Tolerance vs. Allergenicity; Factors Dictating Differing Responses

耐受性与过敏性；

• 批准号: 7976575
• 负责人: Lloyd F Mayer
• 金额: $ 37.85万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7976575
• 关键词: Accounting; Acids; Allergens; Allergic; Anaphylaxis; CD4 Positive T Lymphocytes; CD8B1 gene; Caseins; Cattle; Cell Degranulation; Cells; Defect; Development; Digestion; Disease; Dose; Epithelial; Epithelium; Event; Failure; Food Hypersensitivity; Food Processing; Furuncles; Goals; Grant; Heating; Hypersensitivity; IgE; Immune response; Immune system; Immunologics; Individual; Intestines; M cell; Milk; Milk Proteins; Modeling; Mus; Nature; Pathway interactions; Peanuts - dietary; Peptides; Phase; Play; Process; Protein Fragment; Proteins; Proteolysis; Resistance; Role; Route; Sampling; Site; Symptoms; T-Lymphocyte; anergy; base; food allergen; immunogenicity; mast cell; pasteurization; response; trafficking; uptake

The nature of the normal response to orally administered compounds is one of tolerance or an active nonresponse to Ags. While there are many ways to achieve this tolerant state, several diseases appear to result when these mechanisms fail. Food allergy is one such manifestation resulting from the failure of normal tolerance to occur. Two phases of this response exist: the first where sensitization to the Ag occurs (with the induction of IgE) and second when re-exposure results in the symptoms of the allergic response. Since the second event occurs quite rapidly the defects in tolerance that exist in food allergy likely occur at the sensitizing phase of the response. The Ag itself also plays a role. Of all the Ags ingested orally only a very small number account for food allergy. We therefore ask what makes an Ag a food allergen? The same foods processed differently can either induce or protect from food allergy (dry roasted vs boiled peanuts) but are these processes are more important for sensitization or the actual allergic response. In the last granting period we looked at distinct milk Ags for their ability to sensitize vs. trigger an anaphylactic response in a murine model of milk induced anaphylaxis. Soluble proteins (ALA, BLG) are largely taken up by small intestinal absorptive epithelium. Casein, which exists in a micellular (aggregated) form is a potent inducer of an IgE response and is taken up by M cells overlying PPs. Interestingly aggregation of ALA and BLG (via pasteurization) alters the pathway of uptake (from I EC to M cell) and this change is associated with an increase in immunogenicity and IgE induction but a decreased ability to trigger the actual anaphylactic response. We have proposed a model whereby sensitization to food allergens occurs via Ag sampling in PPs whereas the actual triggering of anaphylaxis favors soluble Ags that undergo transepithelial transport. We have developed a unique intestinal loop model, where loops containing either PPs or lECs only (without interdigitating DCs) are fashioned. We have shown that tolerance can be induced via peptide (or protein fragment) administration into either loop and that low dose (regulatory) tolerance can be induced with peptides specific for either CD4 or CD8+ T cells (OVA323-339 vs SIINFEKL respectively). In this next granting period we propose to analyze the components of tolerance vs induction of an allergic response by both clarifying the role of the Ag and the nature of the immune response generated. These studies will be performed in concert with studies in Project 1 and 2 (the effect and trafficking of baked milk proteins and IEC transepithelial transport via CD23). We will accomplish these goals by Aim #1. Determine whether the route of sensitization plays a critical role in the subsequent development of an allergic response to milk allergens. Aim #2 Define the individual factors that make Ags food allergens and determine the initial steps in the priming process of milk allergens Aim #3. Determine the role of CDS vs CD4+ T cells in priming vs tolerance.

对口服化合物的正常反应的本质是耐受或主动无反应之一 到阿格斯。虽然有很多方法可以达到这种耐受状态，但似乎会导致几种疾病 当这些机制失效时。食物过敏就是由于正常的免疫系统失败而导致的一种表现。 耐受发生。这种反应存在两个阶段：第一个阶段发生对 Ag 的敏化（随着 IgE 的诱导），其次是再次接触导致过敏反应症状。自从 第二个事件发生得相当快，食物过敏中存在的耐受缺陷很可能发生在 反应的敏化阶段。 Ag 本身也发挥着作用。在所有口服摄入的 Ag 中，只有极少数是通过口服摄入的。 食物过敏占少数。因此我们要问，是什么使银成为食物过敏原？相同 以不同方式加工的食物可以诱发或防止食物过敏（干烤花生与煮花生），但是 这些过程对于致敏还是实际的过敏反应更重要？在最后一次授予中 在此期间，我们研究了不同的牛奶抗原，了解它们致敏与触发过敏反应的能力。 牛奶引起的过敏反应的小鼠模型。可溶性蛋白质（ALA、BLG）大部分被小分子吸收 肠吸收上皮。酪蛋白以胶束（聚集）形式存在，是一种有效的诱导剂 IgE 反应并被 PP 上的 M 细胞吸收。有趣的是 ALA 和 BLG 的聚合（通过 巴氏灭菌）改变了摄取途径（从 I EC 到 M 细胞），这种变化与 免疫原性和 IgE 诱导增加，但触发实际过敏反应的能力下降 回复。我们提出了一个模型，通过 PP 中的银采样来发生对食物过敏原的过敏 而过敏反应的实际触发有利于可溶性抗原进行跨上皮转运。我们 开发了一种独特的肠循环模型，其中循环仅包含 PP 或 LEC（不含 叉指状 DC）已形成。我们已经证明可以通过肽（或蛋白质）诱导耐受性 片段）施用到任一环中，并且可以诱导低剂量（调节）耐受性 CD4 或 CD8+ T 细胞特异性肽（分别为 OVA323-339 与 SIINFEKL）。在这接下来 授予期我们建议通过以下方式分析耐受性与过敏反应诱导的组成部分 两者都阐明了 Ag 的作用和产生的免疫反应的性质。这些研究将 与项目 1 和 2 的研究（烘焙牛奶蛋白的影响和运输以及 IEC 通过 CD23 进行跨上皮转运）。我们将通过目标#1 来实现这些目标。判断是否有路由 致敏作用在随后对牛奶过敏原的过敏反应的发展中起着至关重要的作用。 目标 #2 定义导致 Ags 食物过敏原的个体因素，并确定该方案的初始步骤 牛奶过敏原的启动过程目标#3。确定 CDS 与 CD4+ T 细胞在启动与耐受中的作用。