Innate Immune Function of FcERI-Bearing Cells

携带 FcERI 的细胞的先天免疫功能

• 批准号: 7150228
• 负责人: JOHN T. SCHROEDER
• 金额: $ 22.59万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7150228
• 关键词: allergens; antibody receptor; antigen presenting cell; cell surface receptors; cooperative study; crosslink; dendritic cells; food hypersensitivity; human subject; hypersensitivity; immune response; immunity; immunoglobulin E; immunoregulation; interleukin 13; interleukin 4; monoclonal antibody; pathologic process; patient oriented research; receptor expression

Since its discovery some forty years ago, immunoglobulin (lg)E antibody is perhaps the most central factor known contributing to the pathogenesis of allergic inflammation and disease. Whereas its role in triggering histamine and leukotriene C4 (LTC4) release from basophils and mast cells has long been appreciated, the nature of this immunoglobulin in modulating the function of other IgE receptor-bearing cells is poorly understood. In particular, this immunoglobulin is also known to bind and modulate the function of dendritic cells (DC), which are the most potent antigen-presenting cells (APCs) known to initiate immune responses by activating naive T cells for effector functions. Our preliminary in vitro data has recently identified novel phenotypic and functional changes in DC upon cross-linking IgE on the surface of these cells. Specifically, these data imply a mechanism were allergen, by cross-linking IgE/receptor complexes, counter-regulates specific innate immune responses in DC that are normally pro-Th1 (i.e. anti-allergic) in nature. Thus, IgE may very well augment the maturation of DC into APC that promote allergic disease by preventing cytokine responses in these cells that normally prevent progression of allergic inflammation. By depleting IgE in vivo using omalizumab administration, the Aims presented in this project should provide "proof-of-concept" that IgE does, indeed, play a critical role in regulating innate and adaptive immune capabilities of DC and consequently the activity of other immune cells dependent of and/or regulated by DC function. In Aim 1. we will monitor the loss of IgE receptor expression on DC from Cat and Food allergic subjects receiving omalizumab and investigate these cells for changes in specific innate and adoptive immune responses ex vivo. In Aim 2. phenotypic and functional markers related to innate and adaptive immunity will also be monitored in/on human basophils following omalizumab administration. We hypothesis that relevant cytokines (IL-4 and IL-13) prominently secreted by these cells in response to allergen, but also in response to specific innate immune stimuli, will additionally be inhibited with IgE depletion. Finally, we have shown that allergen exposure induces systemic "priming" effects in blood basophils, which inversely relate to DC innate immune responses. In Aim 3. we'll explore the effect of depleting IgE using omalizumab to better define the role of this immunoglobulin in these clinically relevant responses, including those occurring in the lung. Overall, these studies should resolve mystery surrounding the role IgE plays in suppressing innate immune responses, and provide new insights into the pathophysiology and treatment of allergic disease states.

免疫球蛋白（lg）E抗体自40年前发现以来，可能是最核心的免疫球蛋白（lg）E抗体。 已知有助于过敏性炎症和疾病的发病机制的因子。而其在 触发组胺和白三烯C4（LTC4）从嗜碱性粒细胞和肥大细胞释放， 我们认识到，这种免疫球蛋白在调节其他携带IgE受体的免疫球蛋白的功能中的性质。 对细胞了解甚少。特别地，还已知该免疫球蛋白结合并调节免疫球蛋白。 树突状细胞（DC）是已知的最有效的抗原呈递细胞（APC）， 通过激活初始T细胞的效应子功能来启动免疫应答。我们的初步体外数据 最近鉴定了DC在交联IgE后的新的表型和功能变化， 这些细胞的表面。具体地说，这些数据暗示了过敏原通过交联 IgE/受体复合物，反调节DC中的特异性先天免疫应答，这些应答通常是 Pro-Th1（即抗过敏）。因此，IgE可以很好地促进DC成熟为APC 通过阻止这些细胞中的细胞因子反应来促进过敏性疾病， 过敏性炎症的进展。通过使用奥马珠单抗施用在体内消耗IgE， 在这个项目中提出的应该提供“概念证明”，IgE确实发挥了关键作用， 调节DC的先天性和适应性免疫能力，从而调节其他免疫系统的活性。 依赖于DC功能和/或受DC功能调节的细胞。在目标1中。我们将监测IgE受体的丢失 在来自接受奥马珠单抗的猫和食物过敏受试者的DC上的表达，并研究这些细胞 特异性先天性和过继性免疫应答的变化。在目标2中。表型和 还将在人嗜碱性粒细胞中/上监测与先天性和适应性免疫相关的功能标记 奥马珠单抗给药后。我们假设相关的细胞因子（IL-4和IL-13）显著地 由这些细胞响应于过敏原而分泌，但也响应于特异性先天免疫刺激， 将另外被IgE耗竭抑制。最后，我们已经表明，过敏原暴露诱导 在血液嗜碱性粒细胞中的系统性"引发"效应，其与DC先天免疫应答负相关。在 目标3.我们将探索使用奥马珠单抗消耗IgE的效果，以更好地定义这种作用。 免疫球蛋白在这些临床相关的反应，包括那些发生在肺。总的来说， 这些研究应该解决围绕IgE在抑制先天性免疫中所起作用的谜团， 反应，并提供了新的见解的病理生理学和治疗过敏性疾病状态。