Inflammatory Skin Disease

T-Cell mediated skin diseases, mainly comprising psoriasis (prevalence >2%), allergic contact dermatitis (ACD, prevalence about 9%) and atopic dermatitis (prevalence > 3% in developed countries and especially among Caucasians), are the most prevalent and severe chronic inflammatory skin diseases. While psoriasis is thought to be based primarily on an exaggerated Th1 or maybe Th17-type immune response, atopic dermatitis more likely represents an overt Th2-type immune response. ACD lies somewhere in the middle, revealing characteristics of either immune response, but seeming to be inclined more towards the Th1-type, especially during the induction or sensitization phase. ACD is an eczematous reaction to repeated exposure against an allergen and can be regarded as a delayed-type hypersensitivity response with a sensitization phase, generally asymptomatic, an effector and a resolution phase. Only superficial regions of the skin are affected with inflammation present in the outer dermis and epidermis, and the cellular infiltrate is mainly composed of mononuclear cells.

Generally, ACD has been regarded as a Thl-type immune response, and the crucial role of the Th1 cytokine IFN-g, especially during the induction (sensi-tization) phase, remains undisputed. Thus, it does not come as a surprise that the transcription factor Stat-1, as the principal effector molecule in IFN-g signalling, is considered to be a pivotal drug target not only in ACD but also in psoriasis. Topical corticosteroids, which have been widely used in ACD therapy, exert their anti-inflammatory effects mainly through inhibition of the transcription factors AP-1 and NF-kB. However, long-term treatment with these corticosteroids may produce significant adverse effects, such as skin atrophy at the site of application, and these have spurred the search for other treatment modalities, such as drugs based on nucleic acid.

In comparison with common topical steroids, the efficacy of a Stat-1 decoy ODN containing ointment on dinitrohalobenzene-induced ACD, both in guinea pigs and domestic pigs, has recently been examined. In guinea pigs, single application of the Stat-1 decoy ODN, but not that of an appropriate control ODN, in a rather simple ointment not only facilitated its penetration deep into the dermis (see Figure 7.6), but also resulted in a profound dose-dependent improvement of both the macroscopic and histopathological signs of inflammation. This was accompanied by a significant decrease in leukocyte (polymorphonuclear neutrophils, monocytes, T-cells) infiltration into the dermis (Figure 7.9) and reduced skin thickening. Moreover, the Stat-1 decoy ODN ointment strongly attenuated the expression of IL-1 p, IL-8 and IL-12 as well as that of TNF-a and IFN-g. When compared to the simultaneously tested topical steroids (clobetasol, hydrocortisone), the Stat-1 decoy ODN ointment appeared to be at least as effective. A related Stat-1 decoy ODN, when injected intra-articularly, also profoundly blocked the delayed-type hypersensitivity reaction to injection of the antigen seven days after the induction of arthritis.30

Another interesting target molecule for the treatment of inflammatory skin diseases is NF-kB. Thus, a 1-2% ointment of an NF-kB decoy ODN was successfully tested in a spontaneous atopic dermatitis model (NC/Nga mice) with12 or without31 additional dust-mite antigen challenge, as well as in a delayed-type hypersensitivity response model in mice.32 In the chronic dust-mite antigen skin inflammation treatment model, the NF-kB decoy ODN ointment appeared to be equipotent to the corticosteroid betamethasone val-erate, both in the prevention and treatment arm of the study, and down-regulated expression of a similar subset of pro-inflammatory gene products in the mouse skin.12 However, administration of the NF-kB decoy ODN also resulted in a marked increase in the number of apoptotic cells, which may have comprised primarily inflamed skin cells. Nonetheless, administration of such decoy ODNs should probably be restricted to the topical route of application, since systemic suppression of NF-kB might be harmful, given that knockout mice for various NF-kB signalling components suffer from immune deficiency or lack lymphocyte activation.33 However, when compared to topical steroids, repeated administration of the NF-kB decoy ODN ointment did not result in skin atrophy or any other local adverse effects.12

A vehicle

B DNCB + vehicle

E DNCB + clobetasol

Figure 7.9 Effects of (A) vehicle, (B) 0.5% DNCB (dinitrochlorobenzene), (C) DNCB plus 0.13% Stat-1 decoy ODN, (D) DNCB plus control ODN and (E) DNCB plus 0.25% clobetasol propionate on polymorphonuclear neutrophils (PMN) skin infiltration over 24 hours in a guinea pig ACD model. The naphthol AS D chloroacetate esterase stain was used to visualize the infiltrating PMNs (magnification 200 x).

Figure 7.9 Effects of (A) vehicle, (B) 0.5% DNCB (dinitrochlorobenzene), (C) DNCB plus 0.13% Stat-1 decoy ODN, (D) DNCB plus control ODN and (E) DNCB plus 0.25% clobetasol propionate on polymorphonuclear neutrophils (PMN) skin infiltration over 24 hours in a guinea pig ACD model. The naphthol AS D chloroacetate esterase stain was used to visualize the infiltrating PMNs (magnification 200 x).

Finally, also, a Stat-6 decoy ODN was found to be effective especially against the late-phase response in a dinitrofluorobenzene-induced contact dermatitis model in mice.34 However, the decoy ODN was rather long (28-mer) and therefore had to be administered as a haemagglutinating virus of Japan (HVJ)-liposomal formulation. The most prominent effect was observed upon subcutaneous injection at concentrations ranging from 5 to 20 mM, a topical route of administration has not been attempted and the magnitude of the antiinflammatory effect of the Stat-6 decoy ODN turned out to be strain-specific, which suggests that it is directed against a Th2- rather than a Thl-driven immune response.

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