Suppression of IgE B Cells and IgE Binding to FcεRI by Gene Therapy with Single-Chain Anti-IgE

Ota, Takayuki; Aoki-Ota, Miyo; Duong, Bao; Nemazee, David

doi:10.4049/jimmunol.0900300

Cited by 18 publications

(19 citation statements)

References 38 publications

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“…S1). The apparent decrease in FceRI expression in the presence of IgE we believe reflects the decreased affinity of MAR-1 for FceRI once it is occupied by IgE (32). Taken together, FceRIβ exon skipping could potentially suppress the prosurvival effect of elevated IgE in vivo and thus the increase in mast cell population as well as reduce IgE-dependent degranulation in allergic disease.…”

Section: Resultsmentioning

confidence: 92%

Exon skipping of FcεRIβ eliminates expression of the high-affinity IgE receptor in mast cells with therapeutic potential for allergy

Cruse

Yin

Fukuyama

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Allergic diseases are driven by activation of mast cells and release of mediators in response to IgE-directed antigens. However, there are no drugs currently available that can specifically down-regulate mast cell function in vivo when chronically administered. Here, we describe an innovative approach for targeting mast cells in vitro and in vivo using antisense oligonucleotide-mediated exon skipping of the β-subunit of the high-affinity IgE receptor (FceRIβ) to eliminate surface high-affinity IgE receptor (FceRI) expression and function, rendering mast cells unresponsive to IgE-mediated activation. As FceRIβ expression is restricted to mast cells and basophils, this approach would selectively target these cell types. Given the success of exon skipping in clinical trials to treat genetic diseases such as Duchenne muscular dystrophy, we propose that exon skipping of FceRIβ is a potential approach for mast cell-specific treatment of allergic diseases.A sthma and related allergic diseases affect up to 1 in 10 people in developed countries, and about 10% of patients with asthma cannot be controlled with current therapeutic approaches. The most widely used therapies for asthma rely upon dampening the inflammatory response with either oral or inhaled glucocorticosteroids and relaxing the constricted airway smooth muscle cells with β-adrenoreceptor agonists. However, high doses of steroids when needed for severe asthma are associated with undesirable side effects and inhaled β-adrenoreceptor agonists can increase the risk of death from asthma if not used in combination with glucocorticosteroids. It is suggested that β-adrenoreceptor agonists may promote underlying inflammation that could contribute to the airway wall remodeling seen in asthma (1). Other clinical approaches that aim for more long-term alleviation of symptoms, including desensitization with incremental increases in dose of allergen or hyposensitization to induce immune tolerance, have proven beneficial for some, but not all, patients, and serious adverse effects can occur (2).In addition to asthma, other allergic diseases have similar treatment strategies and also have an unmet clinical need. An example is atopic dermatitis (AD), which like asthma, is also a multifactorial disease with complex pathophysiology, remains incurable, and affects 10-20% of children in the United States (3). The two major symptoms of AD are inflammatory lesions and severe pruritus. Both the prevalence and the economic burden of AD are increasing worldwide. Symptomatic treatment with topical and/or systemic glucocorticosteroids or calcineurin inhibitors are still considered the gold standard. However, due to the known adverse effects of these drugs, prescription rates are low and patient compliance is often poor (3). Thus, there is still a need for new therapeutic approaches with a better safety profile.An approach for intervention in allergic inflammation that we have pursued is based on the finding that the gene loci 11q12-q13 are strongly linked to allergy and asthma suscepti...

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Section: Resultsmentioning

confidence: 92%

Exon skipping of FcεRIβ eliminates expression of the high-affinity IgE receptor in mast cells with therapeutic potential for allergy

Cruse

Yin

Fukuyama

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…It seemed plausible that an acid-wash method to stain surface IgE (Katona et al, 1983) might lack sufficient sensitivity to detect the low surface IgE expression that we observed in GC B cells, potentially explaining why these cells were not detected in a previous study (Erazo et al, 2007). We instead tested and optimized a flow cytometry procedure with increased sensitivity based on the concept of intracellular IgE staining (Ota et al, 2009). Technical details of the procedure are described in the Experimental Procedures.…”

Section: Detection Of Ige + Gc B Cells In Wild-type Micementioning

confidence: 96%

Fluorescent In Vivo Detection Reveals that IgE+ B Cells Are Restrained by an Intrinsic Cell Fate Predisposition

2012

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IgE antibodies may be protective in parasite immunity, but their aberrant production can lead to allergic disease and life-threatening anaphylaxis. Despite the importance of IgE regulation, few studies have directly examined the B cells that express IgE, because these cells are rare and difficult to detect. Here, we describe fluorescent IgE reporter mice and validate a flow cytometry procedure to allow sensitive and specific identification of IgE-expressing B cells in vivo. Similar to IgG1(+) cells, IgE(+) B cells differentiated into germinal center (GC) B cells and plasma cells (PCs) during primary immune responses to a T cell-dependent hapten-protein conjugate and the helminth Nippostrongylus brasiliensis. However, the participation of IgE(+) B cells in GCs was transient. IgE(+) B cells had an atypical propensity to upregulate the transcription factor Blimp-1 and undergo PC differentiation. Most IgE(+) PCs were short lived and showed reduced affinity maturation, revealing intrinsic mechanisms that restrict the IgE antibody response.

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“…Mice were injected intraperitoneally with antibodies XENP8252 or XENP8253 at 10 mg/kg twice weekly throughout the study, starting on day 0. Both antibodies are derived from R1E4, a rat antimouse IgE used as a surrogate for omalizumab 27,28 and contain identical rat antimouse IgE Fv domains. XENP8252 is a chimeric murine surrogate for omalizumab containing a native human IgG1 Fc domain.…”

Section: Activation Of Human B Cells In Huscid Mice By Polyclonal Antmentioning

confidence: 99%

Reduction of total IgE by targeted coengagement of IgE B-cell receptor and FcγRIIb with Fc-engineered antibody

Chu¹,

Horton²,

Pong

et al. 2012

Journal of Allergy and Clinical Immunology

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Suppression of IgE B Cells and IgE Binding to FcεRI by Gene Therapy with Single-Chain Anti-IgE

Cited by 18 publications

References 38 publications

Exon skipping of FcεRIβ eliminates expression of the high-affinity IgE receptor in mast cells with therapeutic potential for allergy

Exon skipping of FcεRIβ eliminates expression of the high-affinity IgE receptor in mast cells with therapeutic potential for allergy

Fluorescent In Vivo Detection Reveals that IgE+ B Cells Are Restrained by an Intrinsic Cell Fate Predisposition

Reduction of total IgE by targeted coengagement of IgE B-cell receptor and FcγRIIb with Fc-engineered antibody

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