Differential Cytokine Secretion by Human Basophils

描述（由申请人提供）：该资助描述了旨在扩大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用于治疗干预的元素或过程。更具体地说，这项资助的重点是人类嗜碱性粒细胞在慢性过敏过程中发挥的作用，因为携带IgE的细胞具有产生大量IL-4和IL-13的显着能力，这两种最公认的Th 2细胞因子是过敏素质的核心。IL-4和IL-13在启动B细胞中的IgE合成和将初始T细胞分化为能够产生与过敏性炎症相关的其它细胞因子的Th 2细胞中都是关键的。这些细胞因子还通过上调内皮细胞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到过敏性病变中。虽然在小鼠模型中的精液研究首次表明肥大细胞响应IgE介导的活化而产生这些细胞因子，但这些发现尚未扩展到人类。相反，我们已经证明，嗜碱性粒细胞产生的IL-4和IL-13远远超过任何其他血液白细胞。最近的研究表明，这也适用于过敏性病变中发现的细胞。在嗜碱性粒细胞中IL-4和IL-13的释放所涉及的机制彼此不同，并且与控制介质释放的机制不同，这表明它们分泌的药理学控制也不同。新的研究结果表明，IL-4和IL-13也在嗜碱性粒细胞暴露于结合Toll样受体（TLR）家族特定成员的配体后受到差异调节。特别地，我们发现负责结合CpG-DNA的受体TLR 9在嗜碱性粒细胞上表达，并且暴露于CpG-DNA导致IgE介导的IL-4和IL-13分泌的抑制。这可能提供了一种新的CpG-DNA样物质（AIC）的临床疗效的机制，该物质目前正在豚草免疫治疗的临床试验中。相比之下，由嗜碱性粒细胞分泌的IL-13响应于IgE非依赖性刺激，增强与其他TLR/配体相互作用。因此，通过TLR介导的对嗜碱性粒细胞IL-4和IL-13的这些不同作用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.