PMID- 31393854
OWN - NLM
STAT- MEDLINE
DCOM- 20200921
LR  - 20210426
IS  - 2379-3708 (Electronic)
IS  - 2379-3708 (Linking)
VI  - 5
IP  - 17
DP  - 2019 Aug 8
TI  - Stress responses, M2 macrophages, and a distinct microbial signature in fatal 
      intestinal acute graft-versus-host disease.
LID - 129762 [pii]
LID - 10.1172/jci.insight.129762 [doi]
LID - e129762
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 novel 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 
      (N=22), to repeat biopsies when the patients became steroid refractory (N=22), 
      and normal controls (N=10). We also performed single gene analyses of factors 
      associated with tolerance (programmed death ligand-1 [PDL1], indoleamine 2,3 
      dioxygenase [IDO1], and T cell immunoreceptor with Ig and ITIM 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 metallothioneines, 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 GI aGVHD and highlight new mechanisms for therapeutic 
      exploration.
FAU - Holtan, Shernan G
AU  - Holtan SG
AD  - Blood and Marrow Transplant Program, Department of Medicine.
FAU - Shabaneh, Ashraf
AU  - Shabaneh A
AD  - Institute for Health Informatics, and.
FAU - Betts, Brian C
AU  - Betts BC
AD  - Blood and Marrow Transplant Program, Department of Medicine.
FAU - Rashidi, Armin
AU  - Rashidi A
AD  - Blood and Marrow Transplant Program, Department of Medicine.
FAU - MacMillan, Margaret L
AU  - MacMillan ML
AD  - Blood and Marrow Transplant Program, Department of Pediatrics, University of 
      Minnesota, Minneapolis, Minnesota, USA.
FAU - Ustun, Celalletin
AU  - Ustun C
AD  - Rush University Blood and Marrow Transplant Program, Chicago, Illinois, USA.
FAU - Amin, Khalid
AU  - Amin K
AD  - Department of Pathology.
FAU - Vaughn, Byron P
AU  - Vaughn BP
AD  - Division of Gastroenterology, Department of Medicine.
FAU - Howard, Justin
AU  - Howard J
AD  - Division of Gastroenterology, Department of Medicine.
FAU - Khoruts, Alexander
AU  - Khoruts A
AD  - Division of Gastroenterology, Department of Medicine.
FAU - Arora, Mukta
AU  - Arora M
AD  - Blood and Marrow Transplant Program, Department of Medicine.
FAU - DeFor, Todd E
AU  - DeFor TE
AD  - Biostatistics, Masonic Cancer Center.
FAU - Johnson, Darrell
AU  - Johnson D
AD  - Genomics Core Facility, and.
FAU - Blazar, Bruce R
AU  - Blazar BR
AD  - Blood and Marrow Transplant Program, Department of Pediatrics, University of 
      Minnesota, Minneapolis, Minnesota, USA.
FAU - Weisdorf, Daniel J
AU  - Weisdorf DJ
AD  - Blood and Marrow Transplant Program, Department of Medicine.
FAU - Wang, Jinhua
AU  - Wang J
AD  - Cancer Bioinformatics, Masonic Cancer Center, University of Minnesota, 
      Minneapolis, Minnesota, USA.
LA  - eng
GR  - P30 CA077598/CA/NCI NIH HHS/United States
GR  - UL1 TR002494/TR/NCATS NIH HHS/United States
GR  - R01 HL118979/HL/NHLBI NIH HHS/United States
GR  - R37 AI034495/AI/NIAID NIH HHS/United States
GR  - R01 HL056067/HL/NHLBI NIH HHS/United States
GR  - P01 CA111412/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20190808
PL  - United States
TA  - JCI Insight
JT  - JCI insight
JID - 101676073
RN  - 0 (AREG protein, human)
RN  - 0 (Amphiregulin)
RN  - 0 (Steroids)
SB  - IM
MH  - Acute Disease
MH  - Adult
MH  - Aged
MH  - Amphiregulin/metabolism
MH  - Bone Marrow Transplantation
MH  - DNA Damage
MH  - Female
MH  - Gene Expression
MH  - Graft vs Host Disease/genetics/*immunology/*microbiology
MH  - Hematopoietic Stem Cell Transplantation
MH  - Humans
MH  - Immune Tolerance/genetics
MH  - Immunity, Cellular
MH  - Intestines/*immunology
MH  - Macrophages/*immunology
MH  - Male
MH  - Middle Aged
MH  - Steroids
MH  - Transcriptome
MH  - Young Adult
PMC - PMC6777917
OTO - NOTNLM
OT  - Bone marrow transplantation
OT  - Cellular immune response
OT  - Epithelial transport of ions and water
OT  - Inflammation
OT  - Transplantation
COIS- Conflict of interest: The authors have declared that no conflict of interest 
      exists.
EDAT- 2019/08/09 06:00
MHDA- 2020/09/22 06:00
PMCR- 2019/09/05
CRDT- 2019/08/09 06:00
PHST- 2019/08/09 06:00 [entrez]
PHST- 2019/08/09 06:00 [pubmed]
PHST- 2020/09/22 06:00 [medline]
PHST- 2019/09/05 00:00 [pmc-release]
AID - 129762 [pii]
AID - 10.1172/jci.insight.129762 [doi]
PST - epublish
SO  - JCI Insight. 2019 Aug 8;5(17):e129762. doi: 10.1172/jci.insight.129762.