IL-33 and food allergy

项目摘要 在过去的几十年里，食物过敏的患病率有所增加，估计有5%的人 工业化国家的儿童和3-4%的成年人受到影响。食物过敏的定义是 暴露于特定食物后的免疫反应，可以表现为局部症状， 瘙痒、肿胀、腹泻等急性过敏反应。目前，几乎没有可用的治疗方法 预防或治疗食物过敏，现有的药物只能治疗过敏发作后的症状 反应考虑到食物过敏对公众健康和经济的影响， 开发治疗药物的新靶点，以及治疗这种疾病的潜在诊断工具， 使人虚弱的状况 众所周知，过敏性疾病往往在儿童时期以顺序方式发展， 这种现象被称为“特应性进行曲”。这种现象通常表现为儿童特应性 皮炎继续，随后发展为哮喘，或对空气过敏原的过敏反应。除了 哮喘和过敏性鼻炎，流行病学研究表明皮肤炎症 与特应性皮炎（AD）相关的过敏性皮炎是发生食物过敏的重要危险因素。在 此外，使用表皮致敏模型的动物研究表明， 致敏可使其它屏障部位易于发生抗原诱导的过敏性炎症。综合起来看， 这些数据表明皮肤可能是食物过敏原致敏的高度相关部位。但 皮肤中的抗原致敏可通过免疫机制使过敏性 肠道炎症尚不清楚。 越来越清楚的是，由屏障表面的上皮细胞产生的细胞因子发挥了重要作用。 在形成对食物抗原的反应中起重要作用。这些细胞因子包括TSLP、IL-25和IL-33， 其以协调的方式表达并具有促进2型炎症反应的能力 通过激活特定的先天免疫细胞群。对于本项目的工作很重要的是， 研究发现，TSLP介导的表皮致敏可加重过敏原诱导的气道或呼吸道疾病， 胃肠道炎症，支持TSLP在特应性进行中的作用。我们建立了一个食物模型 小鼠的过敏反应，使我们能够在低水平的 TSLP或IL-33，然后用相同抗原经口攻击。有趣的是，似乎IL-33是关键的， 在致敏和口服激发期间都很重要。我们将使用这个模型，结合样品 研究IL-33在食物过敏耐受性丧失中的作用。 抗原（目的1），并确定是否在IL-33和IL-1 RL 1的多态性与过敏性 对食物抗原的反应（目标2）。

Project Summary The prevalence of food allergies has increased in the past several decades with an estimated 5% of children and 3-4% of adults in industrialized countries affected. Food allergies are defined by an adverse immune response following exposure to a given food and can manifest in symptoms ranging from localized itching, swelling and diarrhea to acute anaphylaxis. Currently, there are few available treatments to either prevent or cure food allergies, and available medications only treat symptoms following onset of the allergic response. Given the public health and economic impact of food allergies, there is an urgent need to identify new targets for the development of therapeutics for treatment, as well as potential diagnostic tools, to treat this debilitating condition. It is well-established that allergic diseases tend to develop in a sequential manner in childhood, a phenomenon referred to as the `atopic march'. This phenomenon commonly manifests as a child with atopic dermatitis going on to subsequently develop asthma, or allergic reactions to aeroallergens. In addition to asthma and allergic rhinitis, epidemiological studies have demonstrated that cutaneous inflammation associated with atopic dermatitis (AD) is a significant risk factor for the development of food allergies. In addition, animal studies using models of epicutaneous sensitization have demonstrated that this route of sensitization can predispose to antigen-induced allergic inflammation at other barrier sites. Taken together, these data indicate that the skin may be a highly relevant site of food allergen sensitization. However, the immunological mechanisms through which antigen sensitization in the skin can predispose to allergic inflammation in the intestine are unclear. It is becoming increasingly clear that cytokines produced by epithelial cells at barrier surfaces play an important role in shaping the responses to food antigens. These cytokines include TSLP, IL-25 and IL-33, which are expressed in coordinated fashion and have the ability to promote type 2 inflammatory responses through the activation of specific innate immune cell populations. Important for the work in this project, several studies have found that TSLP-mediated epicutaneous sensitization can exacerbate allergen-induced airway or GI tract inflammation, supporting a role for TSLP in the atopic march. We have established a model of food allergic responses in mice that allows us to perform epicutaneous sensitization in the presence of low levels of TSLP or IL-33, followed by oral challenge with the same antigen. Interestingly, it appears that IL-33 is critically important during both sensitization and oral challenge. We will use this model, in conjunction with samples from human patients with food allergies, to investigate the role of IL-33 in the loss of tolerance to food-related antigens (Aim 1), and determine whether polymorphisms in the IL-33 and IL-1RL1 correlate with allergic responses to food antigens (Aim 2).