Differential Cytokine Secretion by Human Basophils

人类嗜碱性粒细胞的差异细胞因子分泌

• 批准号: 6856521
• 负责人: JOHN T. SCHROEDER
• 金额: $ 32.7万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-06-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6856521
• 关键词: CpG islands; antibody formation; antibody receptor; basophils; clinical research; enzyme linked immunosorbent assay; flow cytometry; gel mobility shift assay; human subject; hypersensitivity; immunoglobulin G; interleukin 13; interleukin 3; interleukin 4; leukocyte activation /transformation; nerve growth factors; nuclear factor kappa beta; pathologic process; receptor binding; receptor expression; secretion; tissue /cell culture; toll like receptor; transcription factor; western blottings

DESCRIPTION (provided by applicant): This grant describes studies that are intended to expand our knowledge of the components involved in the pathogenesis of human allergic disease, with the general goal of identifying elements or processes that might be targeted for therapeutic intervention. Most specifically, this grant focuses on the role human basophils play in chronic allergic processes as IgE-bearing cells having remarkable ability to produce large quantities of IL-4 and IL-13 -the two most recognized Th2 cytokines at the core of the allergic diathesis. Both IL-4 and IL-13 are critical in initiating IgE synthesis in B cells and in differentiating naive T cells into Th2 cells capable of producing other cytokines associated with allergic inflammation. These cytokines also promote the selective trafficking of eosinophils, lymphocytes, and basophils into allergic lesions by up-regulating specific adhesion molecules on the endothelium. While seminal studies in the mouse model first suggested that mast cells produce these cytokine in response to IgE-mediated activation, these findings have not extended to humans. In contrast, we have demonstrated that basophils produce far more IL-4 and IL-13 in comparison to any other blood leukocyte. Recent studies suggest that this is also true for cells found in allergic lesions. The mechanisms involved in the release of IL-4 and IL-13 in basophils are both different from each other and from those controlling mediator release, suggesting that pharmacological control of their secretion will also differ. New findings suggest that IL-4 and IL-13 are also differentially regulated in basophils following exposure to ligands that bind specific members of the Toll-like receptor (TLR) family. In particular, we have found that TLR9, the receptor responsible for binding CpG-DNA, is expressed on basophils and that exposure to CpG-DNA results in an inhibition of IgE-mediated IL-4 and IL-13 secretion. This may provide one mechanism for the clinical efficacy seen with a novel CpG-DNA-like material (AIC) that is currently in clinical trials for ragweed immunotherapy. In contrast, the IL-13 secreted by basophils in response to IgE-independent stimuli is enhanced with other TLR/ligand interactions. Thus, these differential effects on basophil IL-4 and IL-13, mediated through TLR, may also help in delineating the mechanisms regulating cytokine production.

描述（由申请人提供）：这项资助描述了旨在扩展我们对人类过敏性疾病发病机制所涉及的成分的了解的研究，其总体目标是确定可能针对治疗干预的元素或过程。最具体地说，这项资助重点关注人类嗜碱性粒细胞在慢性过敏过程中的作用，因为携带 IgE 的细胞具有产生大量 IL-4 和 IL-13 的卓越能力，这两种最受认可的 Th2 细胞因子是过敏素质的核心。 IL-4 和 IL-13 对于启动 B 细胞中 IgE 合成以及将初始 T 细胞分化为能够产生与过敏性炎症相关的其他细胞因子的 Th2 细胞至关重要。这些细胞因子还通过上调内皮上的特异性粘附分子，促进嗜酸性粒细胞、淋巴细胞和嗜碱性粒细胞选择性运输至过敏性病变。虽然小鼠模型中的开创性研究首先表明肥大细胞响应 IgE 介导的激活而产生这些细胞因子，但这些发现尚未扩展到人类。相比之下，我们已经证明，与任何其他血液白细胞相比，嗜碱性粒细胞产生更多的 IL-4 和 IL-13。最近的研究表明，对于过敏性病变中发现的细胞来说也是如此。嗜碱性粒细胞中 IL-4 和 IL-13 释放所涉及的机制彼此不同，也与控制介质释放的机制不同，这表明对其分泌的药理学控制也不同。新的研究结果表明，在暴露于结合 Toll 样受体 (TLR) 家族特定成员的配体后，嗜碱性粒细胞中的 IL-4 和 IL-13 也受到差异性调节。特别是，我们发现 TLR9（负责结合 CpG-DNA 的受体）在嗜碱性粒细胞上表达，暴露于 CpG-DNA 会导致 IgE 介导的 IL-4 和 IL-13 分泌受到抑制。这可能为目前正在进行豚草免疫疗法临床试验的新型 CpG-DNA 类材料 (AIC) 的临床疗效提供一种机制。相比之下，嗜碱性粒细胞响应 IgE 独立刺激而分泌的 IL-13 通过其他 TLR/配体相互作用而增强。因此，这些通过 TLR 介导的对嗜碱性粒细胞 IL-4 和 IL-13 的不同影响也可能有助于描述调节细胞因子产生的机制。