Genetic restriction of antigen-presentation dictates allergic sensitization and disease in humanized mice

Abstract

BackgroundImmunoglobulin(Ig)E-associated allergies result from misguided immune responses against innocuous antigens. CD4+ T lymphocytes are critical for initiating and perpetuating that process, yet the crucial factors determining whether an individual becomes sensitized towards a given allergen remain largely unknown.ObjectiveTo determine the key factors for sensitization and allergy towards a given allergen.MethodsWe here created a novel human T cell receptor(TCR) and human leucocyte antigen (HLA)-DR1 (TCR-DR1) transgenic mouse model of asthma, based on the human-relevant major mugwort (Artemisia vulgaris) pollen allergen Art v 1 to examine the critical factors for sensitization and allergy upon natural allergen exposure via the airways in the absence of systemic priming and adjuvants.ResultsAcute allergen exposure led to IgE-independent airway hyperreactivity (AHR) and T helper(Th)2-prone lung inflammation in TCR-DR1, but not DR1, TCR or wildtype (WT) control mice, that was alleviated by prophylactic interleukin(IL)-2-αIL-2 mAb complex-induced expansion of Tregs. Chronic allergen exposure sensitized one third of single DR1 transgenic mice, however, without impacting on lung function. Similar treatment led to AHR and Th2-driven lung pathology in >90% of TCR-DR1 mice. Prophylactic and therapeutic expansion of Tregs with IL-2-αIL-2 mAb complexes blocked the generation and boosting of allergen-specific IgE associated with chronic allergen exposure.ConclusionsWe identify genetic restriction of allergen presentation as primary factor dictating allergic sensitization and disease against the major pollen allergen from the weed mugwort, which frequently causes sensitization and disease in humans. Furthermore, we demonstrate the importance of the balance between allergen-specific T effector and Treg cells for modulating allergic immune responses.

A hypoallergenic peptide mix containing T cell epitopes of the clinically relevant house dust mite allergens

“…HLA‐restricted allergen presentation has been suggested already earlier to be associated with IgE recognition of allergens . A recent study performed in mice transgenic for an allergen‐specific human T cell receptor, for the corresponding human HLA molecule and for both, has also provided support for the existence of a genetic restriction of allergen recognition …”

“…35,36 A recent study performed in mice transgenic for an allergen-specific human T cell receptor, for the corresponding human HLA molecule and for both, has also provided support for the existence of a genetic restriction of allergen recognition. 37 In our study, we have defined a hypoallergenic peptide mix including also Der p 5, 7, and 21. T cell epitopes were spread over the whole sequences of Der p 1, 2, 5, 7, 21, and 23, which was in agreement with former studies on T cell epitopes of Der p 1, 2, and 23.…”

All the small things: How virus‐like particles and liposomes modulate allergic immune responses

“…For that purpose, they relied on the full‐length major mugwort pollen allergen Art v 1 fused to the MoMLV matrix protein p15, which targets any fusion partner, so also the allergen, to the inside of the MoMLV VNP envelope. In a new mouse model of mugwort allergy , these authors could show that such VNP preparations are non‐anaphylactogenic and non‐sensitizing (IgE inducing) but instead able to induce tolerance if applied intranasally . To corroborate these finding, the authors plan to screen more patient sera and also plan to perform basophil activation tests with whole blood of mugwort allergic individuals.…”

“…For these reasons, it appeared likely that, in principle, modulation with the help of VNP the allergen-specific immune responses at the level of T cell activation could be successful. To circumvent the necessity for the display of a collection of HLA/peptide combinations on VNP in a patient-tailored way for the treatment of allergic individuals, Kratzer et al explored a clever alternative strategy by expressing full-length allergens in a non-anaphylactic and non-IgE inducing form, by encapsulating them within MoMLV VNP [105]. For that purpose, they relied on the full-length major mugwort pollen allergen Art v 1 fused to the MoMLV matrix protein p15, which targets any fusion partner, so also the allergen, to the inside of the MoMLV VNP envelope.…”

Prevention of allergy by virus‐like nanoparticles (VNP) delivering shielded versions of major allergens in a humanized murine allergy model

“…Moreover, we determined the basophil activation and in vivo ‐sensitizing capabilities of allergen‐specific VNP, taking advantage of a recently established, human‐relevant TCR/DR1 transgenic mouse model . These transgenic mice express a human Art v 1 25‐36 ‐specific αβTCR and HLA‐DR1 and show hallmarks of allergic disease such as lung inflammation, airway hyper‐responsiveness (AHR), and allergen‐specific IgE upon natural i.n.…”