How does allergen immunotherapy‐induced tolerance improve the airway epithelial barrier function: A mechanistical‐driven hypothesis

In recent years, there has been a growing emphasis on understanding the critical importance of the epithelial barrier and exploring various mechanisms that contribute to the onset and progression of allergic, autoimmune, and neurodegenerative disorders. The epithelial barrier hypothesis clarifies the impact of environmental factors, such as allergens, climate change, pollution, biodiversity changes, altered external exposome, and protease enzymes on the integrity of epithelial barriers, leading to a type 2 immune response.1, 2 To address this, mitigation strategies involve implementing strict regulations, making global policy adjustments, educating patients, and developing personalized treatment approaches.3 This editorial specifically examines these findings in the context of respiratory allergies and the immunomodulatory effects of allergen immunotherapy (AIT). Our aim is to provide a comprehensive perspective on the advancements in our understanding of the nonallergen-specific benefits of AIT in the management of allergic respiratory diseases. Allergen immunotherapy is the only disease-modifying treatment of allergic diseases with long-term and sustained effects following cessation of treatment.4 Although the specific effects of AIT on allergen tolerance are widely documented, emerging evidence indicates the induction of substantial and nonallergen-specific advantages resulting from the treatment. Several double-blind, placebo-controlled (DBPC) trials have indicated novel and interesting perspectives on the use of AIT. In the GRAZAX® asthma prevention (GAP) trial, children treated with the SQ grass SLIT tablet had a significantly reduced risk of developing asthma symptoms and to use asthma medication.5 This was, surprisingly, not only observed in summer during grass pollen exposure but also during winter without grass pollen exposure. Analyzing the number-needed-to-treat (NNT) for preventing asthma symptoms and medication use in children over a 2-year follow-up period, it was found that the NNT was lower in younger children. This suggests that initiating AIT early on can be recommended to maximize the potential preventive effects.5 Results from another clinical trial of SQ house dust mite (HDM)-SLIT in patients with AR to HDM showed that patients sensitized to grass and/or tree allergens had a greater reduction in the use of symptomatic pharmacotherapy during grass pollen exposure, suggesting a beneficial effect on grass-pollen-induced rhinitis and a more stabilized or natural functioning airway epithelium (unpublished results data on file).6 Furthermore, a recent meta-analysis of AIT in randomized controlled trials and nonrandomized controlled trials proposed that AIT indeed has possible preventative effects on the onset of new allergic sensitizations and the development of asthma and, furthermore, highlighted that the effect of AIT might be particularly significant when administered in mono-sensitized children and for at least 3 years.7 In a recently published DBPC trial, treatment with the SQ HDM-SLIT tablet significantly enhanced interferon (IFN)-ß and IFN-λ and decreased IL-33, indicative of improved innate airway epithelial responses to viral infection suggesting a causal link for the preventive effects seen on asthma exacerbations.8 In allergic mice exposed to HDM, allergen immunotherapy (AIT) effectively ameliorated airway inflammatory infiltration and airway hyperreactivity and restored epithelial integrity by suppressing IL-25-induced endoplasmic reticulum stress.9 Other trials have also investigated the potential of enhancing the epithelial barrier to reduce airway inflammation caused by inhaled particles. For instance, a cross-over double-blind, randomized controlled trial involving six mild atopic steroid-naïve asthmatic subjects demonstrated that three doses of an inhaled cationic airway lining modulator had well-tolerated effects, resulting in attenuation of allergen-induced sputum eosinophils and reduction of IL-5, MCP-1, and eotaxin levels.10 Moreover, a separate study identified the human CST1 protein as an inhibitor of allergenic protease activity, effectively safeguarding the bronchial epithelial barrier in individuals with asthma, and suggesting CST1 as a promising biomarker for asthma control.11 The findings from real-world evidence studies provide a valuable complement to those from randomized controlled trials, as they reflect the practical application of evidence-based treatments in real-world settings. Allergen sensitization, exposure, and viral infections are significant risk factors for asthma exacerbation and pneumonia and hospitalizations; however, AIT significantly reduces these risks.12, 13 All these findings indicate that AIT not only has the widely known allergen-specific but also nonallergen-specific effects, like reduction of infections or pneumonia, reduced use of antibiotics or even an effect on respiratory allergic symptoms that are not induced by the allergens used for treatment. How can these effects be explained? Built on clinical evidence, a critical role for the respiratory epithelium in the onset and perpetuation of airway allergic inflammation is suggested. The epithelium may, thus, also be an important component to consider for immune modulation. A novel concept regarding the migration of allergens in the airways of allergic individuals has emerged. It has been elucidated that allergens can be absorbed directly by the epithelium, undergo lysosomal processing, and then be presented on epithelial MHC class II molecules, facilitating direct interaction with intraepithelial lymphocytes.14 Besides the direct uptake, proteolytic allergens such as HDM-derived Der p 1 and Der p 2 have been demonstrated to disrupt tight and adherent junctions allowing for paracellular migration and increased airway epithelial permeability.15 Furthermore, proteolytic allergens have also been demonstrated to signal through protease-activated-receptors (PARs) which, together with the disruption of cell–cell contacts, can lead to increased inflammation, immune cell recruitment, airway hyperresponsiveness, mucus production, and tissue remodeling. Increased mucus production by allergen-driven epithelial inflammasome activation may, furthermore, increase epithelial cell necrosis and drive IL-1-dependent inflammation. In sensitized individuals, CD23-dependent transcytosis of IgE–allergen complex formation was critical for the perpetuation of allergic diseases.16 The airway epithelium expresses multiple receptors for allergen interactions such as toll-like-receptors (TLR), PARs, and the low-affinity IgE receptor (CD23, FcεRII) that perpetuate allergic inflammation which may, thus, potentially be abrogated by the treatment with AIT (Figure 1). Especially, allergen activation of TLR-4 and PAR-2 by Der p has been demonstrated to enhance downstream allergic inflammation and T2 immunity. While HDM-impairment of TLR-3, retinoic acid-inducible gene (RIG)-I, and nuclear factor kappa light chain enhancer of activated B cells (NFκβ) has been linked with abrogated antiviral responses.17-19 Thus, impaired antiviral responses may lead to viral propagation, increased epithelial damage, and uncontrolled airway inflammation considered the key component in the development of asthma exacerbations. Blocking allergen–IgE cross-linking of the FcεRI on plasmacytoid dendritic cells increased the antiviral release of IFN-α and was associated with a significant reduction in virus-triggered exacerbation in allergic children. AIT might share similarities in this regard by the induction of blocking IgG4, but at a permanent level in contrast to the temporary effects of mABs. AIT induces immune tolerance by causing changes in the repertoire of systemic innate immune cells. This includes the induction of a new regulatory subset of tolerogenic IL-10+ ILC2 cells with a critical role in restoring epithelial cell integrity, suppressing type 2 responses, and promoting tolerance to aeroallergens.20 In conclusion, AIT-induced immune tolerance reduces the airway epithelial inflammation, restores the barrier function, and improves timely interferon release, resulting in a reduced risk of infection by viruses and bacteria and decreased allergen penetration. None. Oliver Pfaar reports grants and/or personal fees from ALK-Abelló, Allergopharma, Stallergenes Greer, HAL Allergy Holding B.V./HAL Allergie GmbH, Bencard Allergie GmbH/Allergy Therapeutics, Lofarma, ASIT Biotech Tools S.A., Laboratorios LETI/LETI Pharma, GlaxoSmithKline, ROXALL Medizin, Novartis, Sanofi-Aventis and Sanofi-Genzyme, Med Update Europe GmbH, streamedup! GmbH, Pohl-Boskamp, Inmunotek S.L., John Wiley and Sons, AS, Paul-Martini-Stiftung (PMS), Regeneron Pharmaceuticals Inc., RG Aerztefortbildung, Institut für Disease Management, Springer GmbH, AstraZeneca, IQVIA Commercial, Ingress Health, Wort&Bild Verlag, Verlag ME, Altamira Medica AG, Meinhardt Congress GmbH, Deutsche Forschungsgemeinschaft, Thieme, Deutsche AllergieLiga e.V., AeDA, Königlich Dänisches Generalkonsulat, Procter and Gamble, Alfried-Krupp Krankenhaus, Red Maple Trials Inc., Technical University Dresden, ECM Expo& Conference Management, all outside the submitted work; and he is a member of EAACI Excom, a member of ext. board of directors DGAKI; a coordinator, main- or co-author of different position papers and guidelines in rhinology, allergology, and allergen-immunotherapy. Benedikt Fritzsching reports personal fees/speaker honorarium from Abbvie, ALK, Merck Sharp & Dohme, Novartis, Stallergenes Greer, RG Aerztefortbildung, Institut für Disease Management, Springer GmbH. Hendrik Wolf is employee of ALK and holds stock options of ALK. Christian Woehlk is temporarily employed by ALK. Eike Wüstenberg is employee of ALK and holds stock options of ALK. E. Wüstenberg and H. Wolf made the concept, performed the literature search, and wrote the first draft of the manuscript together with C. Woehlk. O. Pfaar coordinated the further development from draft stage and also contributed together with B. Fritzsching from draft stage by literature search, thorough and critical review and amendment of the manuscript where useful. All authors approved submission of the final manuscript. The data that support the findings of this study are available from the corresponding author upon reasonable request.