Ruffner Melanie A, Zhang Zhe, Maurer Kelly, Muir Amanda B, Cianferoni Antonella, Sullivan Kathleen E, Spergel Jonathan M
Division of Allergy and Immunology The Children's Hospital of Philadelphia Philadelphia PA USA.
Department of Pediatrics The Perelman School of Medicine at University of Pennsylvania Philadelphia PA USA.
Clin Transl Immunology. 2021 Jul 22;10(7):e1314. doi: 10.1002/cti2.1314. eCollection 2021.
There are no disease-modifying therapies for the treatment of eosinophilic oesophagitis (EoE), which is driven by non-IgE-mediated allergic inflammation. A recent clinical trial of milk epicutaneous immunotherapy (EPIT) has shown initial promise, with 47% of treated EoE patients tolerating milk without recurrence of disease. Mechanisms of EPIT in EoE have not been studied in humans. Here, we identify transcriptional changes in the peripheral CD4 T-cell compartment during active EoE and following EPIT.
RNA isolation, sequencing and integrative data analysis were performed on peripheral CD4 T cells isolated from 15 of 20 patients enrolled in a clinical trial of EPIT for EoE. Gene expression changes in peripheral CD4 T cells were examined during diet therapy and following trial of milk antigen EPIT.
We identify 244 differentially expressed genes in peripheral blood CD4 cells of EoE patients consuming versus those eliminating milk, and 129 DEGs in CD4 cells were isolated after EPIT versus after placebo (FDR ≤ 0.05). Gene set enrichment analysis identifies enrichment of hallmark interferon-α and interferon-γ response pathways in peripheral CD4 T cells from EoE patients during active disease on a milk-containing diet. We demonstrate overlap of this gene signature with the altered gene expression signature seen in EoE patient biopsy tissue. EPIT therapy response is associated with significant enrichment in pathways related to T-cell receptor signalling ( = 1.16 × 10), antigen presentation and costimulation, and cytokine signalling ( = 1.11 × 10), as well as upregulation of genes associated with regulatory T-cell function.
EoE is associated with distinct global transcriptional changes in CD4 T cells, one feature of which is an IFN response signature. Clinically favorable response to EPIT is likely multifactorial but is associated with a distinct transcriptional profile in peripheral CD4 cells supporting the hypothesis that EPIT alters peripheral CD4 responses in EoE patients.
嗜酸性粒细胞性食管炎（EoE）由非IgE介导的过敏性炎症驱动，目前尚无改变疾病进程的治疗方法。最近一项关于牛奶经皮免疫疗法（EPIT）的临床试验已显示出初步成效，47%接受治疗的EoE患者能够耐受牛奶且疾病无复发。EPIT在EoE中的作用机制尚未在人体中进行研究。在此，我们确定了活动性EoE期间及EPIT治疗后外周CD4 T细胞区室中的转录变化。
对参与EoE的EPIT临床试验的20名患者中的15名患者分离出的外周CD4 T细胞进行RNA分离、测序和综合数据分析。在饮食治疗期间以及牛奶抗原EPIT试验后，对外周CD4 T细胞中的基因表达变化进行检测。
我们确定了食用牛奶与不食用牛奶的EoE患者外周血CD4细胞中有244个差异表达基因，EPIT治疗后与安慰剂治疗后相比，CD4细胞中有129个差异表达基因（错误发现率≤0.05）。基因集富集分析确定，在含牛奶饮食的活动性疾病期间，EoE患者外周CD4 T细胞中标志性干扰素-α和干扰素-γ反应途径富集。我们证明了该基因特征与EoE患者活检组织中观察到的基因表达特征改变存在重叠。EPIT治疗反应与T细胞受体信号传导（=1.16×10）、抗原呈递和共刺激以及细胞因子信号传导（=1.11×10）相关的途径显著富集有关，同时与调节性T细胞功能相关基因的上调有关。
EoE与CD4 T细胞中明显的整体转录变化相关，其中一个特征是IFN反应特征。对EPIT的临床良好反应可能是多因素的，但与外周CD4细胞中独特的转录谱相关，支持EPIT改变EoE患者外周CD4反应这一假说。
