Immunosuppression using the mTOR inhibition mechanism affects replacement of rat liver with transplanted cells.
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.
Wu
Yao-Ming
YM
Marion Bessin Liver Research Center, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Joseph
Brigid
B
Gupta
Sanjeev
S
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D022781:Hepatocytes / Q000637:transplantation*; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016031:Liver Transplantation / Q000379:methods*; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D011494:Protein Kinases / Q000187:drug effects*; D051381:Rats; D011916:Rats, Inbred F344; D020318:Rats, Long-Evans; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D016559:Tacrolimus / Q000494:pharmacology
D007166:Immunosuppressive Agents; D011494:Protein Kinases; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D009173:Mycophenolic Acid; D020123:Sirolimus; D016559:Tacrolimus