PMID- 30574153
OWN - NLM
STAT- MEDLINE
DCOM- 20191025
LR  - 20211204
IS  - 1664-3224 (Electronic)
IS  - 1664-3224 (Linking)
VI  - 9
DP  - 2018
TI  - Inhibition of Human Dendritic Cell ER Stress Response Reduces T Cell 
      Alloreactivity Yet Spares Donor Anti-tumor Immunity.
PG  - 2887
LID - 10.3389/fimmu.2018.02887 [doi]
LID - 2887
AB  - Acute graft- vs. -host disease (GVHD) is an important cause of morbidity and 
      death after allogeneic hematopoietic cell transplantation (HCT). We identify a 
      new approach to prevent GVHD that impairs monocyte-derived dendritic cell (moDC) 
      alloactivation of T cells, yet preserves graft- vs.-leukemia (GVL). Exceeding 
      endoplasmic reticulum (ER) capacity results in a spliced form of X-box binding 
      protein-1 (XBP-1s). XBP-1s mediates ER stress and inflammatory responses. We 
      demonstrate that siRNA targeting XBP-1 in moDCs abrogates their stimulation of 
      allogeneic T cells. B-I09, an inositol-requiring enzyme-1alpha (IRE1alpha) inhibitor that 
      prevents XBP-1 splicing, reduces human moDC migration, allo-stimulatory potency, 
      and curtails moDC IL-1beta, TGFbeta, and p40 cytokines, suppressing Th1 and Th17 cell 
      priming. B-I09-treated moDCs reduce responder T cell activation via calcium flux 
      without interfering with regulatory T cell (Treg) function or GVL effects by 
      cytotoxic T lymphocytes (CTL) and NK cells. In a human T cell mediated xenogeneic 
      GVHD model, B-I09 inhibition of XBP-1s reduced target-organ damage and pathogenic 
      Th1 and Th17 cells without impacting donor Tregs or anti-tumor CTL. DC XBP-1s 
      inhibition provides an innovative strategy to prevent GVHD and retain GVL.
FAU - Betts, Brian C
AU  - Betts BC
AD  - Department of Blood and Marrow Transplantation and Cellular Immunotherapy, Tampa, 
      FL, United States.
AD  - Department of Immunology, Moffitt Cancer Center, Tampa, FL, United States.
AD  - Division of Hematology, Oncology, and Transplantation, University of Minnesota, 
      Minneapolis, MN, United States.
FAU - Locke, Frederick L
AU  - Locke FL
AD  - Department of Blood and Marrow Transplantation and Cellular Immunotherapy, Tampa, 
      FL, United States.
AD  - Department of Immunology, Moffitt Cancer Center, Tampa, FL, United States.
FAU - Sagatys, Elizabeth M
AU  - Sagatys EM
AD  - Department of Hematopathology and Laboratory Medicine, Moffitt Cancer Center, 
      Tampa, FL, United States.
FAU - Pidala, Joseph
AU  - Pidala J
AD  - Department of Blood and Marrow Transplantation and Cellular Immunotherapy, Tampa, 
      FL, United States.
AD  - Department of Immunology, Moffitt Cancer Center, Tampa, FL, United States.
FAU - Walton, Kelly
AU  - Walton K
AD  - Department of Immunology, Moffitt Cancer Center, Tampa, FL, United States.
AD  - Division of Hematology, Oncology, and Transplantation, University of Minnesota, 
      Minneapolis, MN, United States.
FAU - Menges, Meghan
AU  - Menges M
AD  - Department of Immunology, Moffitt Cancer Center, Tampa, FL, United States.
FAU - Reff, Jordan
AU  - Reff J
AD  - Department of Immunology, Moffitt Cancer Center, Tampa, FL, United States.
FAU - Saha, Asim
AU  - Saha A
AD  - Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic 
      Cancer Center, University of Minnesota, Minneapolis, MN, United States.
AD  - The Center for Immunology, University of Minnesota Medical School, Minneapolis, 
      MN, United States.
FAU - Djeu, Julie Y
AU  - Djeu JY
AD  - Department of Immunology, Moffitt Cancer Center, Tampa, FL, United States.
FAU - Kiluk, John V
AU  - Kiluk JV
AD  - Comprehensive Breast Program, Moffitt Cancer Center, Tampa, FL, United States.
FAU - Lee, Marie C
AU  - Lee MC
AD  - Comprehensive Breast Program, Moffitt Cancer Center, Tampa, FL, United States.
FAU - Kim, Jongphil
AU  - Kim J
AD  - Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL, 
      United States.
FAU - Kang, Chang Won
AU  - Kang CW
AD  - Department of Chemistry, University of South Florida, Tampa, FL, United States.
FAU - Tang, Chih-Hang
AU  - Tang CH
AD  - Department of Translational Tumor Immunology, The Wistar Institute, Philadelphia, 
      PA, United States.
FAU - Frieling, Jeremy
AU  - Frieling J
AD  - Department of Tumor Biology, Moffitt Cancer Center, Tampa, FL, United States.
FAU - Lynch, Conor C
AU  - Lynch CC
AD  - Department of Tumor Biology, Moffitt Cancer Center, Tampa, FL, United States.
FAU - List, Alan
AU  - List A
AD  - Department of Malignant Hematology, Moffitt Cancer Center, Tampa, FL, United 
      States.
FAU - Rodriguez, Paulo C
AU  - Rodriguez PC
AD  - Department of Immunology, Moffitt Cancer Center, Tampa, FL, United States.
FAU - Blazar, Bruce R
AU  - Blazar BR
AD  - Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic 
      Cancer Center, University of Minnesota, Minneapolis, MN, United States.
AD  - The Center for Immunology, University of Minnesota Medical School, Minneapolis, 
      MN, United States.
FAU - Conejo-Garcia, Jose R
AU  - Conejo-Garcia JR
AD  - Department of Immunology, Moffitt Cancer Center, Tampa, FL, United States.
FAU - Del Valle, Juan R
AU  - Del Valle JR
AD  - Department of Chemistry, University of South Florida, Tampa, FL, United States.
FAU - Hu, Chih-Chi
AU  - Hu CC
AD  - Department of Translational Tumor Immunology, The Wistar Institute, Philadelphia, 
      PA, United States.
FAU - Anasetti, Claudio
AU  - Anasetti C
AD  - Department of Blood and Marrow Transplantation and Cellular Immunotherapy, Tampa, 
      FL, United States.
AD  - Department of Immunology, Moffitt Cancer Center, Tampa, FL, United States.
LA  - eng
GR  - R01 HL133823/HL/NHLBI NIH HHS/United States
GR  - R01 CA163910/CA/NCI NIH HHS/United States
GR  - P01 CA065493/CA/NCI NIH HHS/United States
GR  - R37 AI034495/AI/NIAID NIH HHS/United States
GR  - P30 CA076292/CA/NCI NIH HHS/United States
GR  - R01 CA184185/CA/NCI NIH HHS/United States
GR  - K08 HL116547/HL/NHLBI NIH HHS/United States
GR  - R01 CA190860/CA/NCI NIH HHS/United States
GR  - R01 HL118979/HL/NHLBI NIH HHS/United States
GR  - P30 CA010815/CA/NCI NIH HHS/United States
GR  - K23 CA201594/CA/NCI NIH HHS/United States
GR  - U19 AI051731/AI/NIAID NIH HHS/United States
GR  - R37 HL056067/HL/NHLBI NIH HHS/United States
GR  - R01 HL056067/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20181206
PL  - Switzerland
TA  - Front Immunol
JT  - Frontiers in immunology
JID - 101560960
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Inflammasomes)
RN  - 0 (Isoantibodies)
RN  - 0 (Isoantigens)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (X-Box Binding Protein 1)
RN  - 0 (XBP1 protein, human)
RN  - EC 2.7.11.1 (ERN1 protein, human)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 3.1.- (Endoribonucleases)
SB  - IM
MH  - Animals
MH  - Cell Line, Tumor
MH  - Dendritic Cells/drug effects/*immunology/metabolism
MH  - Endoplasmic Reticulum Stress/drug effects/immunology
MH  - Endoribonucleases/antagonists & inhibitors/metabolism
MH  - Enzyme Inhibitors/pharmacology
MH  - Female
MH  - Gene Knockdown Techniques
MH  - Graft vs Host Disease/immunology/*prevention & control
MH  - Graft vs Leukemia Effect/immunology
MH  - Hematopoietic Stem Cell Transplantation/*adverse effects
MH  - Humans
MH  - Immunosuppression Therapy/*methods
MH  - Inflammasomes/drug effects/immunology/metabolism
MH  - Isoantibodies/immunology/metabolism
MH  - Isoantigens/immunology
MH  - Leukemia/immunology/*therapy
MH  - Lymphocyte Activation/drug effects
MH  - Male
MH  - Mice
MH  - Protein Serine-Threonine Kinases/antagonists & inhibitors/metabolism
MH  - RNA, Small Interfering/metabolism
MH  - Skin Transplantation
MH  - T-Lymphocyte Subsets/immunology/metabolism
MH  - Transplantation Chimera
MH  - Transplantation, Homologous/adverse effects
MH  - X-Box Binding Protein 1/*antagonists & inhibitors/genetics/immunology/metabolism
MH  - Xenograft Model Antitumor Assays
PMC - PMC6291501
OTO - NOTNLM
OT  - GvHD
OT  - GvL
OT  - XBP-1S
OT  - dendritic cell (DC)
OT  - er stress
EDAT- 2018/12/24 06:00
MHDA- 2019/10/28 06:00
PMCR- 2018/01/01
CRDT- 2018/12/22 06:00
PHST- 2018/10/08 00:00 [received]
PHST- 2018/11/26 00:00 [accepted]
PHST- 2018/12/22 06:00 [entrez]
PHST- 2018/12/24 06:00 [pubmed]
PHST- 2019/10/28 06:00 [medline]
PHST- 2018/01/01 00:00 [pmc-release]
AID - 10.3389/fimmu.2018.02887 [doi]
PST - epublish
SO  - Front Immunol. 2018 Dec 6;9:2887. doi: 10.3389/fimmu.2018.02887. eCollection 
      2018.