Immunologic Basis of Cow Milk Induced Hypersensitvities

牛奶过敏[CMA]影响2.5%的出生前两年的婴儿或美国每年约100,000例新病例。在这些牛奶过敏性疾病中，免疫球蛋白E介导的机制占60%，其中大部分涉及皮肤，而大多数非IgE介导的反应涉及胃肠道。大约80%的婴儿在出生后的头3-4年里会“超过”他们的CMA[形成临床耐受性]，但35%的IgE介导的CMA儿童会发展成其他食物过敏，60%会发展成呼吸道过敏。在过去的授权期内，我们招募了一大批定义明确的CMA患者，比较了不同患者组的体液和细胞反应，并确定了持续性CMA患者独特的过敏表位识别。然而，这些疾病的潜在的牛奶诱导的免疫病理机制及其随后的解决方案仍然知之甚少。CMA患者组和正常对照组的原代肠上皮细胞系在抗原处理方面没有差异，包括转运、组织蛋白酶的表达和活性、抗原肽以及刺激CD4+或CD8+T细胞增殖的能力。我们建立了IgE介导的CMA小鼠模型和分离的肠环，以探讨CMA所涉及的免疫调节机制以及正常吸收上皮(E环)与M细胞及其相关的Peyer‘s结(M环)在耐受形成中的作用。 该计划项目的综合资源为确定四种常见CMA的免疫学基础提供了一个独特的机会。在参与该计划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背后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CD23作为IgE双向转运体的功能及其在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 CMA的正常肠道相关耐受性和病理反应。第四个项目将进一步研究CMA和牛奶耐受小鼠模型中的致病免疫调节反应，并评估[根据项目1中收集的信息]使用“工程”重组蛋白逆转牛奶诱导的过敏反应小鼠的CMA。

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.