Differential effect of cyclosporine and mycophenolic acid on the human regulatory T cells and TH-17 cells balance.
BACKGROUND
Beyond the usual TH1/TH2 polarization, a reciprocal pathway between FoxP3+ regulatory T cells (Tregs) and interleukin (IL)-17-secreting effector T cells (TH-17) has recently been identified. We have investigated the effects of two immunosuppressive drugs, cyclosporine (CsA) and mycophenolic acid (MPA) on the development of Treg/TH-17 cell responses.


METHODS
We compared the influence of CsA and MPA on the transcription levels of FOXP3 (Treg marker) and IL17 (TH-17 marker) in activated human peripheral blood mononuclear cells (PBMC).


RESULTS
After 48 hours of activation, IL17 transcription was rapidly induced, remaining stable over 96 hours, whereas only a transient increase in FOXP3 was noted, suggesting that the Treg/TH-17 cell balance was tipped toward TH-17 during PBMC activation. The addition of either CsA or MPA did not affect the level of transcription of FOXP3. MPA but not CsA was found to significantly inhibit IL17 expression by activated PBMC. This effect of MPA seemed to result from its capacity to hamper (1) the production of IL1beta by monocytes and (2) the expression of TIM-1 by CD4+ T cells, two key signals involved in human TH-17 differentiation.


CONCLUSIONS
Through a preferential inhibition of IL17, MPA might favorably influence the Treg/TH- 17 balance. Our results suggest that the immunosuppressive drugs used in the clinic may differentially influence lymphocyte polarization, including the newly identified TH-17 pathway.
Abadja
F
F
Laboratoire de Néphrologie, EA3065, Université Jean Monnet, Saint Etienne, France.
Videcoq
C
C
Alamartine
E
E
Berthoux
F
F
Mariat
C
C
D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018929:Cell Culture Techniques; D016572:Cyclosporine / Q000494:pharmacology*; D051858:Forkhead Transcription Factors / Q000235:genetics*; D005819:Genetic Markers; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D020381:Interleukin-17 / Q000235:genetics*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D009173:Mycophenolic Acid / Q000494:pharmacology*; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D014158:Transcription, Genetic / Q000187:drug effects*
C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D005819:Genetic Markers; D007166:Immunosuppressive Agents; D020381:Interleukin-17; D016572:Cyclosporine; D009173:Mycophenolic Acid