Inhibitory effects of cyclosporine on human regulatory T cells in vitro.
BACKGROUND
Inevitable hepatitis C virus (HCV) recurrence after liver transplantation is a major barrier to the survival of a transplanted liver. It may be promoted by immunosuppression and the emergence of CD4+CD25+ regulatory T cells (Treg). Treg cells can mediate the induction and maintenance of immunological self-tolerance as well as transplant tolerance. We investigated the effects of cyclosporine (CsA), a widely used immunosuppressive agent, on human CD4+CD25+ Treg cells.


METHODS
Human CD4+CD25+ cells isolated from healthy donors were cultured in the presence of 40 or 400 ng/mL CsA. The suppressive activity of Treg was assessed in mixed leukocyte reactions (MLR) using CD25+ and autologous activated peripheral blood mononuclear cells (PBMC). Phenotype analysis (flow cytometric, Q-PCR) and cytokine production (ELISA) of Treg cells were then performed on cultures.


RESULTS
CsA (40 or 400 ng/mL) inhibited the proliferative capacity of PBMC and CD4+CD25+ Treg in a dose-dependent manner. Interestingly, addition of 40 ng/mL CsA in MLR impaired the suppressive activity of CD4+CD25+ cells, whereas a higher dose of CsA had no effect on Treg function. It appears that a therapeutic dose of CsA (40 ng/mL) did not change the phenotype of CD4+CD25+ T cells, but altered Treg activity by switching the regulatory to an inflammatory cytokine profile.


CONCLUSIONS
CsA significantly impaired the function of CD4+CD25+ Treg cells by inducing interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) secretion. The present studies suggested that CsA may block the induction of immune tolerance and decrease the risk of hepatitis C recurrence.
CNRS (Unité Mixte de Recherche: 8161) - Institut de Biologie de Lille, Lille, France.
C
C
Miroux
O
O
Moralès
A
A
Carpentier
S
S
Dharancy
F
F
Conti
E
E
Boleslowski
P
P
Podevin
C
C
Auriault
V
V
Pancré
N
N
Delhem
D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D018929:Cell Culture Techniques; D016572:Cyclosporine / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006526:Hepatitis C / Q000276:immunology / Q000601:surgery; D006801:Humans; D016130:Immunophenotyping; D007166:Immunosuppressive Agents / Q000494:pharmacology; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D016031:Liver Transplantation / Q000276:immunology; D012008:Recurrence; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects / Q000276:immunology*
D007166:Immunosuppressive Agents; D053645:Interleukin-2 Receptor alpha Subunit; D016572:Cyclosporine