BACKGROUND: Little is known on the impact of immunosuppressive drugs on the development of the different T-cell subsets that compose the immune balance. We have explored the influence of mycophenolic acid (MPA) and tacrolimus on T cells response with a special focus on the Th17-cell subset. METHODS: In an in vitro model of human CD4 cells activation, we first compared the influence of MPA and tacrolimus on the transcription of different set of genes related to each of the main T-cell subsets and then investigated how these two drugs interfere with interleukin (IL)-17 production. We also studied, in stable kidney transplant patients, the relation between IL-17 serum concentration and systemic drug exposure. RESULTS: MPA and tacrolimus exhibited a comparable impact on T-cell response, dampening most Th1-related genes transcription and preserving regulatory T cells/Th2 molecular phenotypes. Although both MPA and tacrolimus decreased Th17-related transcripts after T-cell activation, MPA exerted a stronger inhibitory effect on IL-17 production than tacrolimus. Accordingly, renal transplant patients treated with MPA in combination with minimized dose of tacrolimus tended to have lower circulating IL-17 levels than patients treated with tacrolimus alone given at conventional dose. CONCLUSIONS: A treatment combining MPA and tacrolimus is susceptible to favorably tip the immune balance and might confer optimal allograft immunoprotection. Because of its ability to profoundly inhibit IL-17 production, MPA may help to better overcome Th17-related alloreactivity in the context of calcineurin inhibitor-minimizing protocol.
BACKGROUND: Little is known on the impact of immunosuppressive drugs on the development of the different T-cell subsets that compose the immune balance. We have explored the influence of mycophenolic acid (MPA) and tacrolimus on T cells response with a special focus on the Th17-cell subset. METHODS: In an in vitro model of human CD4 cells activation, we first compared the influence of MPA and tacrolimus on the transcription of different set of genes related to each of the main T-cell subsets and then investigated how these two drugs interfere with interleukin (IL)-17 production. We also studied, in stable kidney transplant patients, the relation between IL-17 serum concentration and systemic drug exposure. RESULTS:MPA and tacrolimus exhibited a comparable impact on T-cell response, dampening most Th1-related genes transcription and preserving regulatory T cells/Th2 molecular phenotypes. Although both MPA and tacrolimus decreased Th17-related transcripts after T-cell activation, MPA exerted a stronger inhibitory effect on IL-17 production than tacrolimus. Accordingly, renal transplantpatients treated with MPA in combination with minimized dose of tacrolimus tended to have lower circulating IL-17 levels than patients treated with tacrolimus alone given at conventional dose. CONCLUSIONS: A treatment combining MPA and tacrolimus is susceptible to favorably tip the immune balance and might confer optimal allograft immunoprotection. Because of its ability to profoundly inhibit IL-17 production, MPA may help to better overcome Th17-related alloreactivity in the context of calcineurin inhibitor-minimizing protocol.
Authors: R De Bruyne; D Bogaert; N De Ruyck; B N Lambrecht; M Van Winckel; P Gevaert; M Dullaers Journal: Clin Exp Immunol Date: 2015-06 Impact factor: 4.330