Immunologic Basis of Cow's Milk-Induced Hypersensitivities

描述(申请人提供)：食物过敏已成为西化国家的主要健康问题，目前影响3.5%-4%的美国人口，牛奶过敏[CMA]影响2.5%的幼儿。CMA为研究过敏性疾病和耐受诱导的免疫机制提供了理想的模型。这是一种常见的食物过敏症，既反映了在许多其他儿童食物过敏[如鸡蛋、大豆、小麦]中所见的“暂时性”食物过敏形式，也反映了类似于终身花生、坚果和海鲜过敏的“持久”、更严重的形式。对于盲目的食物挑战，诊断是确定的，负责的过敏原[牛奶蛋白]被很好地描述，包括它们的三维结构，并且已经建立了良好的动物模型，能够在分子水平上剖析免疫学和系统机制。在过去的授权期内，我们证明了大多数IgE介导的CMA儿童可以安全地摄入烘焙[热变性]奶制品，没有不良反应，并确定了各种免疫标志物[体液和细胞]，将他们与少数不能耐受任何形式乳蛋白的顽固性CMA儿童区分开来。利用动物模型和上皮细胞系，研究表明，IgE和CD23是增强小肠对变应原摄取所必需的，并在食物过敏但不过敏的儿童的粪便中发现，支持它们在过敏素质中的作用以及它们作为临床食物过敏生物标志物的潜力。在CMA小鼠模型中的研究还表明，特定的牛奶蛋白在G1粘膜中的运输方式可能在宿主的最终反应中发挥关键作用；即免疫耐受与变应原致敏以及临床耐受与过敏反应。基于我们在之前的中心资助中获得的知识，我们将在一项临床试验中进一步探索临床和潜在的免疫学反应，以检验分级暴露于热变性乳制品的影响，并在第二项临床试验中对牛奶口服免疫疗法[OIT]加奥马珠单抗进行研究，我们假设这将导致“耐受性”，而不是标准牛奶OIT的“脱敏”。我们还将使用新的模型来描述使某些牛奶蛋白变应原的属性，探索它们是如何在细胞水平上被处理的，并确定促进CD23运输在食物过敏疾病中的作用。通过该中心申请中概述的独特资源和合作项目，成功完成这些目标可能会在食物过敏的管理和治疗方面带来新的范例，并为患者的诊断和管理提供新的生物标志物。 项目1：IgE介导的牛乳过敏中对牛乳蛋白的免疫应答(Sampson，H) 项目1描述(由申请者提供)：牛奶是儿童食物过敏的最常见原因，大约1.8%的美国婴儿对牛奶产生IgE介导的过敏反应[约74,000例/年]。大约80%的人会在6岁之前对牛奶过敏，35%的人会对其他食物过敏，60%的人会出现呼吸道过敏和哮喘。牛奶过敏为研究与食物耐受性和过敏性疾病相关的免疫学机制提供了理想的“自然实验”。它是美国儿童中最常见的食物过敏，既反映了类似于许多其他儿童食物过敏[如鸡蛋、大豆、小麦]的“过敏性”“暂时性”形式，也反映了类似花生、坚果和海鲜过敏的“持续性”更严重形式。它可以被明确诊断为盲目的食物挑战，负责的过敏原，牛奶蛋白，包括它们的三维结构，得到了很好的特征。虽然严格的牛奶避免饮食一直是牛奶过敏患者的“护理标准”，但我们最近的数据表明，大多数儿童可以忍受没有有害影响的热变性产品。此外，口服免疫疗法[OIT]的初步研究报告了对牛奶过敏患者有效的“脱敏”，但这种疗法是否能诱导真正的“耐受性”仍有待证实。在该项目的第一个目标中，我们将根据牛奶过敏患者对不同形式的热变性牛奶蛋白的反应来描述他们的临床表型，识别区分亚群的新生物标记物，并阐明伴随耐受性获得的免疫学变化。此外，我们假设，积极摄取牛奶蛋白的儿童将更快地产生免疫耐受，耐受性将与体液和细胞功能的明显变化有关。在目标2中，我们将确定与单独使用OIT相比，联合使用抗LGE抗体和牛奶OIT是否会诱导临床“耐受”，并监测相关的免疫学变化。与该中心申请的其他项目一起，这些目标的成功完成将为与发展对食物的口服耐受性相关的免疫学变化提供新的见解，描绘牛奶过敏性个体的表型和免疫学差异，并可能导致牛奶过敏性个体的医疗管理和治疗的新范式。

DESCRIPTION (provided by applicant): Food allergy has become a major health problem in westernized countries and now affects 3.5% - 4% of the U.S. population with cow's milk allergy [CMA] affecting 2.5% of young children. CMA provides an ideal model to study immunologic mechanisms responsible for allergic disease and tolerance induction. It is a common food allergic disorder that reflects both the "transient" form of food allergy that is "outgrown," as seen in many other childhood food allergies [e.g. egg, soy, wheat], and the "persistent," more severe form, similar to life-long peanut, tree nut and seafood allergies. Diagnosis is definitive with the blinded food challenge, the responsible allergens [milk proteins] are well characterized including their 3-dimensional structures, and good animal models have been established that enable dissection of immunologic and systemic mechanisms at the molecular level. Over the past granting period, we demonstrated that the majority of children with IgE-mediated CMA can safely ingest baked [heat-denatured] milk products without adverse effects and identified a variety of immunologic markers [humoral and cellular] that distinguish them from the minority of children with persistent CMA who cannot tolerate any form of milk protein. Using animal models and epithelial cell lines, it was shown that IgE and CD23 are required for enhanced allergen uptake in the small intestine and are found in the stool of food-allergic but not non-allergic children, supporting their role in the allergic diathesis as well as their potential for use as a biomarker of clinical food allergy. Studies in a murine model of CMA also showed that the way specific milk proteins traffick in the Gl mucosa may play a critical role in the ultimate response of the host; i.e. immunologic tolerance vs. allergen sensitization and clinical tolerance vs. allergic reaction. Based on knowledge acquired in our previous Center grant, we will further explore clinical and underlying immunologic responses in one clinical trial examining the effects of graded exposure to heat-denatured milk products, and in a second clinical trial of milk oral immunotherapy [OIT] plus omalizumab, which we hypothesize will induce "tolerance," as opposed to "desensitization" seen with standard milk OIT. We also will use novel models to delineate properties that make certain milk proteins allergenic, explore how they are processed at the cellular level, and define the role of facilitated CD23 transport in food allergic disease. Through the unique resources and collaborative projects outlined in this Center application, successful completion of the aims may lead to new paradigms in the management and treatment of food allergies and provide novel biomarkers for the diagnosis and management of patients. PROJECT 1: Immunologic Responses to Cow's Milk Proteins in IgE-mediated Cow's Milk Allergy (Sampson, H) PROJECT 1 DESCRIPTION (provided by applicant): Cow's milk is the most common cause of food allergy in children, with approximately 1.8% of American infants developing IgE-mediated allergic reactions to cow's milk [~74,000 cases/year]. While ~80% "outgrow" their milk allergy by the 6th birthday, 35% will develop other food allergies and about 60% develop respiratory allergy and asthma. Milk allergy provides an ideal "experiment of nature" to study immunologic mechanisms associated with oral tolerance induction to food and allergic disease. It is the most common food allergy in American children and reflects both the "transient" form of food allergy that is "outgrown," similar to many other childhood food allergies [e.g. egg, soy, wheat], and the "persistent," more severe form, similar to peanut, nuts and seafood allergies. It can be definitively diagnosed with the blinded food challenge and the responsible allergens, milk proteins, are well characterized, including their 3-dimensional structures. Although strict milk avoidance diets have been the "standard of care" for milk-allergic patients, our recent data suggest that the majority of children will tolerate heat-denatured products without deleterious effects. In addition, preliminary studies with oral immunotherapy [OIT] have reported effective "desensitization" of milk-allergic patients, but whether true "tolerance" can be induced with this therapy remains to be demonstrated. In Aim #1 of this project, we will delineate clinical phenotypes of milk-allergic patients based upon their response to various forms of heat-denatured milk proteins, identify novel biomarkers differentiating the subgroups, and elucidate immunologic changes that accompany acquisition of tolerance. Furthermore, we hypothesize that progression toward immunological tolerance will occur more rapidly in children who are actively ingesting milk protein, and that tolerance will be associated with distinct changes in humoral and cellular function. In Aim #2 we will determine whether the combination of anti-lgE and milk OIT will induce clinical "tolerance" compared to the "desensitization" seen with OIT alone, and monitor associated immunologic changes. In conjunction with the other projects in this Center application, successful completion of these Aims will provide new insight into the immunologic changes associated with the development of oral tolerance to food, delineate phenotypic and immunologic differences in milk-allergic individuals, and possibly lead to a new paradigm in the medical management and treatment of milk-allergic individuals.