Department of Asthma, Allergy and Respiratory Science, Division of Asthma, Allergy & Lung Biology, MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, King's College London, , London, UK.
Thorax. 2014 Apr;69(4):335-45. doi: 10.1136/thoraxjnl-2013-204324. Epub 2013 Nov 20.
T-cell targeted peptide epitope tolerogens from grass pollen allergens may be useful in treating seasonal allergic rhinitis, but there is urgent need for optimisation of approaches from improved understanding of mechanism.
We sought to identify human leukocyte antigen (HLA)-DR1-restricted epitopes from the Timothy grass pollen allergen, Phleum pratense, and characterise T-cell immune regulation following intranasal administration of a single, immunodominant epitope.
T-cell epitopes within P pratense were identified using HLA-DR1 transgenic mice and tetramer-guided epitope mapping (TGEM) in HLA-DR1-positive individuals with grass allergy. An immunodominant epitope was tested in HLA-DR1 transgenics for impact on responses to whole Phl p5 b or peptide. Microarrays and quantitative PCR were used to characterise T-cell immunity.
Peptide 26 (p26) was identified in HLA-DR1 transgenic mice and by TGEM analysis of HLA-DR1-positive individuals with grass allergy. p26 shows promiscuous binding to a wide range of HLA class II alleles, making it of relevance across immunogenetically diverse patients. The epitope is conserved in rye and velvet grass, making it applicable across a spectrum of grass pollen allergy. Intranasal pretreatment of mice with p26 results in significantly reduced T-cell responses. Transcriptomic array analysis in mice showed T-cell regulation in the intranasal treatment group associated with increased expression of members of the Cbl-b and Itch E3 ubiquitin ligase pathway.
We defined an immunodominant P pratense epitope, p26, with broad binding across multiple HLA class II alleles. Intranasal treatment of mice with p26 results in T-cell regulation to whole allergen, involving the Cbl-b and Itch regulatory pathway.
来自草花粉过敏原的 T 细胞靶向肽表位耐受原可能对治疗季节性过敏性鼻炎有用,但迫切需要通过深入了解机制来优化方法。
我们试图从 Timothy 草花粉过敏原 Phleum pratense 中鉴定人类白细胞抗原 (HLA)-DR1 限制性表位,并在单次鼻内给予单一免疫显性表位后,对 T 细胞免疫调节进行特征描述。
使用 HLA-DR1 转基因小鼠和 HLA-DR1 阳性草过敏个体中的四聚体引导表位作图 (TGEM) 鉴定 P 草中的 T 细胞表位。在 HLA-DR1 转基因动物中测试免疫显性表位对全 Phl p5 b 或肽反应的影响。使用微阵列和定量 PCR 来描述 T 细胞免疫。
在 HLA-DR1 转基因小鼠和草过敏 HLA-DR1 阳性个体的 TGEM 分析中鉴定出肽 26 (p26)。p26 与广泛的 HLA Ⅱ类等位基因具有混杂结合,使其与具有不同免疫遗传背景的患者相关。该表位在黑麦和绒毛草中保守,使其适用于广泛的草花粉过敏。用 p26 对小鼠进行鼻内预处理可显著降低 T 细胞反应。在小鼠中进行的转录组阵列分析显示,鼻内治疗组的 T 细胞调节与 Cbl-b 和 Itch E3 泛素连接酶途径成员的表达增加相关。
我们定义了一个免疫显性的 P 草表位 p26,其具有广泛的跨多种 HLA Ⅱ类等位基因的结合能力。用 p26 对小鼠进行鼻内治疗可导致针对整个过敏原的 T 细胞调节,涉及 Cbl-b 和 Itch 调节途径。