PMID- 16871590
OWN - NLM
STAT- MEDLINE
DCOM- 20060824
LR  - 20211203
IS  - 0270-9139 (Print)
IS  - 0270-9139 (Linking)
VI  - 44
IP  - 2
DP  - 2006 Aug
TI  - Immunosuppression using the mTOR inhibition mechanism affects replacement of rat 
      liver with transplanted cells.
PG  - 410-9
AB  - Successful grafting of tissues or cells from mismatched donors requires systemic 
      immunosuppression. It is yet to be determined whether immunosuppressive 
      manipulations perturb transplanted cell engraftment or proliferation. We used 
      syngeneic and allogeneic cell transplantation assays based on F344 recipient rats 
      lacking dipeptidyl peptidase IV enzyme activity to identify transplanted 
      hepatocytes. Immunosuppressive drugs used were tacrolimus (a calcineurin 
      inhibitor) and its synergistic partners, rapamycin (a regulator of the mammalian 
      target of rapamycin [mTOR]) and mycophenolate mofetil (an inosine monophosphate 
      dehydrogenase inhibitor). First, suitable drug doses capable of inducing 
      long-term survival of allografted hepatocytes were identified. In 
      pharmacologically effective doses, rapamycin enhanced cell engraftment by 
      downregulating hepatic expression of selected inflammatory cytokines but 
      profoundly impaired proliferation of transplanted cells, which was necessary for 
      liver repopulation. In contrast, tacrolimus and/or mycophenolate mofetil 
      perturbed neither transplanted cell engraftment nor their proliferation. 
      Therefore, mTOR-dependent extracellular and intracellular mechanisms affected 
      liver replacement with transplanted cells. In conclusion, insights into the 
      biological effects of specific drugs on transplanted cells are critical in 
      identifying suitable immunosuppressive strategies for cell therapy.
FAU - Wu, Yao-Ming
AU  - Wu YM
AD  - Marion Bessin Liver Research Center, Department of Medicine, Albert Einstein 
      College of Medicine, Bronx, New York 10461, USA.
FAU - Joseph, Brigid
AU  - Joseph B
FAU - Gupta, Sanjeev
AU  - Gupta S
LA  - eng
GR  - 2P01-DK52956/DK/NIDDK NIH HHS/United States
GR  - P30-DK41296/DK/NIDDK NIH HHS/United States
GR  - R01 DK46952/DK/NIDDK NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - 0 (Immunosuppressive Agents)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (mTOR protein, rat)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - HU9DX48N0T (Mycophenolic Acid)
RN  - W36ZG6FT64 (Sirolimus)
RN  - WM0HAQ4WNM (Tacrolimus)
SB  - IM
MH  - Animals
MH  - Cell Proliferation/drug effects
MH  - Graft Rejection/immunology/pathology/*prevention & control
MH  - Hepatocytes/*transplantation
MH  - *Immunosuppression Therapy
MH  - Immunosuppressive Agents/*pharmacology
MH  - Liver Transplantation/*methods
MH  - Mycophenolic Acid/analogs & derivatives/pharmacology
MH  - Protein Kinases/*drug effects
MH  - Rats
MH  - Rats, Inbred F344
MH  - Rats, Long-Evans
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - Tacrolimus/pharmacology
EDAT- 2006/07/28 09:00
MHDA- 2006/08/25 09:00
CRDT- 2006/07/28 09:00
PHST- 2006/07/28 09:00 [pubmed]
PHST- 2006/08/25 09:00 [medline]
PHST- 2006/07/28 09:00 [entrez]
AID - 10.1002/hep.21277 [doi]
PST - ppublish
SO  - Hepatology. 2006 Aug;44(2):410-9. doi: 10.1002/hep.21277.