title: In vitro effects of cyclosporine A and tacrolimus on regulatory T-cell proliferation and function.
abstract: BACKGROUND
  Liver transplantation is the treatment of end-stage liver diseases, including hepatitis C. Immunosuppression prevents graft rejection but seems to accelerate the recurrence of hepatitis C. Regulatory T cells (Tregs) may be beneficial in tolerance but deleterious in recurrent hepatitis C. We evaluated the effects of cyclosporine or tacrolimus, the principal immunosuppressive drugs, on Treg proliferation and function.
  
  
  METHODS
  Human Tregs were isolated from healthy donors and cultured with cyclosporine, tacrolimus, or NIM811, a cyclosporine analog devoid of calcineurin-inhibiting activity. Treg proliferation and suppressive activity were assessed. The phenotype, cytokine production, and phosphorylation profile of nuclear factor of activated T cell of Tregs were also analyzed.
  
  
  RESULTS
  Cyclosporine and tacrolimus both decreased Treg proliferation, but only low doses of cyclosporine reduced Treg activity, by inducing the production of interleukin 2 proinflammatory cytokines in these cells. Moreover, NIM811 also inhibited Treg activity. The phosphorylation of nuclear factor of activated T cell in Tregs was not altered by cyclosporine, suggesting that the effects of this drug are independent of the calcineurin pathway.
  
  
  CONCLUSIONS
  In summary, low doses of cyclosporine inhibit Treg activity, a finding that might explain the beneficial effect of this drug on hepatitis C recurrence. In contrast, by maintaining Treg activity, tacrolimus could be more helpful than cyclosporine in controlling rejection.
authors: CNRS UMR8161, Institut de Biologie de Lille, Universités Lille Nord de France, Lille, France.
authors: Céline
authors: C
authors: Miroux
authors: Olivier
authors: O
authors: Morales
authors: Khaldoun
authors: K
authors: Ghazal
authors: Samia Ben
authors: SB
authors: Othman
authors: Yvan
authors: Y
authors: de Launoit
authors: Véronique
authors: V
authors: Pancré
authors: Filomena
authors: F
authors: Conti
authors: Nadira
authors: N
authors: Delhem
mesh_terms: D065095:Calcineurin Inhibitors; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology*; D016207:Cytokines / Q000096:biosynthesis; D006801:Humans; D016130:Immunophenotyping; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016031:Liver Transplantation; D008213:Lymphocyte Activation / Q000187:drug effects*; D050778:NFATC Transcription Factors / Q000378:metabolism; D010766:Phosphorylation; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D016559:Tacrolimus / Q000494:pharmacology*
chemical_list: D065095:Calcineurin Inhibitors; D016207:Cytokines; D007166:Immunosuppressive Agents; D050778:NFATC Transcription Factors; D016572:Cyclosporine; C090438:(melle-4)cyclosporin; D016559:Tacrolimus