PMID- 32237049
OWN - NLM
STAT- MEDLINE
DCOM- 20210709
LR  - 20211204
IS  - 2211-5463 (Electronic)
IS  - 2211-5463 (Linking)
VI  - 10
IP  - 5
DP  - 2020 May
TI  - Interferon-gamma-induced HLA Class II expression on endothelial cells is decreased by 
      inhibition of mTOR and HMG-CoA reductase.
PG  - 927-936
LID - 10.1002/2211-5463.12854 [doi]
AB  - In organ transplantation, donor-specific HLA antibody (DSA) is considered a major 
      cause of graft rejection. Because DSA targets primarily donor-specific human 
      leukocyte antigen (HLA) expressed on graft endothelial cells, the prevention of 
      its expression is a possible strategy for avoiding or salvaging DSA-mediated 
      graft rejection. We examined the effect of various clinically used drugs on HLA 
      class II expression on endothelial cells. Interferon-gamma (IFN-gamma)-induced HLA class 
      II DR (HLA-DR) was downregulated by everolimus (EVR, 49.1% +/- 0.8%; P < 0.01) and 
      fluvastatin (FLU, 33.8% +/- 0.6%; P < 0.01). Moreover, the combination of EVR and 
      FLU showed a greater suppressive effect on HLA-DR expression. In contrast, 
      cyclosporine, tacrolimus, mycophenolic acid, and prednisolone did not exhibit any 
      significant suppressive effect. FLU, but not EVR, suppressed mRNA of HLA-DR. 
      Imaging analysis revealed that HLA-DR expressed in cytosol or on the cell surface 
      was repressed by EVR (cytosol: 58.6% +/- 4.9%, P < 0.01; cell surface: 
      80.9% +/- 4.0%, P < 0.01) and FLU (cytosol: 19.0% +/- 3.4%, P < 0.01; cell surface: 
      48.3% +/- 4.8%, P < 0.01). These data indicated that FLU and EVR suppressed 
      IFN-gamma-induced HLA-DR expression at the transcriptional and post-translational 
      level, respectively, suggesting a potential approach for alleviating DSA-related 
      issues in organ transplantation.
CI  - (c) 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.
FAU - Maenaka, Akihiro
AU  - Maenaka A
AD  - Department of Pharmacy, Aichi Medical University School of Medicine, Nagakute, 
      Japan.
AD  - Department of Renal Transplant Surgery, Aichi Medical University School of 
      Medicine, Nagakute, Japan.
FAU - Kenta, Iwasaki
AU  - Kenta I
AUID- ORCID: 0000-0003-3229-5192
AD  - Department of Kidney Disease and Transplant Immunology, Aichi Medical University 
      School of Medicine, Nagakute, Japan.
FAU - Ota, Akinobu
AU  - Ota A
AUID- ORCID: 0000-0002-6296-2921
AD  - Department of Biochemistry, Aichi Medical University School of Medicine, 
      Nagakute, Japan.
FAU - Miwa, Yuko
AU  - Miwa Y
AD  - Department of Kidney Disease and Transplant Immunology, Aichi Medical University 
      School of Medicine, Nagakute, Japan.
FAU - Ohashi, Wataru
AU  - Ohashi W
AD  - Division of Biostatistics, Clinical Research Center, Aichi Medical University 
      School of Medicine, Nagakute, Japan.
FAU - Horimi, Kosei
AU  - Horimi K
AD  - Department of Renal Transplant Surgery, Aichi Medical University School of 
      Medicine, Nagakute, Japan.
FAU - Matsuoka, Yutaka
AU  - Matsuoka Y
AD  - Department of Renal Transplant Surgery, Aichi Medical University School of 
      Medicine, Nagakute, Japan.
FAU - Ohnishi, Masafumi
AU  - Ohnishi M
AD  - Department of Pharmacy, Aichi Medical University School of Medicine, Nagakute, 
      Japan.
FAU - Uchida, Kazuharu
AU  - Uchida K
AD  - Department of Kidney Disease and Transplant Immunology, Aichi Medical University 
      School of Medicine, Nagakute, Japan.
FAU - Kobayashi, Takaaki
AU  - Kobayashi T
AD  - Department of Renal Transplant Surgery, Aichi Medical University School of 
      Medicine, Nagakute, Japan.
LA  - eng
PT  - Journal Article
DEP - 20200415
PL  - England
TA  - FEBS Open Bio
JT  - FEBS open bio
JID - 101580716
RN  - 0 (HLA Antigens)
RN  - 0 (HLA-DR Antigens)
RN  - 0 (Histocompatibility Antigens Class II)
RN  - 0 (Trans-Activators)
RN  - 4L066368AS (Fluvastatin)
RN  - 82115-62-6 (Interferon-gamma)
RN  - 9HW64Q8G6G (Everolimus)
RN  - EC 1.1.1.- (Hydroxymethylglutaryl CoA Reductases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Cell Line
MH  - Endothelial Cells/metabolism
MH  - Everolimus/pharmacology
MH  - Fluvastatin/pharmacology
MH  - Gene Expression/drug effects/genetics
MH  - Graft Rejection/immunology
MH  - HLA Antigens/immunology
MH  - HLA-DR Antigens/*biosynthesis/*genetics/immunology
MH  - Histocompatibility Antigens Class II/genetics/immunology
MH  - Humans
MH  - Hydroxymethylglutaryl CoA Reductases/metabolism/pharmacology
MH  - Interferon-gamma/metabolism/pharmacology
MH  - Organ Transplantation
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Trans-Activators/biosynthesis/genetics/pharmacology
PMC - PMC7193171
OTO - NOTNLM
OT  - CIITA
OT  - HLA class II
OT  - endothelial cell
OT  - everolimus
OT  - fluvastatin
COIS- The authors declare no conflict of interest.
EDAT- 2020/04/03 06:00
MHDA- 2021/07/10 06:00
PMCR- 2020/04/15
CRDT- 2020/04/03 06:00
PHST- 2019/12/18 00:00 [received]
PHST- 2020/03/10 00:00 [revised]
PHST- 2020/03/26 00:00 [accepted]
PHST- 2020/04/03 06:00 [pubmed]
PHST- 2021/07/10 06:00 [medline]
PHST- 2020/04/03 06:00 [entrez]
PHST- 2020/04/15 00:00 [pmc-release]
AID - FEB412854 [pii]
AID - 10.1002/2211-5463.12854 [doi]
PST - ppublish
SO  - FEBS Open Bio. 2020 May;10(5):927-936. doi: 10.1002/2211-5463.12854. Epub 2020 
      Apr 15.