ANTIGEN PROCESSING IN COW MILK ALLERGY

牛奶过敏是导致儿童食物过敏的最常见原因之一。导致食物过敏的机制还不是很清楚。牛奶过敏是一个有趣的问题，因为虽然胃肠道不断暴露于多种抗原，但免疫反应由肠道相关淋巴组织控制，以确保不会发生压倒性炎症。肠上皮细胞结构性地表达主要组织相容性复合体(MHC)II类分子，除了在消化过程中的生理作用外，还能够处理和递呈抗原来刺激CD-8T抑制细胞，而不是传统的抗原提呈细胞(APC)，后者主要刺激CD-4T细胞。对牛奶过敏原的体液和细胞过敏反应的发展可能与IEC处理抗原的不同有关。这项建议首先寻求确定牛奶过敏原在IECS中的运输是否与传统抗原不同。我们将利用来自牛奶患者的原代上皮细胞，然后从相同的上皮细胞衍生的细胞系。为了确定牛奶蛋白是否遵循与IEC中其他抗原相似的路线，我们将使用真实的运输。我们将在与抗原处理相关的细胞器中共同定位牛奶蛋白，并试图改变与细胞因子的运输，这些细胞因子可能存在于局部过敏反应中，包括IL-4、IL-10和IL13。我们还将确定伽玛-干扰素和IL-12是否具有相反的作用。然后，我们将通过比较不同处理间隔中的多肽片段来研究牛奶过敏和非过敏患者IEC抗原处理的性质。如果牛乳过敏性IEC产生不同的表位，这些多肽可能选择性地诱导牛乳蛋白反应性T细胞的产生，从而促进过敏性体液(IgE)，并试图恢复免疫T细胞或T细胞克隆的抗原特异性反应。我们将对牛奶蛋白产生的T细胞进行表型分析，以确定是否存在CD-4或CD-8 T细胞的诱导。这种理解牛奶机制的方法是独一无二的，因为它将注意力集中在诱导部位而不是效应部位。这些研究的结果可能会改进牛奶过敏儿童的治疗方法。

Cow milk allergy represents one of the most common causes of food hypersensitivity in children. The mechanisms responsible for the induction of food hypersensitivity are poorly understood. Cow milk allergy is an interesting problem since while the gastrointestinal tract is constantly exposed to numerous antigens, immune response are held in check by the gut-associated lymphoid tissue to ensure that overwhelming inflammation does not occur. Intestinal epithelial cells constitutively express major histocompatibility complex (MHC) class II molecules and, in addition to their physiologic roles in digestion, are capable of processing and presenting antigens to stimulate CD-8+ T suppressor cells as opposed to conventional antigen presenting cells (APC) which stimulate predominantly CD-4+T cells. The development of humoral and cellular allergic responses to cow milk allergens may be related to differences in antigen handling by the IEC. This proposal seeks first to determine if cow milk allergens traffic differently than conventional antigens in IECs. We will utilize primary epithelial cells from cow milk patients and then cell lines derived from the same epithelial cells. To determine if cow milk proteins follow a route similar to other antigens in IEC we will use real trafficking. We will co-localize cow milk proteins in organelles associated with antigen processing and will attempt to alter trafficking with cytokines that may be present locally in allergic responses including IL-4, IL-10, and IL13. We will also determine whether gamma-IFN and IL-12 have the opposite effect. We will then study the nature of the antigen processing of the IEC of cow milk allergic and non-allergic patients by comparing peptide fragments in the different processing compartments. If distinct epitopes are generated by the cow milk allergic IEC, such peptides might selectively induce the production of cow milk protein reactive T cells which may promote allergic humoral (IgE) and attempt to restore antigen specific responses in primed T cells or T cell clones. We will phenotypically analyze the T cells generated in response to cow milk proteins to determine if there induction of CD-4+ or CD-8+ T cells. This approach to understanding the mechanisms of cow milk is unique as it directs attention at the inductive site rather than the effector site. Results from these studies may lead to improved treatments for cow milk allergic children.