期刊
CLINICAL & TRANSLATIONAL IMMUNOLOGY
卷 10, 期 7, 页码 -出版社
WILEY
DOI: 10.1002/cti2.1314
关键词
CD4-positive lymphocytes; eosinophilic oesophagitis; food allergy; immunotherapy; interferon response; RNA sequencing
类别
资金
- National Institutes of Health National Center for Advancing Translational Sciences [KL2TR001879]
- National Institute of Child Health Development [T32-HD043021]
- National Institute of Diabetes and Digestion and Kidney Diseases [K08DK106444]
- Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR) [U54 AI117804]
- NIH NCATS
- NIAID
- NIDDK
- NCATS
- Wallace Endowed Chair
- Stuart Starr Endowed Chair
- Children's Hospital of Philadelphia Eosinophilic Esophagitis Family Fund
This study focused on milk-induced eosinophilic oesophagitis (EoE) patients undergoing epicutaneous immunotherapy (EPIT) and identified transcriptional changes in peripheral CD4(+) T cells, suggesting potential therapeutic effects of EPIT on EoE.
Objective. 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. Methods. 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. Results. 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-alpha and interferon-gamma 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 (P = 1.16 x 10(-14)), antigen presentation and costimulation, and cytokine signalling (P = 1.11 x 10(-16)), as well as upregulation of genes associated with regulatory T-cell function. Conclusions. 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.
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