Abstract

Steroid-refractory intestinal acute graft-versus-host disease (aGVHD) is a frequently fatal condition, with little known about mechanisms driving failed steroid responses in gut mucosa. To uncover molecular insights in steroid-refractory aGVHD, we compared gene expression profiles of rectosigmoid biopsies from patients at diagnosis of clinical stage 3-4 lower intestinal aGVHD with repeat biopsies when the patients became steroid refractory and normal controls. We also performed single-gene analyses of factors associated with tolerance (programmed cell death ligand 1 [PDL1], indoleamine 2,3-dioxygenase [IDO1], and T cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibition motif domains [TIGIT]) and found that significantly higher expression levels of these aGVHD inhibitory genes (PDL1, IDO1, TIGIT) at aGVHD onset became decreased in the steroid-refractory state. We examined genes triggered by microbial ligands to stimulate gut repair, amphiregulin (AREG) and the aryl hydrocarbon receptor (AhR), and found that both AREG and AhR gene expression levels were increased at aGVHD onset and remained elevated in steroid-refractory aGVHD. We also identified higher expression levels of metallothioneins, metal-binding enzymes induced in stress responses, and M2 macrophage genes in steroid-refractory aGVHD. We observed no differences in T cell subsets between onset and steroid-refractory aGVHD. Patients with a rapidly fatal course showed greater DNA damage and a distinct microbial signature at aGVHD onset, whereas patients with more prolonged survival exhibited a gene expression profile consistent with activation of Smoothened. Our results extend the paradigm beyond T cell-centric therapies for steroid-refractory gastrointestinal aGVHD and highlight potentially new mechanisms for therapeutic exploration.

Original languageEnglish (US)
Article numbere129762
JournalJCI Insight
Volume4
Issue number17
DOIs
StatePublished - Sep 5 2019

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Graft vs Host Disease
Macrophages
Steroids
Aryl Hydrocarbon Receptors
Ligands
Transcriptome
Immunoreceptor Tyrosine-Based Inhibition Motif
Cell Death
Microbial Genes
Indoleamine-Pyrrole 2,3,-Dioxygenase
Genes
T-Lymphocytes
Biopsy
Metallothionein
T-Lymphocyte Subsets
Cell- and Tissue-Based Therapy
DNA Damage
Statistical Factor Analysis
Mucous Membrane
Metals

PubMed: MeSH publication types

  • Journal Article

Cite this

@article{509c8d3134404b79a22dfdaba9aefdab,
title = "Stress responses, M2 macrophages, and a distinct microbial signature in fatal intestinal acute graft-versus-host disease",
abstract = "Steroid-refractory intestinal acute graft-versus-host disease (aGVHD) is a frequently fatal condition, with little known about mechanisms driving failed steroid responses in gut mucosa. To uncover molecular insights in steroid-refractory aGVHD, we compared gene expression profiles of rectosigmoid biopsies from patients at diagnosis of clinical stage 3-4 lower intestinal aGVHD with repeat biopsies when the patients became steroid refractory and normal controls. We also performed single-gene analyses of factors associated with tolerance (programmed cell death ligand 1 [PDL1], indoleamine 2,3-dioxygenase [IDO1], and T cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibition motif domains [TIGIT]) and found that significantly higher expression levels of these aGVHD inhibitory genes (PDL1, IDO1, TIGIT) at aGVHD onset became decreased in the steroid-refractory state. We examined genes triggered by microbial ligands to stimulate gut repair, amphiregulin (AREG) and the aryl hydrocarbon receptor (AhR), and found that both AREG and AhR gene expression levels were increased at aGVHD onset and remained elevated in steroid-refractory aGVHD. We also identified higher expression levels of metallothioneins, metal-binding enzymes induced in stress responses, and M2 macrophage genes in steroid-refractory aGVHD. We observed no differences in T cell subsets between onset and steroid-refractory aGVHD. Patients with a rapidly fatal course showed greater DNA damage and a distinct microbial signature at aGVHD onset, whereas patients with more prolonged survival exhibited a gene expression profile consistent with activation of Smoothened. Our results extend the paradigm beyond T cell-centric therapies for steroid-refractory gastrointestinal aGVHD and highlight potentially new mechanisms for therapeutic exploration.",
author = "Holtan, {Shernan G.} and Ashraf Shabaneh and Betts, {Brian C.} and Armin Rashidi and MacMillan, {Margaret L.} and Celalletin Ustun and Khalid Amin and Vaughn, {Byron P.} and Justin Howard and Alexander Khoruts and Mukta Arora and DeFor, {Todd E.} and Darrell Johnson and Blazar, {Bruce R.} and Weisdorf, {Daniel J.} and Jinhua Wang",
year = "2019",
month = "9",
day = "5",
doi = "10.1172/jci.insight.129762",
language = "English (US)",
volume = "4",
journal = "JCI insight",
issn = "2379-3708",
publisher = "The American Society for Clinical Investigation",
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TY - JOUR

T1 - Stress responses, M2 macrophages, and a distinct microbial signature in fatal intestinal acute graft-versus-host disease

AU - Holtan, Shernan G.

AU - Shabaneh, Ashraf

AU - Betts, Brian C.

AU - Rashidi, Armin

AU - MacMillan, Margaret L.

AU - Ustun, Celalletin

AU - Amin, Khalid

AU - Vaughn, Byron P.

AU - Howard, Justin

AU - Khoruts, Alexander

AU - Arora, Mukta

AU - DeFor, Todd E.

AU - Johnson, Darrell

AU - Blazar, Bruce R.

AU - Weisdorf, Daniel J.

AU - Wang, Jinhua

PY - 2019/9/5

Y1 - 2019/9/5

N2 - Steroid-refractory intestinal acute graft-versus-host disease (aGVHD) is a frequently fatal condition, with little known about mechanisms driving failed steroid responses in gut mucosa. To uncover molecular insights in steroid-refractory aGVHD, we compared gene expression profiles of rectosigmoid biopsies from patients at diagnosis of clinical stage 3-4 lower intestinal aGVHD with repeat biopsies when the patients became steroid refractory and normal controls. We also performed single-gene analyses of factors associated with tolerance (programmed cell death ligand 1 [PDL1], indoleamine 2,3-dioxygenase [IDO1], and T cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibition motif domains [TIGIT]) and found that significantly higher expression levels of these aGVHD inhibitory genes (PDL1, IDO1, TIGIT) at aGVHD onset became decreased in the steroid-refractory state. We examined genes triggered by microbial ligands to stimulate gut repair, amphiregulin (AREG) and the aryl hydrocarbon receptor (AhR), and found that both AREG and AhR gene expression levels were increased at aGVHD onset and remained elevated in steroid-refractory aGVHD. We also identified higher expression levels of metallothioneins, metal-binding enzymes induced in stress responses, and M2 macrophage genes in steroid-refractory aGVHD. We observed no differences in T cell subsets between onset and steroid-refractory aGVHD. Patients with a rapidly fatal course showed greater DNA damage and a distinct microbial signature at aGVHD onset, whereas patients with more prolonged survival exhibited a gene expression profile consistent with activation of Smoothened. Our results extend the paradigm beyond T cell-centric therapies for steroid-refractory gastrointestinal aGVHD and highlight potentially new mechanisms for therapeutic exploration.

AB - Steroid-refractory intestinal acute graft-versus-host disease (aGVHD) is a frequently fatal condition, with little known about mechanisms driving failed steroid responses in gut mucosa. To uncover molecular insights in steroid-refractory aGVHD, we compared gene expression profiles of rectosigmoid biopsies from patients at diagnosis of clinical stage 3-4 lower intestinal aGVHD with repeat biopsies when the patients became steroid refractory and normal controls. We also performed single-gene analyses of factors associated with tolerance (programmed cell death ligand 1 [PDL1], indoleamine 2,3-dioxygenase [IDO1], and T cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibition motif domains [TIGIT]) and found that significantly higher expression levels of these aGVHD inhibitory genes (PDL1, IDO1, TIGIT) at aGVHD onset became decreased in the steroid-refractory state. We examined genes triggered by microbial ligands to stimulate gut repair, amphiregulin (AREG) and the aryl hydrocarbon receptor (AhR), and found that both AREG and AhR gene expression levels were increased at aGVHD onset and remained elevated in steroid-refractory aGVHD. We also identified higher expression levels of metallothioneins, metal-binding enzymes induced in stress responses, and M2 macrophage genes in steroid-refractory aGVHD. We observed no differences in T cell subsets between onset and steroid-refractory aGVHD. Patients with a rapidly fatal course showed greater DNA damage and a distinct microbial signature at aGVHD onset, whereas patients with more prolonged survival exhibited a gene expression profile consistent with activation of Smoothened. Our results extend the paradigm beyond T cell-centric therapies for steroid-refractory gastrointestinal aGVHD and highlight potentially new mechanisms for therapeutic exploration.

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