Immunologic characterization of 3 murine regimens of allergen-specific immunotherapy

Fox, Ellen Mueller; Torrero, Marina N.; Evans, Holly; Mitre, Edward

doi:10.1016/j.jaci.2014.07.052

Cited by 14 publications

(12 citation statements)

References 46 publications

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“…At present, the commonly-used allergen in the IgE-FcεRI-mediated allergy research is ovalbumin (OVA) to mimic type I hypersensitivity4849. However, our previous result showed that the sensibility of common mice response to OVA was not satisfactory, especially in the absence of an adjuvant (data not shown), which might be associated with the immune tolerance induced by a long-term consumption of eggs powder in rodents’ fodder50.…”

Section: Discussionmentioning

confidence: 98%

The Three-Herb Formula Shuang-Huang-Lian stabilizes mast cells through activation of mitochondrial calcium uniporter

Gao

Hou

Fei

et al. 2017

Sci Rep

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Mast cells (MCs) are key effector cells of IgE-FcεRI- or MrgprX2-mediated signaling event. Shuang-Huang-Lian (SHL), a herbal formula from Chinese Pharmacopoeia, has been clinically used in type I hypersensitivity. Our previous study demonstrated that SHL exerted a non-negligible effect on MC stabilization. Herein, we sought to elucidate the molecular mechanisms of the prominent anti-allergic ability of SHL. MrgprX2- and IgE-FcεRI-mediated MC activation in vitro and in vivo models were developed by using compound 48/80 (C48/80) and shrimp tropomyosin (ST), respectively. Our data showed that SHL markedly dampened C48/80- or ST-induced MC degranulation in vitro and in vivo. Mechanistic study indicated that cytosolic Ca2+ (Ca2+[c]) level decreased rapidly and sustainably after SHL treatment, and then returned to homeostasis when SHL was withdrawn. Moreover, SHL decreases Ca2+[c] levels mainly through enhancing the mitochondrial Ca2+ (Ca2+[m]) uptake. After genetically silencing or pharmacologic inhibiting mitochondrial calcium uniporter (MCU), the effect of SHL on the Ca2+[c] level and MC degranulation was significantly weakened. Simultaneously, the activation of SHL on Ca2+[m] uptake was completely lost. Collectively, by activating MCU, SHL decreases Ca2+[c] level to stabilize MCs, thus exerting a remarkable anti-allergic activity, which could have considerable influences on clinical practice and research.

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Section: Discussionmentioning

confidence: 98%

The Three-Herb Formula Shuang-Huang-Lian stabilizes mast cells through activation of mitochondrial calcium uniporter

Gao

Hou

Fei

et al. 2017

Sci Rep

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“…In all of the mice, 0.01 mg rMet e 1 was well tolerated without triggering systemic symptoms and so this was adopted as the low dosage; 0.05 mg rMet e 1 was adopted as the medium dosage with reference to a previous mouse model of AIT using the intraperitoneal (i.p.) route [15]; and 0.1 mg rMet e 1, which triggers severe anaphylactic symptoms in mice, was adopted as the high dosage. rMet e 1 was delivered i.p.…”

Section: Methodsmentioning

confidence: 99%

Low-Dose Allergen-Specific Immunotherapy Induces Tolerance in a Murine Model of Shrimp Allergy

Leung

Wai

Shu

et al. 2017

Int Arch Allergy Immunol

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Background: The efficacy and safety of allergen-specific immunotherapy (AIT) are highly dose-dependent. Methods: We investigated the dosage effects of AIT and the underlying mechanisms in a murine model of shrimp hypersensitivity. BALB/c mice were sensitized with recombinant shrimp allergen rMet e 1 and challenged orally with a high dose of rMet e 1 to elicit an allergic response. These sensitized mice were then treated with a low (0.01 mg), medium (0.05 mg), or high dosage (0.1 mg) of rMet e 1 intraperitoneally before receiving a second oral challenge. The allergic responses and immunological changes in the gut were compared between animals receiving different dosages. Results: We found that all sensitized mice that received rMet e 1 immunotherapy were desensitized, regardless of the dosage, and protected at the second oral challenge. Nevertheless, the mice in the high-dosage group experienced severe systemic reactions during the treatment phase. In contrast, regulatory T (T_reg) cell-associated genes were upregulated only in the low- and medium-dosage groups, and Foxp3+ cells were more abundant in the gut lymphoid tissues than in the high-dosage group. Conclusions: Our results demonstrate that low-dosage immunotherapy favors the induction of local Foxp3+ T_reg cells and the upregulation of regulatory cytokines. The safety advantages and long-term efficacy of low-dosage immunotherapy should be taken into consideration when developing immunotherapy dose schedules.

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“…In this study, we used a cutaneous model of local anaphylaxis to evaluate the allergic responsiveness in vivo of mice that underwent rush DS. In the model, which was previously described by our laboratory, mice are sensitized to the model antigen ovalbumin (OVA) and challenged by intradermal injection in the ear . Allergic responsiveness was measured by the extent of swelling or vascular permeability in the ear that occurs in response to allergen challenge.…”

Section: Introductionmentioning

confidence: 99%

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

Killoran

Kropp

Lindrose

et al. 2019

Clin Experimental Allergy

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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.

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Immunologic characterization of 3 murine regimens of allergen-specific immunotherapy

Cited by 14 publications

References 46 publications

The Three-Herb Formula Shuang-Huang-Lian stabilizes mast cells through activation of mitochondrial calcium uniporter

The Three-Herb Formula Shuang-Huang-Lian stabilizes mast cells through activation of mitochondrial calcium uniporter

Low-Dose Allergen-Specific Immunotherapy Induces Tolerance in a Murine Model of Shrimp Allergy

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

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