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• W2912491946 abstract "BackgroundSteroid-refractory acute GVHD (aGVHD) is a fatal disease with little known regarding its pathophysiology at the tissue level. We studied the gene expression profiles of onset and steroid-refractory aGVHD intestinal biopsies, including both supervised analyses of tolerance (indoleamine 2,3 dioxygenase [IDO1]), repair factors (amphiregulin [AREG]), and immune cell composition, plus unsupervised analyses to define the transcriptome profile.Patients and MethodsWe performed ribonucleic acid sequencing (RNA-seq) on archival rectal biopsies from 22 patients with clinical stage 3-4 GI aGVHD (a) at the onset of GI aGVHD and (b) in the same patients at the diagnosis of steroid-refractory GI aGVHD, compared to 10 healthy controls at the University of Minnesota. We compared differential gene expression using Limma package, analyzed pathways using Enrichr®, and estimated immune cell composition using CIBERSORT®.ResultsSeveral immune- and damage-relevant genes differed between GVHD and normal samples. The mostly highly differentially expressed gene in aGVHD compared to normal was chitinase 3-L-1 (CHI3L1, fold-change 3.4, adjusted p=0.003), with known pathogenic roles in neovascularization, macrophage recruitment, and bacterial adhesion. The most significantly decreased gene in aGVHD was aquaporin-8 (AQP8, fold change -5.0, adjusted p<0.001), a water channel reduced in ulcerative colitis. Comparing steroid-refractory aGVHD vs onset aGVHD in unsupervised analyses, we found no single gene significantly increased or decreased. However, using Enrichr, we observed processes involving metallothioneines (MT, Figure 1) were significantly increased, whereas the only process that was significantly decreased was regulation of T-cell apoptosis (GO:0070234). In supervised analyses, we found significantly higher AREG and IDO1 expression in aGVHD compared to normal samples, but IDO1 subsequently decreased in steroid-refractory aGVHD (Figure 2). We observed no differences in T, B, or NK cell subsets between groups, although M2 macrophage content increased in steroid-refractory GI.DiscussionWhile we observed distinctions between normal and onset aGVHD samples (increased CHI3L1 and decreased AQP8), we did not identify differences in T-cell driven inflammation in onset versus steroid-refractory aGVHD. Steroid-refractory aGVHD may be characterized by increased stress-induced MT expression, loss of host tissue tolerance signals, and accumulation of M2 macrophages. Our results expand the paradigm of T cell-centric therapies for steroid-refractory GI aGVHD and highlight new mechanisms for therapeutic exploration. Steroid-refractory acute GVHD (aGVHD) is a fatal disease with little known regarding its pathophysiology at the tissue level. We studied the gene expression profiles of onset and steroid-refractory aGVHD intestinal biopsies, including both supervised analyses of tolerance (indoleamine 2,3 dioxygenase [IDO1]), repair factors (amphiregulin [AREG]), and immune cell composition, plus unsupervised analyses to define the transcriptome profile. We performed ribonucleic acid sequencing (RNA-seq) on archival rectal biopsies from 22 patients with clinical stage 3-4 GI aGVHD (a) at the onset of GI aGVHD and (b) in the same patients at the diagnosis of steroid-refractory GI aGVHD, compared to 10 healthy controls at the University of Minnesota. We compared differential gene expression using Limma package, analyzed pathways using Enrichr®, and estimated immune cell composition using CIBERSORT®. Several immune- and damage-relevant genes differed between GVHD and normal samples. The mostly highly differentially expressed gene in aGVHD compared to normal was chitinase 3-L-1 (CHI3L1, fold-change 3.4, adjusted p=0.003), with known pathogenic roles in neovascularization, macrophage recruitment, and bacterial adhesion. The most significantly decreased gene in aGVHD was aquaporin-8 (AQP8, fold change -5.0, adjusted p<0.001), a water channel reduced in ulcerative colitis. Comparing steroid-refractory aGVHD vs onset aGVHD in unsupervised analyses, we found no single gene significantly increased or decreased. However, using Enrichr, we observed processes involving metallothioneines (MT, Figure 1) were significantly increased, whereas the only process that was significantly decreased was regulation of T-cell apoptosis (GO:0070234). In supervised analyses, we found significantly higher AREG and IDO1 expression in aGVHD compared to normal samples, but IDO1 subsequently decreased in steroid-refractory aGVHD (Figure 2). We observed no differences in T, B, or NK cell subsets between groups, although M2 macrophage content increased in steroid-refractory GI. While we observed distinctions between normal and onset aGVHD samples (increased CHI3L1 and decreased AQP8), we did not identify differences in T-cell driven inflammation in onset versus steroid-refractory aGVHD. Steroid-refractory aGVHD may be characterized by increased stress-induced MT expression, loss of host tissue tolerance signals, and accumulation of M2 macrophages. Our results expand the paradigm of T cell-centric therapies for steroid-refractory GI aGVHD and highlight new mechanisms for therapeutic exploration. Figures 1 and 2.Figure 2Differential expression of amphiregulin (AREG), indoleamine 2,3 dioxygenase (IDO1), and M2 macrophage profile.View Large Image Figure ViewerDownload Hi-res image Download (PPT)" @default.
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• W2912491946 title "RNA Sequencing of Intestinal Biopsies Expands the T Cell-Centric Paradigm of Steroid-Refractory Acute Graft-Versus-Host Disease" @default.
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