Differential Cytokine Secretion by Human Basophils

描述(由申请者提供)：这项资助描述了旨在扩大我们对人类过敏性疾病发病机制中涉及的组成部分的知识的研究，总的目标是确定可能成为治疗干预目标的因素或过程。最具体地说，这笔赠款侧重于人类嗜碱性粒细胞在慢性过敏过程中所起的作用，因为携带IgE的细胞具有产生大量IL-4和IL-13的非凡能力，这两种最公认的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合成和将初始T细胞分化为Th2细胞方面都是关键的，能够产生与过敏性炎症相关的其他细胞因子。这些细胞因子还通过上调内皮细胞上的特定黏附分子，促进嗜酸性粒细胞、淋巴细胞和嗜碱性粒细胞选择性地运输到变态反应性病变中。虽然在小鼠模型中的开创性研究首次表明肥大细胞在IgE介导的激活反应中产生这些细胞因子，但这些发现并未扩展到人类。相反，我们已经证明，与任何其他血液白细胞相比，嗜碱性粒细胞产生的IL-4和IL-13要多得多。最近的研究表明，在过敏病变中发现的细胞也是如此。嗜碱性粒细胞释放IL-4和IL-13的机制不同，与控制介质释放的机制也不同，表明药物对其分泌的控制也不同。新的发现表明，在接触结合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也受到不同的调节。特别是，我们发现负责结合CpG-DNA的受体TLR9在嗜碱性粒细胞上表达，暴露于CpG-DNA会抑制IgE介导的IL-4和IL-13的分泌。这可能为一种新型的CpG-DNA样材料(AIC)的临床疗效提供了一种机制，该材料目前正在进行豚草免疫治疗的临床试验。相反，嗜碱性粒细胞对不依赖于IgE的刺激所分泌的IL-13则通过TLR/配体的其他相互作用而增强。因此，通过TLR对嗜碱性粒细胞IL-4和IL-13的不同影响也可能有助于阐明细胞因子产生的调控机制。

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.