Biomarkers of Severe Peanut Allergy

严重花生过敏的生物标志物

• 批准号: 8053373
• 负责人: SARBJIT Singh SAINI
• 金额: $ 20.3万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8053373
• 关键词: Adult; Affect; Allergens; Allergic; Allergic Disease; Allergic Reaction; Allergy to peanuts; Anaphylaxis; Asthma; Basophils; Binding; Biological Markers; Cattle; Cells; Characteristics; Child; Clinical; Cutaneous; Dose; Double-Blind Method; Effector Cell; Epitopes; FPR1 gene; Food; Food Hypersensitivity; Future; Goals; Health; Heating; High Prevalence; Histamine Release; Hypersensitivity skin testing; IgE; Immunoglobulin G; In Vitro; Ingestion; Life; Measures; Mediating; Milk; Milk Hypersensitivity; Organ; Peanuts - dietary; Placebo Control; Prevalence; Prospective Studies; Proteins; Reaction; Recording of previous events; Relative (related person); Reporting; Research; Risk; Role; Sampling Studies; Screening procedure; Serological; Serum; Severities; Surface; Testing; United States; anti-IgE; early onset; food allergen; food challenge; high risk; insight; novel; omalizumab; prevent; response

DESCRIPTION (provided by applicant): The prevalence of children with peanut allergy, the most common cause of life-threatening food allergic reactions, has doubled from 0.4% in 1997 to 0.8% in 2002. It persists for a lifetime in most subjects, yet little is known about peanut allergy in adults. While ~8% of US adults have a positive skin test to peanut allergen (PA), the majority tolerate peanuts and predictors of clinical reactivity are undefined. Thus, there is a need for biomarkers that identify adults at risk for PA-related anaphylaxis. Blood basophils bind IgE via FceRI and are effector cells of anaphylaxis. In food allergic subjects, both basophils and serum have unique characteristics. Basophil spontaneous histamine release (SHR, ranging from 25-100% of total cell content) is typically seen in those with food allergies, is modulated by food allergen exposure and can be transferred via serum to a healthy donor's basophils. Recently, allergen-induced basophil responses were correlated with the degree of clinical reactivity to milk allergen. Milk-induced basophil reactivity is greatest in children who are intolerant to both heat-denatured and fresh milk as compared to children who are intolerant only to fresh milk. In the latter group, reduced basophil reactivity is related to an allergen-specific, suppressive IgG. Wider diversity in serum IgE binding to PA-epitopes is found in subjects with severe PA-reactions. Our goal is to examine biomarkers that identify IgE-sensitized adults at risk for severe PA-reactions. The overall hypothesis is that subjects with severe PA-reactions have basophils with greater reactivity to PA, and serum that transfers SHR and has extensive diversity in IgE binding to PA-epitopes. We will compare the features of basophils and serum among 3 groups of peanut allergic adults. Group A are those with a history of severe peanut allergy (life-threatening reaction or high-risk due to severe asthma and thus cannot ethically undergo PA challenge), Group B are subjects with an intermediate history of peanut reactions confirmed by a double-blind, placebo-controlled food challenge (DBPCFC), and Group C are subjects with an intermediate history of peanut allergy who pass a DBPCFC. In Aim 1, we will test the hypothesis that subjects in group A have the greatest basophil SHR and reactivity as measured by dose-response curves for PA-induced histamine release and the induction of surface CD63 and CD203c. In Aim 2, we will test the hypothesis that serum from group A has greater ability to transfer SHR to healthy donor basophils than serum from groups B and C, and controls. We will also define the role of IgE in SHR transfer by selective IgE-depletion. In Aim 3, we will test the hypothesis that greater diversity in IgE-binding to PA-epitopes, detected by microarray, is related to the severity of peanut allergy. Also, we expect that serum IgG that competes with IgE-binding to arrays leads to reduced clinical severity and basophil PA-reactivity. The completion of these aims will be the most complete study of biomarkers to date in adults with peanut allergy. Food allergy is a health problem that affects 3-4% of adults and 6-8% of children in the United States. Our goal is to identify novel biomarkers that identify subjects at risk for severe food allergy reactions. We will compare the characteristics of basophils and serum factors (e.g., peanut specific IgE, IgG) among three groups of peanut allergic adults classified by the severity of their peanut-reactions.

描述（由申请人提供）：花生过敏是危及生命的食物过敏反应的最常见原因，儿童的患病率从1997年的0.4%增加到2002年的0.8%。它在大多数受试者中持续一生，但对成人的花生过敏知之甚少。虽然约8%的美国成年人对花生过敏原（PA）的皮肤试验呈阳性，但大多数人耐受花生，临床反应性的预测因素尚未确定。因此，需要一种生物标志物来识别有PA相关过敏反应风险的成人。血液嗜碱性粒细胞通过FceRI结合IgE，是过敏反应的效应细胞。在食物过敏受试者中，嗜碱性粒细胞和血清都具有独特的特征。嗜碱性粒细胞自发组胺释放（SHR，范围为总细胞含量的25-100%）通常见于食物过敏者，受食物过敏原暴露调节，并可通过血清转移到健康供体的嗜碱性粒细胞。最近，过敏原诱导的嗜碱性粒细胞反应与牛奶过敏原的临床反应性程度相关。与仅对鲜奶不耐受的儿童相比，对热变性牛奶和鲜奶都不耐受的儿童中牛奶诱导的嗜碱性粒细胞反应性最大。在后一组中，嗜碱性粒细胞反应性降低与过敏原特异性、抑制性IgG有关。在重度PA反应的受试者中，发现血清IgE与PA表位结合的多样性更大。我们的目标是检查生物标志物，以确定IgE致敏的成年人在严重PA反应的风险。总体假设是，重度PA反应受试者的嗜碱性粒细胞对PA具有更高的反应性，血清可转移SHR，并且IgE与PA表位结合具有广泛的多样性。我们将比较三组花生过敏成人的嗜碱性粒细胞和血清的特征。A组为有重度花生过敏史（危及生命的反应或因重度哮喘导致的高风险，因此在伦理上不能接受PA激发）的受试者，B组为经双盲、安慰剂对照食物激发（DBPCFC）证实有花生反应中间史的受试者，C组为通过DBPCFC的有花生过敏中间史的受试者。在目的1中，我们将检验以下假设：A组受试者具有最大的嗜碱性SHR和反应性，如通过PA诱导的组胺释放的剂量-反应曲线和表面CD 63和CD 203 c的诱导所测量的。在目的2中，我们将检验以下假设：A组血清比B、C组和对照组血清具有更强的将SHR转移至健康供体嗜碱性粒细胞的能力。我们还将通过选择性IgE耗竭来确定IgE在SHR转移中的作用。在目标3中，我们将测试的假设，更大的多样性IgE结合PA-表位，检测到的微阵列，与花生过敏的严重程度。此外，我们预期与IgE竞争结合阵列的血清IgG导致临床严重程度和嗜碱性粒细胞PA反应性降低。这些目标的完成将是迄今为止对花生过敏成年人生物标志物的最完整研究。 食物过敏是一种健康问题，影响美国3-4%的成年人和6-8%的儿童。我们的目标是确定新的生物标志物，以确定受试者的严重食物过敏反应的风险。我们将比较嗜碱性粒细胞和血清因子的特征（例如，花生特异性IgE，IgG）。