14]  C. Akdis,et al.  Trained immunity and tolerance in innate lymphoid cells, monocytes, and dendritic cells during allergen-specific immunotherapy. , 2020, The Journal of allergy and clinical immunology.

[15]  P. Tassinari,et al.  Omalizumab restores the ability of human plasmacytoid dendritic cells to induce Foxp3+Tregs , 2020, European Respiratory Journal.

[16]  M. Akdiş,et al.  Tolerance mechanisms of allergen immunotherapy , 2020 .

[17]  R. Dahl,et al.  Basophil sensitivity reflects long‐term clinical outcome of subcutaneous immunotherapy in grass pollen‐allergic patients , 2020, Allergy.

[18]  M. V. van Zelm,et al.  Induction of IgG2 and IgG4 B‐cell memory following sublingual immunotherapy for ryegrass pollen allergy , 2019, Allergy.

[19]  E. Fernández‐Caldas,et al.  Alum impairs tolerogenic properties induced by allergoid‐mannan conjugates inhibiting mTOR and metabolic reprogramming in human DCs , 2019, Allergy.

[20]  G. Nilsson,et al.  Induction of human regulatory innate lymphoid cells from group 2 innate lymphoid cells by retinoic acid. , 2019, The Journal of allergy and clinical immunology.

[21]  C. Akdis,et al.  Der p 1‐specific regulatory T‐cell response during house dust mite allergen immunotherapy , 2019, Allergy.

[22]  S. Durham,et al.  Nasal allergen‐neutralizing IgG4 antibodies block IgE‐mediated responses: Novel biomarker of subcutaneous grass pollen immunotherapy , 2019, The Journal of allergy and clinical immunology.

[23]  C. Akdis,et al.  Role of Der p 1–specific B cells in immune tolerance during 2 years of house dust mite–specific immunotherapy , 2019, The Journal of allergy and clinical immunology.

[24]  F. Alessandrini,et al.  IL‐10 signaling in dendritic cells is required for tolerance induction in a murine model of allergic airway inflammation , 2019, European journal of immunology.

[25]  M. Pybus,et al.  Secreted IgD Amplifies Humoral T Helper 2 Cell Responses by Binding Basophils via Galectin‐9 and CD44 , 2018, Immunity.

[26]  M. Akdiş,et al.  Mechanisms of allergen-specific immunotherapy: Diverse mechanisms of immune tolerance to allergens. , 2018, Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology.

[27]  O. Palomares,et al.  Novel vaccines targeting dendritic cells by coupling allergoids to mannan , 2018, Allergo Journal International.

[28]  Allon M Klein,et al.  Single-cell gene expression reveals a landscape of regulatory T cell phenotypes shaped by the TCR , 2018, Nature Immunology.

[29]  B. Cases,et al.  Oral myeloid cells uptake allergoids coupled to mannan driving Th1/Treg responses upon sublingual delivery in mice , 2018, Allergy.

[30]  Zhiheng Xu,et al.  Regulatory Innate Lymphoid Cells Control Innate Intestinal Inflammation , 2017, Cell.

[31]  K. Ruxrungtham,et al.  High‐dose bee venom exposure induces similar tolerogenic B‐cell responses in allergic patients and healthy beekeepers , 2017, Allergy. European Journal of Allergy and Clinical Immunology.

[32]  M. Akdiş,et al.  Role of IgG4 in IgE-mediated allergic responses. , 2016, The Journal of allergy and clinical immunology.

[33]  P. Reche,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. , 2016, The Journal of allergy and clinical immunology.

[34]  C. Akdis,et al.  IgG4 production is confined to human IL-10-producing regulatory B cells that suppress antigen-specific immune responses. , 2013, The Journal of allergy and clinical immunology.

[35]  D. Isenberg,et al.  Lipid-Antigen Presentation by CD1d+ B Cells Is Essential for the Maintenance of Invariant Natural Killer T Cells , 2012, Immunity.

[36]  S. Durham,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 , 2010, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[37]  Trained Immunity-based Vaccines , 2021, Frontiers Research Topics.

[38]  S. Durham,et al.  Allergen immunotherapy and tolerance. , 2013, Allergology international : official journal of the Japanese Society of Allergology.

[39]  Allergens and Adjuvants in Allergen Immunotherapy for Immune Activation, Tolerance, and Resilience , 2022, The Journal of Allergy and Clinical Immunology: In Practice.