Immunosuppression using the mTOR inhibition mechanism affects replacement of rat liver with transplanted cells

Yao Ming Wu, Brigid Joseph, Sanjeev Gupta

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)410-419
Number of pages10
JournalHepatology
Volume44
Issue number2
DOIs
StatePublished - Aug 2006

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Sirolimus
Immunosuppression
Liver
Immunosuppressive Agents
Mycophenolic Acid
Tacrolimus
Hepatocytes
Pharmaceutical Preparations
Dipeptidyl Peptidase 4
Tissue Transplantation
Inosine Monophosphate
Cell Transplantation
Homologous Transplantation
Inbred F344 Rats
Cell- and Tissue-Based Therapy
Oxidoreductases
Down-Regulation
Cell Proliferation
Cytokines
Enzymes

ASJC Scopus subject areas

  • Hepatology

Cite this

Immunosuppression using the mTOR inhibition mechanism affects replacement of rat liver with transplanted cells. / Wu, Yao Ming; Joseph, Brigid; Gupta, Sanjeev.

In: Hepatology, Vol. 44, No. 2, 08.2006, p. 410-419.

Research output: Contribution to journalArticle

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