ANTIGEN PROCESSING IN COW MILK ALLERGY

牛奶过敏中的抗原处理

• 批准号: 6336276
• 负责人: Kirk E Sperber
• 金额: $ 16.01万
• 依托单位: MOUNT SINAI SCHOOL OF MEDICINE OF CUNY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至 2001-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6336276
• 关键词: adolescence (12-20); antigen presentation; child (0-11); clinical research; confocal scanning microscopy; cytotoxic T lymphocyte; developmental immunology; electron microscopy; food hypersensitivity; gastrointestinal epithelium; helper T lymphocyte; human subject; interferon gamma; interleukin 10; interleukin 12; interleukin 13; interleukin 4; intracellular transport; macrophage; milk; mucosal immunity; protein localization; tissue /cell culture

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.

牛奶过敏是儿童食物过敏最常见的原因之一。引起食物过敏的机制尚不清楚。牛奶过敏是一个有趣的问题，因为当胃肠道不断暴露于大量抗原时，肠道相关的淋巴组织会抑制免疫反应，以确保不会发生压倒性的炎症。肠上皮细胞组成性地表达主要组织相容性复合体（MHC） II类分子，除了它们在消化中的生理作用外，还能够加工和提呈抗原以刺激CD-8+ T抑制细胞，而不是主要刺激CD-4+T细胞的传统抗原提呈细胞（APC）。对牛奶过敏原的体液和细胞过敏反应的发展可能与IEC处理抗原的差异有关。该提案首先试图确定牛奶过敏原在iec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，然后利用来自相同上皮细胞的细胞系。为了确定牛奶蛋白是否遵循与IEC中其他抗原相似的路线，我们将使用真实的贩运。我们将在与抗原加工相关的细胞器中共同定位牛奶蛋白，并将尝试改变可能存在于过敏反应中的细胞因子的运输，包括IL-4、IL-10和il - 13。我们还将确定γ - ifn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隔间中的肽片段，研究牛奶过敏和非过敏患者IEC抗原处理的性质。如果牛奶过敏性IEC产生不同的表位，这些肽可能选择性地诱导牛奶蛋白反应性T细胞的产生，从而促进过敏体液（IgE）的产生，并试图在引物T细胞或T细胞克隆中恢复抗原特异性反应。我们将对牛奶蛋白产生的T细胞进行表型分析，以确定是否有CD-4+或CD-8+ T细胞的诱导。这种理解牛奶机制的方法是独特的，因为它将注意力集中在诱导位点而不是效应位点。这些研究的结果可能会改善牛奶过敏儿童的治疗方法。