PMID- 25307040
OWN - NLM
STAT- MEDLINE
DCOM- 20150615
LR  - 20230124
IS  - 1600-6143 (Electronic)
IS  - 1600-6135 (Print)
IS  - 1600-6135 (Linking)
VI  - 14
IP  - 9
DP  - 2014 Sep
TI  - Adenosine triphosphate-competitive mTOR inhibitors: a new class of 
      immunosuppressive agents that inhibit allograft rejection.
PG  - 2173-80
LID - 10.1111/ajt.12799 [doi]
AB  - The mechanistic/mammalian target of rapamycin (mTOR) is inhibited clinically to 
      suppress T cell function and prevent allograft rejection. mTOR is the kinase 
      subunit of two mTOR-containing complexes, mTOR complex (mTORC) 1 and 2. Although 
      mTORC1 is inhibited by the macrolide immunosuppressant rapamycin (RAPA), its 
      efficacy may be limited by its inability to block mTORC1 completely and its 
      limited effect on mTORC2. Adenosine triphosphate (ATP)-competitive mTOR 
      inhibitors are an emerging class of mTOR inhibitors that compete with ATP at the 
      mTOR active site and inhibit any mTOR-containing complex. Since this class of 
      compounds has not been investigated for their immunosuppressive potential, our 
      goal was to determine the influence of a prototypic ATP-competitive mTOR 
      inhibitor on allograft survival. AZD8055 proved to be a potent suppressor of T 
      cell proliferation. Moreover, a short, 10-day course of the agent successfully 
      prolonged murine MHC-mismatched, vascularized heart transplant survival. This 
      therapeutic effect was associated with increased graft-infiltrating regulatory T 
      cells and reduced CD4(+) and CD8(+) T cell interferon-gamma production. These studies 
      establish for the first time, that ATP-competitive mTOR inhibition can prolong 
      organ allograft survival and warrant further investigation of this next 
      generation mTOR inhibitors.
CI  - (c) Copyright 2014 The American Society of Transplantation and the American Society 
      of Transplant Surgeons.
FAU - Rosborough, B R
AU  - Rosborough BR
AD  - Department of Surgery, School of Medicine, Thomas E. Starzl Transplantation 
      Institute, University of Pittsburgh, Pittsburgh, PA.
FAU - Raich-Regue, D
AU  - Raich-Regue D
FAU - Liu, Q
AU  - Liu Q
FAU - Venkataramanan, R
AU  - Venkataramanan R
FAU - Turnquist, H R
AU  - Turnquist HR
FAU - Thomson, A W
AU  - Thomson AW
LA  - eng
GR  - UL1 TR000005/TR/NCATS NIH HHS/United States
GR  - T32 AI074490/AI/NIAID NIH HHS/United States
GR  - R00 HL097155/HL/NHLBI NIH HHS/United States
GR  - T32AI07449/AI/NIAID NIH HHS/United States
GR  - R00HL097155/HL/NHLBI NIH HHS/United States
GR  - R01AI67541/AI/NIAID NIH HHS/United States
GR  - R01 AI067541/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20140804
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 (DNA Primers)
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (Morpholines)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - 970JJ37FPW 
      ((5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol)
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  - Adenosine Triphosphate/*metabolism
MH  - Animals
MH  - Base Sequence
MH  - Binding, Competitive
MH  - CD4-Positive T-Lymphocytes/cytology/drug effects
MH  - CD8-Positive T-Lymphocytes/cytology/drug effects
MH  - Cell Proliferation/drug effects
MH  - DNA Primers
MH  - Graft Rejection/*prevention & control
MH  - Graft Survival
MH  - Immunosuppressive Agents/*pharmacology
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Morpholines/pharmacokinetics/*pharmacology
MH  - Polymerase Chain Reaction
MH  - Sirolimus/pharmacokinetics/pharmacology
MH  - TOR Serine-Threonine Kinases/*metabolism
PMC - PMC4196715
MID - NIHMS590574
OTO - NOTNLM
OT  - Basic (laboratory) research
OT  - T cell
OT  - biology
OT  - immune modulation
OT  - immunosuppressant
OT  - immunosuppression
OT  - mechanistic target of rapamycin (mTOR)
OT  - science
COIS- Disclosure The authors of this manuscript have no conflicts of interest to 
      disclose as described by the American Journal of Transplantation.
EDAT- 2014/10/14 06:00
MHDA- 2015/06/16 06:00
PMCR- 2015/09/01
CRDT- 2014/10/14 06:00
PHST- 2013/10/08 00:00 [received]
PHST- 2014/04/01 00:00 [revised]
PHST- 2014/04/24 00:00 [accepted]
PHST- 2014/10/14 06:00 [entrez]
PHST- 2014/10/14 06:00 [pubmed]
PHST- 2015/06/16 06:00 [medline]
PHST- 2015/09/01 00:00 [pmc-release]
AID - S1600-6135(22)25606-8 [pii]
AID - 10.1111/ajt.12799 [doi]
PST - ppublish
SO  - Am J Transplant. 2014 Sep;14(9):2173-80. doi: 10.1111/ajt.12799. Epub 2014 Aug 4.