Innate Immune Function of FcERI-Bearing Cells

携带 FcERI 的细胞的先天免疫功能

基本信息

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
项目类别：
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

项目摘要

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.

自大约四十年前发现以来，免疫球蛋白 (lg)E 抗体可能是最重要的抗体已知导致过敏性炎症和疾病发病机制的因素。鉴于其作用长期以来，人们一直认为触发嗜碱性粒细胞和肥大细胞释放组胺和白三烯 C4 (LTC4) 认识到这种免疫球蛋白在调节其他 IgE 受体承载功能方面的性质对细胞知之甚少。特别是，这种免疫球蛋白还可以结合并调节树突状细胞 (DC) 的功能，树突状细胞是已知最有效的抗原呈递细胞 (APC) 通过激活幼稚 T 细胞的效应功能来启动免疫反应。我们的初步体外数据最近发现 DC 在交联 IgE 时发生了新的表型和功能变化这些细胞的表面。具体来说，这些数据暗示一种机制是过敏原，通过交联 IgE/受体复合物，反调节 DC 中通常发生的特定先天免疫反应本质上是 pro-Th1（即抗过敏）。因此，IgE 可以很好地促进 DC 向 APC 的成熟通过阻止这些细胞中的细胞因子反应来促进过敏性疾病，而细胞因子反应通常会预防过敏性炎症的进展。通过使用奥马珠单抗给药在体内消耗 IgE，这个项目中提出的应该提供“概念验证”，即 IgE 确实在调节 DC 的先天性和适应性免疫能力，从而调节其他免疫活性细胞依赖于 DC 功能和/或受 DC 功能调节。在目标 1 中，我们将监测 IgE 受体的损失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用于离体特定先天和过继免疫反应的变化。目标 2. 表型和与先天性和适应性免疫相关的功能标记也将在人类嗜碱性粒细胞中进行监测奥马珠单抗给药后。我们假设相关细胞因子（IL-4 和 IL-13）在这些细胞不仅响应过敏原而分泌，而且还响应特定的先天免疫刺激，另外，IgE 耗尽也会受到抑制。最后，我们已经证明，接触过敏原会导致血液嗜碱性粒细胞中的全身“启动”效应，与 DC 固有免疫反应成反比。在目标 3. 我们将探讨使用奥马珠单抗消耗 IgE 的效果，以更好地定义其作用免疫球蛋白参与这些临床相关反应，包括发生在肺部的反应。全面的，这些研究应该能够解开有关 IgE 在抑制先天免疫中的作用的谜团反应，并为过敏性疾病状态的病理生理学和治疗提供新的见解。