Tolerance vs. Allergenicity; Factors Dictating Differing Responses

口服化合物的正常反应的本质是耐受性或主动无反应。 致AGS。虽然有许多方法可以达到这种容忍状态，但似乎会导致几种疾病 当这些机制失效时。食物过敏就是这样一种表现，由正常饮食失灵引起。 要有容忍度。这种反应存在两个阶段：第一个阶段是对银的敏化(与 当再次暴露导致过敏反应症状时，第二种是诱导IgE)。自.以来 第二个事件发生得相当快，食物过敏中存在的耐受性缺陷很可能发生在 反应的敏化阶段。银染本身也起到了作用。在所有口服的AGS中，只有一种非常 少数人是食物过敏的原因。因此，我们要问，是什么使银成为食物过敏原？相同 加工不同的食物可以诱发或预防食物过敏(干烤花生和煮花生)，但 这些过程对致敏还是实际的过敏反应更重要。在最后一次批准中 期间，我们观察了不同的牛奶AGS对过敏反应的敏化能力和触发过敏反应的能力 牛奶致过敏反应的小鼠模型。可溶性蛋白质(ALA、BLG)主要被小分子吸收 肠道吸收上皮。酪蛋白以微细胞(聚集)的形式存在，是一种有效的诱导剂 免疫球蛋白E应答，并被覆盖在PPS上的M细胞摄取。有趣的是，ALA和BLG(通过 巴氏杀菌)改变摄取途径(从I EC到M细胞)，这种变化与 免疫原性和IgE诱导性增加，但引发实际过敏反应的能力降低 回应。我们已经提出了一个模型，在这个模型中，食物过敏原通过在PPS中进行Ag采样而发生 然而，过敏反应的实际触发有利于经历跨上皮运输的可溶性AGS。我们 我开发了一种独特的肠循环模型，其中仅包含PPS或LEC(没有 交叉指状DC)的形成。我们已经证明，耐受性可以通过多肽(或蛋白质)诱导 片段)给药，可诱导低剂量(调节)耐受性 针对CD4或CD8+T细胞的多肽(分别为OVA323-339和SIINFEKL)。在接下来的这个 我们建议通过以下方式分析耐受性的组成部分与过敏反应的诱导 既阐明了抗原的作用，又阐明了产生的免疫反应的性质。这些研究将是 与项目1和2(烘焙牛奶蛋白和IEC的影响和贩运)的研究协调进行 通过CD23进行跨上皮运输)。我们将通过目标1实现这些目标。确定路线是否 致敏的程度在随后对牛奶过敏原的过敏反应的发展中起着关键作用。 目标#2定义导致AGS食物过敏原的个别因素，并确定在 牛奶变应原的启动过程目标3.确定CDS和CD4+T细胞在启动和耐受中的作用。

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.