Tolerance vs. Allergenicity; Factors Dictating Differing Responses

对口服给药化合物的正常反应的性质是耐受性或主动无反应 给艾格斯虽然有许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。食物过敏是一种这样的表现，从失败的正常 宽容发生。这种反应存在两个阶段：第一阶段发生对Ag的致敏（随着 IgE的诱导），其次是再次暴露导致过敏反应的症状。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可能发生在 反应的敏感阶段。此外，AG本身也发挥了一定的作用。在所有口服的阿格列汀中， 少数人对食物过敏。因此，我们要问，是什么使Ag成为食物过敏原？相同的 不同加工的食物可以诱导或防止食物过敏（干烤花生与煮花生）， 这些过程对于致敏或实际的过敏反应更重要。在最后一次授予 在此期间，我们观察了不同的牛奶抗原在过敏性反应中致敏与触发过敏反应的能力。 牛奶诱导的过敏反应的小鼠模型。可溶性蛋白质（ALA，BLG）主要被小分子 肠吸收上皮酪蛋白，其以胶束（聚集）形式存在，是一种有效的诱导剂， IgE反应，并被覆盖PP的M细胞吸收。有趣的是，ALA和BLG的聚集（通过 巴氏灭菌）改变了摄取途径（从IEC到M细胞），并且这种变化与 免疫原性和IgE诱导增加，但触发实际过敏反应的能力降低 反应我们提出了一个模型，即通过在PP中进行Ag采样， 而过敏反应的实际触发有利于进行跨上皮转运的可溶性Ag。我们 已经开发了一种独特的肠袢模型，其中仅含有PP或lEC的肠袢（不含 指状交错DC）被形成。我们已经表明，耐受性可以通过肽（或蛋白质）诱导， 片段）给药到任一环中，且低剂量（调节性）耐受性可以用 对CD 4或CD 8 + T细胞具有特异性的肽（分别为OVA 323 -339对SIINFEKL）。在下一 在此期间，我们建议通过以下方法分析耐受性与过敏反应诱导的成分： 阐明了Ag的作用和所产生的免疫应答的性质。这些研究报告将 与项目1和项目2的研究（烘焙乳蛋白的影响和运输以及IEC 通过CD 23的跨上皮转运）。我们将通过目标#1实现这些目标。确定路线是否 致敏性在随后对牛奶过敏原的过敏反应的发展中起着关键作用。 目的#2定义造成Ags食物过敏原的各个因素，并确定治疗的初始步骤。 牛奶过敏原的引发过程目标#3。确定CDS与CD 4 + T细胞在引发与耐受中的作用。

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.