Immunologic Basis of Cow Milk Induced Hypersensitvities

牛奶过敏[CMA]影响2.5%的婴儿在生命的前2年或每年约100，000例新发病例在美国，IgE介导的机制占这些牛奶过敏性疾病的60%，其中大多数涉及皮肤，而大多数非IgE介导的反应涉及胃肠道。大约80%的婴儿在出生后的前3 - 4年内“长大”，但35%的IgE介导的CMA儿童发展为其他食物过敏，60%发展为呼吸道过敏。在过去的授权期间，我们招募了大量明确定义的CMA患者，比较了不同患者组的体液和细胞反应，并确定了持续CMA患者的独特过敏原表位识别。然而，这些疾病的潜在牛奶诱导的免疫病理学及其随后的解决方案仍然知之甚少。利用来自不同CMA患者组和正常对照组的原代肠上皮细胞系，未发现抗原加工（包括运输、组织蛋白酶表达和活性、抗原肽或刺激CD 4+或CD 8 + T细胞增殖的能力）存在差异。建立了IgE介导的CMA和离体肠袢的小鼠模型，以剖析CMA中涉及的免疫调节机制以及正常吸收上皮（E袢）与M细胞和相关Peyer集合淋巴结（M袢）在耐受性发展中的作用。 该项目的综合资源提供了一个独特的机会，以确定四种常见形式的CMA的免疫学基础。在该计划中招募的明确定义的患者队列的基础上，第一个项目将进一步研究这些疾病的独特体液和细胞机制以及与临床耐受性发展相关的变化。第二个项目将重点研究肠上皮细胞CD 23作为IgE双向转运蛋白的功能及其在CMA中的作用。第三个项目将利用一种新的体内肠环模型来剖析与诱导 正常肠道相关耐受和CMA的病理反应。第四个项目将进一步研究CMA和牛奶耐受性小鼠模型中的致病性免疫调节反应，并评估“工程化”重组蛋白[来自项目1中收集的信息]在牛奶诱导过敏反应小鼠中逆转CMA的用途。

Cow milk allergy [CMA] affects 2.5% of infants in the first 2 years of life or about 100,000 new cases per year in the U.S. IgE-mediated mechanisms account for 60% of these milk allergic disorders, with the majority involving the skin, while the majority of non-IgE-mediated reactions involve the gastrointestinal tract. About 80% of infants "outgrow" their CMA [develop clinical tolerance] in the first 3 - 4 years of life, but 35% of children with IgE-mediated CMA develop other food allergies and 60% develop respiratory allergy. Over the past granting period, we have enrolled a large cohort of well-defined patients with CMAs, compared humoral and cellular responses in different patient groups, and identified unique allergenic epitope recognition in patients with persistent CMA. However, the underlying milk-induced immunopathology of these disorders and their subsequent resolution remain poorly understood. Utilizing primary intestinal epithelial cell lines from different patient groups with CMA and normal controls, no differences were found in antigen processing including trafficking, cathepsin expression and activity, antigenic peptides, or the capacity to stimulate CD4 + or CD8 + T cell proliferation. Murine models of IgE-mediated CMA and isolated gut loops were developed to dissect immunoregulatory mechanisms involved in CMA and the role of the normal absorptive epithelium (E loops) vs the M cells and associated Peyer's patches in (M loops) in the development of tolerance. The combined resources of this program project provide a unique opportunity to define the immunologic bases for four common forms of CMA. Building on the well-defined patient cohorts enrolled in the program, the first project will further investigate unique humoral and cellular mechanisms underlying these disorders and changes associated with the development of clinical tolerance. The second project will focus on the function of intestinal epithelial cell CD23 as a bi-directional transporter of IgE and its role in CMA. The third project will utilize a novel in vivo gut-loop model to dissect immunologic mechanisms associated with the induction of normal gut-associated tolerance and pathologic responses of CMA. The fourth project will further investigate pathogenic immunoregulatory responses in murine models of CMA and cow milk tolerance, and evaluate the use of"engineered" recombinant proteins [from information gleaned in Project #1 ] to reverse CMA in mice with milk-induced anaphylaxis.