PMID- 25943210
OWN - NLM
STAT- MEDLINE
DCOM- 20160706
LR  - 20230124
IS  - 1600-6143 (Electronic)
IS  - 1600-6135 (Linking)
VI  - 15
IP  - 9
DP  - 2015 Sep
TI  - Rapamycin Prolongs Cardiac Allograft Survival in a Mouse Model by Inducing 
      Myeloid-Derived Suppressor Cells.
PG  - 2364-77
LID - 10.1111/ajt.13276 [doi]
AB  - Mammalian target of rapamycin (mTOR) inhibitors are the main immunosuppressive 
      drugs for organ transplant recipients. Nevertheless, the mechanisms by which mTOR 
      inhibitors induce immunosuppression is not fully understood. Myeloid-derived 
      suppressor cells (MDSCs) maintain host immunity; however, the relationship 
      between mTOR inhibitors and MDSCs is unclear. Here, the results from a murine 
      cardiac transplantation model revealed that rapamycin treatment (3 mg/kg, 
      intraperitoneally on postoperative days 0, 2, 4, and 6) led to the recruitment of 
      MDSCs and increased their expression of inducible nitric oxide synthase (iNOS). 
      Immunohistochemical analysis revealed that rapamycin induced the migration of 
      iNOS-expressing MDSCs into the subintimal space within the allograft vessels, 
      resulting in a significant prolongation of graft survival compared with that in 
      the untreated group (67 days vs. 7 days, respectively). These effects were 
      counterbalanced by the administration of an anti-Gr-1, which reduced allograft 
      survival to 21 days. Moreover, adoptive transcoronary arterial transfer of MDSCs 
      from rapamycin-treated recipients prolonged allograft survival; this increase was 
      reversed by the anti-Gr-1 antibody. Finally, co-administration of rapamycin and a 
      mitogen-activated protein kinase kinase (MEK) inhibitor trametinib reversed 
      rapamycin-mediated MDSC recruitment. Thus, the mTOR and Raf/MEK/extracellular 
      signal regulated kinase (ERK) signaling pathways appear to play an important role 
      in MDSC expansion.
CI  - (c) Copyright 2015 The American Society of Transplantation and the American Society 
      of Transplant Surgeons.
FAU - Nakamura, T
AU  - Nakamura T
AD  - Department of Transplantation and Regenerative Surgery, Graduate School of 
      Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-Ku, 
      Kyoto-Prefecture, Japan.
AD  - Department of Clinical and Translational Physiology, Kyoto Pharmaceutical 
      University, Yamashina-ku, Kyoto, Japan.
FAU - Nakao, T
AU  - Nakao T
AD  - Department of Transplantation and Regenerative Surgery, Graduate School of 
      Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-Ku, 
      Kyoto-Prefecture, Japan.
AD  - Department of Clinical and Translational Physiology, Kyoto Pharmaceutical 
      University, Yamashina-ku, Kyoto, Japan.
FAU - Yoshimura, N
AU  - Yoshimura N
AD  - Department of Transplantation and Regenerative Surgery, Graduate School of 
      Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-Ku, 
      Kyoto-Prefecture, Japan.
FAU - Ashihara, E
AU  - Ashihara E
AD  - Department of Clinical and Translational Physiology, Kyoto Pharmaceutical 
      University, Yamashina-ku, Kyoto, Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150505
PL  - United States
TA  - Am J Transplant
JT  - American journal of transplantation : official journal of the American Society of 
      Transplantation and the American Society of Transplant Surgeons
JID - 100968638
RN  - 0 (Immunosuppressive Agents)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type II)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Allografts
MH  - Animals
MH  - CD4-Positive T-Lymphocytes/cytology/immunology
MH  - Flow Cytometry
MH  - Graft Rejection/drug therapy
MH  - Graft Survival/*drug effects
MH  - *Heart Transplantation
MH  - Immune Tolerance/*immunology
MH  - Immunosuppression Therapy
MH  - Immunosuppressive Agents/*pharmacology
MH  - Lymphocyte Activation
MH  - Mice
MH  - Mice, Inbred C3H
MH  - Mice, Inbred C57BL
MH  - Myeloid Cells/cytology/*immunology
MH  - Nitric Oxide Synthase Type II/metabolism
MH  - Sirolimus/*pharmacology
MH  - TOR Serine-Threonine Kinases/metabolism
OTO - NOTNLM
OT  - Animal models: murine
OT  - basic (laboratory) research/science
OT  - cellular biology
OT  - heart (allograft) function/dysfunction
OT  - heart transplantation/cardiology
OT  - immune regulation
OT  - immunosuppressant
OT  - immunosuppression/immune modulation
OT  - mechanistic target of rapamycin:sirolimus
OT  - translational research/science
EDAT- 2015/05/07 06:00
MHDA- 2016/07/07 06:00
CRDT- 2015/05/07 06:00
PHST- 2014/10/27 00:00 [received]
PHST- 2015/02/16 00:00 [revised]
PHST- 2015/02/17 00:00 [accepted]
PHST- 2015/05/07 06:00 [entrez]
PHST- 2015/05/07 06:00 [pubmed]
PHST- 2016/07/07 06:00 [medline]
AID - S1600-6135(22)00367-7 [pii]
AID - 10.1111/ajt.13276 [doi]
PST - ppublish
SO  - Am J Transplant. 2015 Sep;15(9):2364-77. doi: 10.1111/ajt.13276. Epub 2015 May 5.