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Anti-IgE therapy for IgE-mediated allergic diseases: from neutralizing IgE antibodies to eliminating IgE+ B cells.

ABSTRACT: Allergic diseases are inflammatory disorders that involve many types of cells and factors, including allergens, immunoglobulin (Ig)E, mast cells, basophils, cytokines and soluble mediators. Among them, IgE plays a vital role in the development of acute allergic reactions and chronic inflammatory allergic diseases, making its control particularly important in the treatment of IgE-mediated allergic diseases. This review provides an overview of the current state of IgE targeted therapy development, focusing on three areas of translational research: IgE neutralization in blood; IgE-effector cell elimination; and IgE+ B cell reduction. IgE-targeted medicines such as FDA approved drug Xolair (Omalizumab) represent a promising avenue for treating IgE-mediated allergic diseases given the pernicious role of IgE in disease progression. Additionally, targeted therapy for IgE-mediated allergic diseases may be advanced through cellular treatments, including the modification of effector cells.

SUBMITTER: Hu J

PROVIDER: S-EPMC6050685 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Anti-IgE therapy for IgE-mediated allergic diseases: from neutralizing IgE antibodies to eliminating IgE<sup>+</sup> B cells.

Hu Jiayun J Chen Jiajie J Ye Lanlan L Cai Zelang Z Sun Jinlu J Ji Kunmei K

Clinical and translational allergy 20180718

Allergic diseases are inflammatory disorders that involve many types of cells and factors, including allergens, immunoglobulin (Ig)E, mast cells, basophils, cytokines and soluble mediators. Among them, IgE plays a vital role in the development of acute allergic reactions and chronic inflammatory allergic diseases, making its control particularly important in the treatment of IgE-mediated allergic diseases. This review provides an overview of the current state of IgE targeted therapy development, ...[more]

PMID: 30026908

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Project description:What is already known about this subjectOmalizumab is a humanized anti-IgE monoclonal antibody that binds and captures circulating IgE, preventing interaction with receptors on mast cells and basophils, thereby interrupting the allergic cascade. It has a well-characterized efficacy and safety profile in patients with asthma. While omalizumab is known to reduce serum free IgE concentrations, effects on total IgE and IgE production are less well characterized.What this study adds(i) Confirmation of prior hypotheses that IgE production can decrease with time when patients are given anti-IgE therapy; (ii) guidance on a biomarker, total IgE, which can be used to ascertain whether individual patients experience a change in their IgE production; and (iii) a way to assess whether patients' IgE production has been sufficiently down-regulated such that they may consider stopping anti-IgE therapy.AimTo determine whether excessive IgE production by patients with atopic allergic asthma decreases with omalizumab therapy.MethodsOmalizumab, free and total IgE data were obtained from an epidemiological study and six randomized, double-blind, placebo-controlled trials in patients with allergic asthma. The binding between omalizumab and IgE together with the production and elimination of IgE were modelled as previously, except that, in order to explain why total IgE was decreasing over a period of 5 years, the expression of IgE was allowed to change.ResultsThe prior constant IgE production model failed to converge on the data once long-term observations were included, whereas models allowing IgE production to decrease fitted. A feedback model indicated that, on average, IgE production decreased by 54% per year. This model was further developed with covariate searches indicating clinically small but statistically significant effects of age, gender, body mass index and race on some parameters. Model predictions were checked internally and externally against 3-5 year data from paediatric and adult atopic asthmatic patients and externally against extensive total IgE data from a long-duration (>1 year) phase 1 study which was not used in the model building.ConclusionsA pharmacokinetic-pharmacodynamic model incorporating omalizumab-IgE binding and feedback for control of IgE production indicates that omalizumab reduces production of IgE. This raises the possibility that indefinite treatment may not be required, only for perhaps a few years. After the initial accumulation, total IgE should provide a means to monitor IgE production and guide individual treatment decisions.

Project description:The high affinity immunoglobulin E (IgE) receptor-Fc?R1 is mainly expressed on the surface of effector cells. Cross-linking of IgE Abs bound to Fc?R1 by multi-valent antigens can induce the activation of these cells and the secretion of inflammatory mediators. Since Fc?R1 plays a central role in the induction and maintenance of allergic responses, this study aimed to investigate the association of Fc?R1 with the allergic phenotype of C? expression and cytokine and histamine release from peripheral leukocytes. Peripheral leukocytes from 67 allergic and 50 non-allergic subjects were used for genotyping analysis. Peripheral mononuclear cells (PBMCs) were used for C? expression and ELISpot analysis, while polymorphonuclear cells (PMNs) were used for histamine release. The association between genotype polymorphism of the Fc?R1? promoter region (rs2427827 and rs2251746) and allergic features of C? expression and histamine were analyzed, and their effects on leukocytes function were compared with wild type. The genotype polymorphisms of Fc?R1? promoter region with CT and TT in rs2427827 and TC in rs2251746 were significantly higher in allergic patients than in non-allergic controls. Patients with single nucleotide polymorphism (SNP) of Fc?R1? promoter region had high levels of total IgE, mite-specific Der p 2 (Group 2 allergen of Dermatophagoides pteronyssinus)-specific IgE and IgE secretion B cells. The mRNA expression of Fc?R1? was significantly increased after Der p2 stimulation in PBMCs with SNPs of the Fc?R1? promoter region. Despite the increased C? mRNA expression in PBMCs and histamine release from PMNs and the up-regulated mRNA expression of interleukin (IL)-6 and IL-8 secretions after Der p2 stimulation, there was no statistically significant difference between SNPs of the Fc?R1? promoter region and the wild type. SNPs of Fc?R1? promoter region were associated with IgE expression, IgE producing B cells, and increased Der p2-induced Fc?R1? mRNA expression. These SNPs may be used as a disease marker for IgE-mediated allergic inflammation caused by Dermatophagoides pteronyssinus.

Dataset Information

Anti-IgE therapy for IgE-mediated allergic diseases: from neutralizing IgE antibodies to eliminating IgE+ B cells.

Publications

Anti-IgE therapy for IgE-mediated allergic diseases: from neutralizing IgE antibodies to eliminating IgE<sup>+</sup> B cells.

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