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Therapeutic monitoring of calcineurin inhibitors (ciclosporin and tacrolimus) consists in pharmacokinetic monitoring. Pharmacodynamics based on calcineurin activity may be particularly interesting in liver transplantation due to the large intra- and interindividual variability of pharmacokinetics of ciclosporin and tacrolimus. A recent investigation on the pharmacokinetic-pharmacodynamic relationship of tacrolimus showed that monitoring of calcineurin activity in PBMC may be particularly relevant within the first three post-transplantation months. Thereafter, the monitoring of trough blood concentrations of tacrolimus remains adequate. Moreover, two clinical investigations carried out within the early and late post-transplantation periods reported a promising result which is a positive correlation between calcineurin activity and incidence of graft rejection, whatever graft type and calcineurin inhibitors. In each study, transplanted recipients with a graft rejection exhibited a greater trough calcineurin activity compared to patients without graft rejection. However, prospective investigations are required because of the small cohorts of patients enrolled in both studies. The aim of these investigations will be to confirm the interest of calcineurin activity monitoring as a marker of cellular immunity and its positive link with pharmacokinetic monitoring.

Topical calcineurin inhibitors, also called topical immunomodulators or downregulators, represent an innovative class of non-steroidal anti-inflammatory agents. Pimecrolimus 1% cream (Elidel) is one representative drug available for the treatment of atopic dermatitis. Unlike topical steroids, this drug does not affect collagen synthesis and does not alter the dendritic cell functions and the barrier function of the skin.

Lymphocytes from patients treated with immunosuppressive agents were cultured for 48 hours either with or without concanavalin A. Phospholipid synthesis was then studied using 32p pulse-incorporation (5-hours pulses). Phosphatidylethanolamine synthesis was strongly decreased under immunosuppressive treatment: 1.5-fold in resting lymphocytes and 3- to 4-fold in concanavalin A-stimulated lymphocytes. Phosphatidylinositol synthesis also decreased about 2-fold in stimulated lymphocytes. These results indicate a loss of sensitivity of immunodeficient lymphocytes to the mitogen and an alteration of the G0 and the late G1 cell cycle phases. In parallel, but after a 72-hours incubation, lymphocytes were analysed by flow-cytofluorimetry with propidium iodide. Under concanavalin A-triggered stimulation, the entry into the S phase was much lower in immunodeficient lymphocytes as compared to standard. The characteristics of the G0-G1 population of lymphocytes were also modified. More importantly, after incubation in the culture medium in the absence of mitogen, we observed, among the immunodeficient lymphocytes, a high level of apoptotic cells, about 20 to 30%. This susceptibility to spontaneous apoptosis seems inherent to the status of immunodeficiency itself, whatever its origin. It may be related to the inhibition of phosphatidylethanolamine synthesis in the G0 phase.

Pimecrolimus inhibits some specific steps of the Th1 and Th2 immune reactions. It belongs to the class of ascomycin macrolactams. The topical drug formulation targets cutaneous inflammation, more particularly lymphocytes and mast cells without impairing systemic immunosurveillance. Topical applications are indicated for treating atopic dermatitis. In this indication, it represents an alternative or an adjuvant drug to topical corticosteroids. The treatment of other dermatoses could also benefit from pimecrolimus.

Tacrolimus is a potent inhibitor of immune mechanisms. It belongs to the macrolactam group. It inhibits the release of both Th1 and Th2 cytokines. It proves to be efficacious after topical application in the treatment of atopic dermatitis. In this indication, tacrolimus challenges topical corticosteroids. Irritation risks are present. The local immuno-depression can boost disseminated infections including herpes. The risk to promote photocarcinogenesis on the long term, and that bound to chronic resorption remain theoretical concerns that have not been assessed so far.

The growth of mouse L-929 fibroblasts in culture is inhibited by dexamethasone, a synthetic glucocorticosteroid, and this effect is itself suppressed by the antiglucocorticosteroid RU486 (mifepristone). Neither RU486 nor the immunosuppressant FK506 alone influence L-929 growth, and FK506 does not modify dexamethasone action. However, FK506 suppresses the antiglucocorticosteroid activity of RU486. The implication of the "anti-antagonist" activity of FK506 in its immunosuppressant properties has still to be explained. The role of the recently cloned, FK506-binding, p59 immunophilin, which binds to the heat shock protein hsp90 which itself interacts with the glucocorticosteroid receptor, is discussed.

In the absence of hormonal ligand, inactive, heterooligomeric, 8-10S steroid receptor complexes include a p59 protein (apparent M(r) approximately 59 kDa) bound to th heat shock protein hsp90 (apparent M(r) approximately 90 kDa), which itself binds to the ligand binding domain LBD of the receptor molecule, p59 is thus an hsp binding immunophilin HBI, which, through its interaction with a chaperone, may intervene in several cellular functions. We report that, in cell-free experiments at 0 degrees C, FK506 and rapamycin do not release p59 nor hsp90 from the 9.5S rabbit uterus progesterone receptor, suggesting that the binding of p59 to hsp90 does not interfere with the rotamase site of HBI. There is no "transformation/activation" of the receptor, but an up to 2 fold increase in progesterone agonist and antagonist binding to the receptor is observed. It is suggested that a functional interaction between HBI and receptor activity may be mediated by hsp90.