Biomarkers of Severe Peanut Allergy

严重花生过敏的生物标志物

• 批准号: 7894230
• 负责人: SARBJIT Singh SAINI
• 金额: $ 20.5万
• 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 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7894230
• 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; 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(申请人提供)：花生过敏儿童的患病率从1997年的0.4%增加到2002年的0.8%，花生过敏是威胁生命的食物过敏反应的最常见原因。在大多数受试者中，花生过敏会持续一生，但对成年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)皮肤测试呈阳性，但大多数人对花生耐受，临床反应性的预测因素尚不确定。因此，需要生物标记物来识别成人PA相关过敏反应的风险。嗜碱性粒细胞通过FceRI与IgE结合，是过敏反应的效应细胞。在食物过敏患者中，嗜碱性粒细胞和血清都有其独特的特点。嗜碱性粒细胞自发组胺释放(SHR，从总细胞含量的25%-100%不等)通常见于那些对食物过敏的人，受食物过敏原的调节，并可通过血清传递给健康捐赠者的嗜碱性粒细胞。近年来，变应原诱导的嗜碱性细胞反应与临床对牛奶变应原的反应程度相关。与只对新鲜牛奶不耐受的儿童相比，对热变性牛奶和新鲜牛奶都不耐受的儿童，牛奶诱导的嗜碱性细胞反应最强。在后一组中，嗜碱性粒细胞反应性降低与过敏原特异的抑制性免疫球蛋白有关。在有严重PA反应的受试者中，发现血清中与PA表位结合的IgE的多样性更大。我们的目标是检查识别有严重PA反应风险的IgE致敏成人的生物标记物。总体假设是，PA反应严重的受试者有对PA反应更强的嗜碱性粒细胞，转移SHR的血清和与PA表位结合的IgE具有广泛的多样性。我们将比较3组花生过敏性成人的嗜碱性粒细胞和血清的特征。A组是那些有严重花生过敏史(威胁生命的反应或严重哮喘的高风险，因此在伦理上不能接受PA挑战)的人，B组是通过双盲、安慰剂控制的食物挑战(DBPCFC)证实有中等花生反应史的受试者，C组是通过DBPCFC的中等花生过敏史的受试者。在目标1中，我们将检验A组受试者具有最大的嗜碱性粒细胞SHR和反应性的假设，通过PA诱导的组胺释放和表面CD63和CD203c的诱导的剂量-反应曲线来衡量。在目标2中，我们将检验这一假设，即A组的血清比B、C组和对照组的血清具有更强的将SHR转移到健康供体嗜碱性粒细胞的能力。我们还将通过选择性去除IgE来确定IgE在SHR转移中的作用。在目标3中，我们将验证这样一个假设，即通过微阵列检测到的PA表位与IgE结合的更大多样性与花生过敏的严重程度有关。此外，我们预计，与与阵列结合的IgE竞争的血清免疫球蛋白会降低临床严重性和嗜碱性粒细胞PA反应性。这些目标的完成将是迄今为止对花生过敏成年人进行的最完整的生物标记物研究。 食物过敏是一个健康问题，在美国有3%-4%的成年人和6%-8%的儿童受到影响。我们的目标是确定新的生物标志物，以确定有严重食物过敏反应风险的受试者。我们将比较三组花生过敏成人的嗜碱性粒细胞和血清因子(如花生特异性IgE、Ig G)的特征，根据花生反应的严重程度进行分类。