Human IgG-mediated Anaphylaxis

人类 IgG 介导的过敏反应

• 批准号: 8493995
• 负责人: FRED Douglass FINKELMAN
• 金额: $ 21.87万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8493995
• 关键词: Allergic Reaction; Anaphylaxis; Antibodies; Antigen-Antibody Complex; Antigens; Basophils; Binding; Biological Assay; Blood; Blood specimen; Categories; Cell Degranulation; Characteristics; Clinical; Clinical Research; Complex; Crohn' s disease; Data; Development; Diagnosis; Disease; Drug Industry; Evaluation; Generations; Human; IgE; IgG Receptors; Immunoglobulin G; In Vitro; Incidence; Individual; Infusion procedures; Interleukin 4 Receptor; Interleukin-4; Lead; Macrophage Activation; Mediating; Mediator of activation protein; Membrane; Monoclonal Antibodies; Multicenter Studies; Mus; Outcome; Outcome Measure; Pathway interactions; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Platelet Activating Factor; Proteins; Reaction; Serum; Shock; T-Lymphocyte; Testing; Therapeutic; Therapeutic Monoclonal Antibodies; Tryptase; Tumor Necrosis Factor-alpha; anti-IgG; base; cohort; disorder prevention; improved; in vivo; infliximab; mast cell; neutrophil; novel; peripheral blood; prevent; primary outcome; receptor expression; research clinical testing; secondary outcome; therapeutic protein

DESCRIPTION (provided by applicant): Therapeutic monoclonal antibodies (mAbs), such as infliximab, constitute the fastest growing segment of the pharmaceutical industry. Use of these mAbs has provided substantial benefits, but can cause development of IgG anti-mAb antibodies and anaphylaxis. Mouse and human studies suggest that anaphylaxis caused by repeated infusion of these mAbs may be mediated by IgG rather than IgE; however, the existence of human IgG-mediated anaphylaxis has never been proven. We have developed novel peripheral blood assays that can distinguish murine IgE- from IgG-mediated anaphylaxis: murine IgE-, but not IgG-mediated anaphylaxis is associated with increases in serum soluble IL- 4R¿ concentration and T cell IL-4R¿ expression, while murine IgG-, but not IgE-mediated anaphylaxis is associated with decreased neutrophil Fc?RIII expression. Preliminary in vitro studies suggest that these same assays will be useful for differentiating human IgE- vs. IgG-mediated anaphylaxis. This proposal will evaluate whether the same assays may be used in vivo in humans to provide evidence for the existence of human IgG-mediated anaphylaxis. Specifically, we will use these assays, an established test for IgE- mediated anaphylaxis (serum tryptase concentration), an assay for IgG anti-infliximab antibodies and clinical evaluation to evaluate whether IgG-mediated anaphylaxis without evidence of IgE-mediated anaphylaxis develops more frequently in infliximab-treated Crohn's disease patients who have IgG antibodies to infliximab (our primary endpoint) and/or in patients who develop reactions to infliximab infusion (our secondary endpoint). A positive result would support the existence of human IgG-mediated anaphylaxis and could lead to improved diagnosis and prevention of this disorder by identifying patients who would benefit from changing therapy or pre-treatment with drugs that may prevent IgG-mediated anaphylaxis.

描述（由适用提供）：英夫利昔单抗等治疗性单克隆抗体（mAb）构成了制药行业中增长最快的部分。这些mAB的使用已提供了实质性的好处，但可能导致IgG抗MAB抗体和过敏反应的发展。小鼠和人类的研究表明，通过反复输注这些mAb引起的过敏反应可能是由IgG而不是IgE介导的。但是，从未证明人IgG介导的过敏反应的存在。我们已经开发了新型的外周血刺客，可以将鼠IgE与IgG介导的过敏反应区分开：鼠IgE- igE-，但不与IgG介导的过敏反应相关，与血清固体IL-4R浓度的升高和T细胞IL-4R的表达相关，而与Mirine Isi iS aphyly iS aphyl iS aphyl iissrip？ 表达。初步的体外研究表明，这些相同的测定对于区分人IgE与IgG介导的过敏反应有用。该提案将评估是否可以在人类的体内使用相同的测定，以提供人类IgG介导的过敏反应的存在的证据。 Specifically, we will use these assays, an established test for IgE- mediated anaphylaxis (serum tryptase concentration), an assay for IgG anti-infliximab antibodies and clinical evaluation to evaluate whether IgG-mediated anaphylaxis without evidence of IgE-mediated anaphylaxis developments more frequently in infliximab-treated Crohn's disease patients who have IgG antibodies to英夫利昔单抗（我们的主要终点）和/或在对英夫利昔单抗输注反应的患者中（我们的次要终点）。积极的结果将支持人类IgG介导的过敏反应的存在，并通过鉴定将受益于改变治疗或使用预先治疗的药物而受益的患者，从而改善诊断和预防该疾病，这些患者可能会阻止IgG介导的过敏反应。