Rush desensitization with a single antigen induces subclinical activation of mast cells and protects against bystander challenge in dually sensitized mice

Abstract

Background: Rush desensitization can provide short-term tolerance to individuals who are allergic to certain medications in instances where other therapeutic interventions are limited. While rush desensitization (DS) is typically successful in preventing adverse type I hypersensitivity reactions, the mechanism of allergic protection remains unknown. Given the rise in prevalence of individuals displaying multiple allergies, understanding the impact of rush DS on "bystander" allergens, or additional allergens to which an individual is sensitized, could help inform clinical recommendations.Objective: To evaluate the effect of rush DS on bystander sensitization. Materials and Methods:We used a murine model of rush DS, whereby BALB/c mice were sensitized to ovalbumin (OVA) and desensitized through repeated intraperitoneal injections of OVA. Using a local anaphylaxis assay, we measured ear swelling by Evans blue extravasation following intradermal challenge. In studies to measure the impact on bystander antigens, a modified protocol was used in which mice were dually sensitized to OVA and Keyhole limpet hemocyanin (KLH), and densensitized to either OVA or KLH prior to allergic challenge.Results: The immunological effects of rush DS were independent of changes in Th1 and Th2 cytokine production and circulating OVA-IgE levels. Instead, rush DS resulted in subclinical degranulation of mast cells prior to challenge. In our dual sensitization model, rush DS with a single antigen conferred protection against allergic challenge to a secondary antigen. Bystander protection required prior sensitization, as DS with an irrelevant antigen did not impact allergic responsiveness. Conclusions and Clinical Relevance:We reveal that a key mechanism of rush DS protection against allergic responsiveness may be the subclinical degranulation of mast cells. Therefore, performing rush DS to a single antigen to which one is IgEsensitized may be sufficient to desensitize to multiple allergens. Future studies could lead to streamlined protocols of rush DS for patients with multiple allergies.

Chronic infection with a tissue‐invasive helminth attenuates sublethal anaphylaxis and reduces granularity and number of mast cells

“…We speculate that the effects we observed on mast cells have broader implications for allergic disease. Depletion or exhaustion of mast cells through repeated degranulation could potentially serve as a mechanism of protection for other type I hypersensitivity reactions and for achieving tolerance during rush desensitization . Future studies will focus on the mechanisms by which chronic helminth infection reduces mast cell numbers and mast cell granularity and explore whether mast cells become “exhausted” and exhibit endoplasmic reticulum stress following chronic activation.…”

Mechanisms of oral immunotherapy

“…In contrast, a second study did not find a reduction in surface IgE or in the signal transduction ability of the high‐affinity IgE receptor (FcεRI), but instead found that reorganization of the actin cytoskeleton in desensitized mast cells led to impaired Ca 2+ signalling and prevention of mast cell degranulation 54 . A recent study using a cutaneous model of local anaphylaxis in dual‐sensitized mice showed that desensitization to one allergen conferred protection when challenged to the second allergen 55 . This suggests that early subclinical degranulation of mast cells plays an important role in desensitization and, like basophils, probably provides bystander protection upon exposure to other allergens.…”

Developments allergy in 2019 through the eyes of clinical and experimental allergy, part I mechanisms

“…In a study by Killoran and colleagues, the authors used a mouse model to investigate the potential of rush desensitization, a process where short‐term exposure to an allergen can provide a window of tolerance, to protect against diverse allergens. Although rush desensitization with a single model allergen resulted in sustained subclinical degranulation of mast cells, mice were then also protected against a second, unrelated, model allergen 54 . These data, although needing further investigation, highlight a potentially valuable future intervention approach whereby poly‐sensitized allergic individuals might be afforded a window of tolerance against multiple allergens.…”

“…Although rush desensitization with a single model allergen resulted in sustained subclinical degranulation of mast cells, mice were then also protected against a second, unrelated, model allergen. 54 These data, although needing further investigation, highlight a potentially valuable future intervention approach whereby poly-sensitized allergic individuals might be afforded a window of tolerance against multiple allergens.…”