PMID- 31307777
OWN - NLM
STAT- MEDLINE
DCOM- 20201014
LR  - 20201014
IS  - 1523-1755 (Electronic)
IS  - 0085-2538 (Linking)
VI  - 96
IP  - 3
DP  - 2019 Sep
TI  - HLA-DQ alloantibodies directly activate the endothelium and compromise 
      differentiation of FoxP3(high) regulatory T lymphocytes.
PG  - 689-698
LID - S0085-2538(19)30485-5 [pii]
LID - 10.1016/j.kint.2019.04.023 [doi]
AB  - Development of donor-specific antibodies is associated with reduced allograft 
      survival in renal transplantation. Recent clinical studies highlight the 
      prevalence of human leukocyte antigen (HLA)-DQ antibodies amongst de novo 
      donor-specific antibodies (DSAs), yet the specific contribution of these DSAs to 
      rejection has not been examined. Antibody-mediated rejection primarily targets 
      the microvasculature, so this study explored how patient HLA-DQ alloantibodies 
      can modulate endothelial activation and so immunoregulation. HLA-DQ antibodies 
      phosphorylated Akt and S6 kinase in microvascular endothelial cells. This 
      activation prior to culture with alloreactive lymphocytes increased IL-6 and 
      RANTES secretion. The antibody-mediated upregulation of IL-6 was indeed 
      Akt-dependent. The binding of HLA-DQ antibodies to endothelial cells selectively 
      reduced T cell alloproliferation and FoxP3(high) Treg differentiation. In 
      clinical studies, detection of HLA-DQ DSAs with other DSAs is associated with 
      worse graft survival than either alone. Endothelial cells stimulated with HLA-DR 
      and HLA-DQ antibodies showed a synergistic increase in pro-inflammatory cytokine 
      secretion and a decrease in Treg expansion. HLA-DQ antibodies strongly promote 
      pro-inflammatory responses in isolation and in combination with other HLA 
      antibodies. Thus, our data give new insights into the pathogenicity of HLA-DQ 
      DSAs.
CI  - Copyright (c) 2019 International Society of Nephrology. Published by Elsevier Inc. 
      All rights reserved.
FAU - Cross, Amy R
AU  - Cross AR
AD  - Human Immunology and Immunopathology, Inserm UMR 976, Paris, France; Institut de 
      Recherche Saint Louis, Sorbonne Paris Cite, Universite Paris Diderot, Sorbonne 
      Paris, Paris, France.
FAU - Lion, Julien
AU  - Lion J
AD  - Human Immunology and Immunopathology, Inserm UMR 976, Paris, France; Institut de 
      Recherche Saint Louis, Sorbonne Paris Cite, Universite Paris Diderot, Sorbonne 
      Paris, Paris, France.
FAU - Poussin, Karine
AU  - Poussin K
AD  - Human Immunology and Immunopathology, Inserm UMR 976, Paris, France.
FAU - Assayag, Maureen
AU  - Assayag M
AD  - Human Immunology and Immunopathology, Inserm UMR 976, Paris, France.
FAU - Taupin, Jean-Luc
AU  - Taupin JL
AD  - Human Immunology and Immunopathology, Inserm UMR 976, Paris, France; Institut de 
      Recherche Saint Louis, Sorbonne Paris Cite, Universite Paris Diderot, Sorbonne 
      Paris, Paris, France; Laboratoire d'Immunologie et Histocompatibilite, Hopital 
      Saint Louis, Paris, France; LabEx Transplantex, Universite de Strasbourg, 
      Strasbourg, France.
FAU - Glotz, Denis
AU  - Glotz D
AD  - Human Immunology and Immunopathology, Inserm UMR 976, Paris, France; Institut de 
      Recherche Saint Louis, Sorbonne Paris Cite, Universite Paris Diderot, Sorbonne 
      Paris, Paris, France; LabEx Transplantex, Universite de Strasbourg, Strasbourg, 
      France; Service de Nephrologie et Transplantation, Hopital Saint Louis, Paris, 
      France.
FAU - Mooney, Nuala
AU  - Mooney N
AD  - Human Immunology and Immunopathology, Inserm UMR 976, Paris, France; Institut de 
      Recherche Saint Louis, Sorbonne Paris Cite, Universite Paris Diderot, Sorbonne 
      Paris, Paris, France; LabEx Transplantex, Universite de Strasbourg, Strasbourg, 
      France. Electronic address: nuala.mooney@univ-paris-diderot.fr.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190510
PL  - United States
TA  - Kidney Int
JT  - Kidney international
JID - 0323470
RN  - 0 (Cytokines)
RN  - 0 (FOXP3 protein, human)
RN  - 0 (Forkhead Transcription Factors)
RN  - 0 (HLA-DQ Antigens)
RN  - 0 (Isoantibodies)
SB  - IM
MH  - Allografts/blood supply/immunology/pathology
MH  - Cell Culture Techniques
MH  - Cell Differentiation/immunology
MH  - Cell Line
MH  - Coculture Techniques
MH  - Cytokines/immunology/metabolism
MH  - Endothelial Cells/immunology/pathology
MH  - Endothelium, Vascular/cytology/*immunology/pathology
MH  - Forkhead Transcription Factors/metabolism
MH  - Graft Rejection/blood/*immunology/pathology
MH  - HLA-DQ Antigens/*immunology
MH  - Humans
MH  - Isoantibodies/*immunology
MH  - Kidney/blood supply/immunology/pathology
MH  - Kidney Transplantation/*adverse effects
MH  - Microvessels/cytology/immunology
MH  - T-Lymphocytes, Regulatory/*immunology/metabolism
OTO - NOTNLM
OT  - DSA
OT  - IL-6
OT  - Treg
OT  - endothelium
OT  - kidney transplantation
OT  - rejection
EDAT- 2019/07/17 06:00
MHDA- 2020/10/21 06:00
CRDT- 2019/07/17 06:00
PHST- 2019/01/11 00:00 [received]
PHST- 2019/03/28 00:00 [revised]
PHST- 2019/04/19 00:00 [accepted]
PHST- 2019/07/17 06:00 [pubmed]
PHST- 2020/10/21 06:00 [medline]
PHST- 2019/07/17 06:00 [entrez]
AID - S0085-2538(19)30485-5 [pii]
AID - 10.1016/j.kint.2019.04.023 [doi]
PST - ppublish
SO  - Kidney Int. 2019 Sep;96(3):689-698. doi: 10.1016/j.kint.2019.04.023. Epub 2019 
      May 10.