Effects of Pimecrolimus on Skin Biopsy Ex-plants From Patients With Atopic Dermatitis

AMP play an important role in the innate immune response against infections. Two major classes of AMP have been identified: the beta defensins (HBD) (Harder 1997) and cathelicidins (LL-37) (Gallo 2002). AMP have been shown to have antibacterial activities against S. aureus (Ong 2002) and antiviral activity against vaccinia virus (VV) (Howell 2004). The skin of AD patients is characterized by a deficiency in AMP, which may account for their propensity to skin infections (Ong 2002). This AMP deficiency is believed to be due to an increase in Th2 cytokines, IL-4 and IL-13, expression (Ong 2002), as well as an increase of IL-10 expression (Howell 2005). Other cytokines known to affect AMP expression are TNF-alpha (TNFa), IL-6, IL-1 and interferon-gamma (IFN-g). These cytokines induce the expression of AMP (Erdag 2002, Liu 2002, Ong 2002, Nomura 2003). However, negligible levels of TNF-a and IFN-g have been shown in AD skin possibly due to their downregulation by Th2 cytokines (Nomura 2003). Therefore, the neutralization of IL-4, IL-13 and IL-10 in AD patients may correct the AMP deficiency of AD patients and decrease their propensity to recurrent skin infections. Interestingly, the addition of anti-IL10 to skin explants from AD patients augmented HBD-2 and LL-37 expression (Howell 2005). In addition, IL-4 and IL-13 were found to enhance VV replication and down-regulate LL-37 in VV-stimulated keratinocytes and neutralization of IL-4/IL-13 in AD skin augmented LL-37 and inhibited VV replication (Howell 2006a). LL-37 and HBD-3 have been found to kill VV(Howell 2004; Howell 2006b). Thus a deficiency of these AMP may contribute to increased propensity to viral infection. Therapeutic strategies are needed to augment AMP expression in AD skin to reduce skin infection. Pimecrolimus is a calcineurin inhibitor that binds with high affinity to macrophilin-12. The complex pimecrolimus-macrophilin inhibits calcineurin, a phosphatase required for the dephosphorylation of the cytosolic form of the nuclear factor of activated T cells (NF-AT). As a consequence, pimecrolimus prevents the nuclear translocation of NFAT and thereby the transcription and release of both Th1 and Th2 cytokines such as IL-2, IFN-g, IL-4, IL-5, IL-10, TNF-a and GM-CSF (Grassberger 1999). As the most common topical corticosteroid treatment used by AD patients, triamcinolone diacetate is included in this study as an active comparator.