Differential Cytokine Secretion by Human Basophils

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组成部分的知识的研究，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，这项资助的重点是人类嗜碱性细胞在慢性过敏过程中的作用，作为携带ige的细胞，具有显著的能力产生大量的IL-4和IL-13，这两种最被认可的Th2细胞因子是过敏素质的核心。IL-4和IL-13在启动B细胞的IgE合成和将幼稚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细胞中起关键作用。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地转运到过敏性病变。虽然小鼠模型的开创性研究首次表明肥大细胞在ige介导的激活下产生这些细胞因子，但这些发现尚未扩展到人类。相反，我们已经证明，与任何其他血液白细胞相比，嗜碱性细胞产生更多的IL-4和IL-13。最近的研究表明，在过敏性病变中发现的细胞也是如此。嗜碱性细胞中IL-4和IL-13的释放机制彼此不同，与控制介质释放的机制也不同，这表明对它们分泌的药理控制也不同。新的研究结果表明，暴露于结合toll样受体（TLR）家族特定成员的配体后，IL-4和IL-13在嗜碱性细胞中也受到差异调节。特别是，我们发现负责结合CpG-DNA的受体TLR9在嗜碱性细胞上表达，暴露于CpG-DNA会抑制ige介导的IL-4和IL-13分泌。这可能为一种新型cpg - dna样材料（AIC）的临床疗效提供了一种机制，这种材料目前正在豚草免疫治疗的临床试验中。相反，嗜碱性细胞在响应ige非依赖性刺激时分泌的IL-13随着其他TLR/配体的相互作用而增强。因此，这些通过TLR介导的对嗜碱性粒细胞IL-4和IL-13的差异影响也可能有助于描述调节细胞因子产生的机制。

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.