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 language | English (US) |
|---|---|
| Article number | e129762 |
| Journal | JCI Insight |
| Volume | 4 |
| Issue number | 17 |
| DOIs | |
| State | Published - Sep 5 2019 |
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Stress responses, M2 macrophages, and a distinct microbial signature in fatal intestinal acute graft-versus-host disease. / Holtan, Shernan G.; Shabaneh, Ashraf; Betts, Brian C.; Rashidi, Armin; MacMillan, Margaret L.; Ustun, Celalletin; Amin, Khalid; Vaughn, Byron P.; Howard, Justin; Khoruts, Alexander; Arora, Mukta; DeFor, Todd E.; Johnson, Darrell; Blazar, Bruce R.; Weisdorf, Daniel J.; Wang, Jinhua.
In: JCI Insight, Vol. 4, No. 17, e129762, 05.09.2019.Research output: Contribution to journal › Article
}
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.
UR - http://www.scopus.com/inward/record.url?scp=85072252411&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85072252411&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.129762
DO - 10.1172/jci.insight.129762
M3 - Article
C2 - 31393854
AN - SCOPUS:85072252411
VL - 4
JO - JCI insight
JF - JCI insight
SN - 2379-3708
IS - 17
M1 - e129762
ER -