Cyclosporine and FK-506 block T cell cytokine production by inhibiting activation of the NFAT transcription factor (note: different from NFkB).
Ciclosporin (INN), cyclosporine (USAN) or cyclosporin (former BAN). Image source: Wikipedia, public domain.
Together with tacrolimus, cyclosporine is a calcineurin inhibitor (CNI).
Cyclophilin. Image source: Wikipedia, public domain.
Cyclosporin is thought to bind to the cytosolic protein cyclophilin (an immunophilin) of lymphocytes, especially T-lymphocytes. This complex of cyclosporin and cyclophilin inhibits calcineurin, which under normal circumstances induces the transcription of interleukin-2.
In this study, T cells were activated in a whole blood sample and interleukin-2 producing cells were measured by cytokine staining. Regulatory T cells were analyzed by intracellular FoxP3 staining. Regulatory T cells (CD4(+)CD25(+)CD127(low)) and effector T cells (CD4(+)CD25(-)CD127(+)) were sorted by flow cytometry.
AD patients treated with low-dose CsA had a significantly larger Treg cell population than healthy controls.
Low-dose CsA therapy reduced the ability of T cells to be activated and increased Treg cells (1.6-fold change). Treg cells from AD patients had skin homing properties.
The authors concluded that the therapeutic effect of low-dose CsA therapy in AD patients might be not only mediated by the inhibition of T cell hyperactivity but also by an increased population of Treg cells.
What is the molecule that tacrolimus binds to in order to exert its therapeutic effect?
Atopic Dermatitis Treatment - Illustrated (click here for full size image).
Low-dose cyclosporine A therapy increases the regulatory T cell population in patients with atopic dermatitis. Brandt C, Pavlovic V, Radbruch A, Worm M, Baumgrass R. Allergy. 2009 Apr 29. [Epub ahead of print].