Pathogenesis and Treatment of Anaphylaxis

过敏反应的发病机制和治疗

• 批准号: 10014172
• 负责人: Dean D Metcalfe
• 金额: $ 73.42万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10014172
• 关键词: Adverse event; Adverse reactions; Allergic Disease; Anaphylaxis; Antigens; Aspirate substance; Asthma; Basophils; Biopsy; Bone Marrow; Cell Compartmentation; Cell Degranulation; Chronic; Clinical; Clinical Trials; Collaborations; Core Facility; Cutaneous; Data; Data Analyses; Dendritic Cells; Diagnosis; Disease; Drug Hypersensitivity; Enrollment; Etiology; European; Food; Food Hypersensitivity; Frequencies; Hematopoietic; Hematopoietic stem cells; High Prevalence; Idiopathic anaphylaxis; IgE; IgE Receptors; Immunotherapy; Individual; Inherited; Inpatients; Insect Sting; Intervention; Investigation; Mediating; Mediator of activation protein; Mutation; Myelogenous; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Prevalence; Procedures; Process; Prospective Studies; Proto-Oncogene Protein c-kit; Protocols documentation; Reaction; Recurrence; Reporting; Safety; Serious Adverse Event; Serum; Surface; Syndrome; Systemic Mastocytosis; Tissues; Tryptase; United States National Institutes of Health; Urticaria; Venoms; base; cohort; experience; interest; mast cell; mastocytosis; omalizumab; randomized trial; transcription factor

We are in the process of evaluating over 90 patients referred for idiopathic anaphylaxis (IA) and antigen-specific anaphylaxis (SA) to explore pathogenesis and identify patients with clonal mast cell disease. Within the patient group with IA, 15% had clonal mast cell disease, 9.6% were diagnosed with alpha-gal sensitivity, and 12.8% were diagnosed with hereditary alpha-tryptasemia syndrome. Among patients with antigen-induced anaphylaxis, those with venom anaphylaxis in European cohorts have been reported to have a higher prevalence of clonal mast cell disease. In our cohort of patients referred for venom anaphylaxis to date (n=5), four have been diagnosed with clonal mast cell disease. In fiscal year (FY) 2019, we continue to admit patients with IA and S). Most patients are admitted to the inpatient unit and undergo a bone marrow procedure in an attempt to elucidate the etiology and evaluate the pathogenesis of their disease. In collaboration with the NIH Clinical Center's myeloid core facility, we assess all patient bone marrow aspirates and biopsies obtained based on the current WHO criteria to diagnose systemic mastocytosis. GATA-2 is a transcription factor critically required for the genesis and/or function of hematopoietic stem cells and is expressed in various hematopoietic and nonhematopoietic tissues. In a study completed in FY 2019, we assessed the impact of mutations in GATA-2 on the mast cell compartment. Patients with IA had comparable KIT expression on bone marrow mast cells but lower total numbers of bone marrow mast cells when compared to patients with GATA-2 deficiency. A decrease of mast cell degranulation was associated with reduced expression of KIT and FcepsilonRI in GATA-2 deficient patients, which is consistent with a decrease in IgE-mediated mast cell activation and potential for IgE-mediated clinical allergic disease. The pathway was intact in patients with IA. Omalizumab is approved for the treatment of severe asthma and acts through a mechanism that down regulates the IgE-receptor on the surface of basophils, mast cells, and dendritic cells. Omalizumab has been reported to be useful as adjunct therapy in the treatment of diseases other than asthma including food allergy and chronic urticaria. In FY 2019, we completed a clinical trial evaluating omalizumab for the treatment of IA and will prepare a full report of our findings after completing the data analysis. There were no serious adverse events attributed to the study drug, in particular drug-induced anaphylaxis. In FY 2019, we reported the safety and efficacy of omalizumab over a 12-year period in the treatment of recurrent anaphylaxis in two patients with systemic mastocytosis. We found that omalizumab was well tolerated and there were no adverse events related to its administration. In both patients, anaphylactic episodes were rare. There was an improvement in cutaneous manifestations of mastocytosis in both individuals, along with a significant reduction in serum tryptase and bone marrow mast cell burden in one patient.

我们正在评估90多名患者，这些患者转介特发性过敏（IA）和抗原特异性过敏反应（SA），以探索发病机理并鉴定患有克隆肥大细胞疾病的患者。在IA患者组中，有15％患有克隆肥大细胞疾病，9.6％被诊断为α-GAL敏感性，而12.8％被诊断出患有遗传性α-肌瘤综合征。 在抗原诱导的过敏反应的患者中，据报道，欧洲队列中毒液过敏反应的患者的克隆肥大细胞病患病率更高。在我们转介毒液过敏症的患者队列中（n = 5），有四名被诊断出患有克隆肥大细胞疾病。 在2019财政年度（FY），我们继续接纳IA和S）的患者。大多数患者被接纳为住院单位并接受骨髓手术，以试图阐明病因并评估其疾病的发病机理。通过与NIH临床中心的髓样核心设施合作，我们根据当前WHO诊断全身性肥大性的标准来评估所有患者骨髓抽吸物和活检。 GATA-2是造血干细胞的起源和/或功能至关重要的转录因子，并在各种造血和非杂造组织中表达。在2019财年完成的一项研究中，我们评估了GATA-2突变对肥大细胞室的影响。与GATA-2缺乏症患者相比，IA患者在骨髓肥大细胞上具有可比的KIT表达，但骨髓肥大细胞的总数较低。肥大细胞脱粒的降低与GATA-2缺陷患者的试剂盒和Fcepsilonri的表达降低有关，这与IgE介导的肥大细胞激活的降低以及IgE介导的临床过敏性疾病的潜力降低。 IA患者的途径完好无损。 Omalizumab被批准用于治疗严重哮喘，并通过一种机制作用，该机制降低了在嗜碱性粒细胞，肥大细胞和树突状细胞表面上调节IgE受体。据报道，奥马珠单抗作为辅助疗法在包括食物过敏和慢性荨麻疹（包括食物过敏和慢性荨麻疹）以外的其他疾病治疗中很有用。在2019财年，我们完成了一项评估Omalizumab治疗IA的临床试验，并将在完成数据分析后准备我们的发现的完整报告。没有严重的不良事件归因于研究药物，特别是药物诱导的过敏反应。 在2019财年，我们报告了两名全身性肥大症患者在12年的复发性过敏反应治疗中，奥马珠单抗的安全性和功效。我们发现，奥马珠单抗的耐受性良好，并且没有与其给药有关的不利事件。在两名患者中，过敏反应很少见。两个个体的肥大性皮肤表现都有所改善，一名患者的血清胰蛋白酶和骨髓肥大细胞负担显着减少。