Cyclosporine effect in atopic dermatitis may be mediated by increase of Treg cells

Atopic dermatitis (AD) is a T cell dependent chronic relapsing inflammatory skin disorder successfully treated with cyclosporine A (CsA). Even low-dose CsA therapy is successful in severely affected AD patients.

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?

(A) NFkB

(B) calcium

(C) ipraimmunophilin

(D) NFAT

(E) calcineurin

(F) calmodulin

(G) AP-1

Answer: E.

Atopic Dermatitis Treatment - Illustrated (click here for full size image).

References:
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].