Skin disease refers to all disorders occurring on the skin of animals including humans. Among skin diseases, atopic dermatitis is a chronic/inflammatory skin disease, whose main symptoms include serious itching, skin dryness and eczema (Rudikoff, D. et al., Lancet. 351:1715-1721, 1998). Generally, atopic dermatitis is hereditary, and is accompanied with allergic asthma, allergic rhinitis, allergic conjunctivitis and urticaria depending on individual characteristics. Reported symptoms related to immunological disorders occurring in patients suffering from atopic dermatitis includes: increased production of IgE, reduced number of Th1 (T-cell Helper type 1) lymphocytes secreting IFN-γ, or the like. Additionally, when viewed from the histological point of view, skin lesions of atopic dermatitis show the increase of T lymphocytes having a CD4+ phenotype, infiltration of monocyte cells/macrophages, and mast cells and eosinophils. Also, skin lesions of atopic dermatitis show the increase of dendritic cells (DCs) and epidermal Langerhans cells (Imokawa, G., et al., J. Invest. Dermatol., 96:523-526, 1991). It has been reported that such conditions occur in normal skin sites as well as lesions (Leung D Y, Bhan A K, Schneeberger E E, Geha R S. J Allergy Clin Immunol., 71 (1 Pt 1), 47-56, 1983). Recently, it was reported that the number of CCR-4 expressing memory CD4+ T lymphocytes increase in lesions of atopic dermatitis (Imai, T. et al., Int. Immunol., 11:81-88, 1999). Additionally, it was reported by Van der Heijden F L et al. that T lymphocytes having a CD4+ phenotype, infiltrated into the lesions, release IL-4 (Van der Heijden F L et al., J Invest Dermatol., 97:389-394, 1991), and the IL-4 serves to accelerate low-affinity Fc receptors to immunoglobuline E in antigen presenting cells.
Further, experimental results showing that T lymphocytes as well as various cytokines released therefrom are closely related to the immunolopathogenic mechanism of atopic dermatitis, were reported recently. Also, it was reported that allergen-specific T helper type 2 lymphocytes producing IL-4, IL-5 and IL-10 increase in the lesions of patients suffering from atopic dermatitis, resulting in a significant effect upon both allergic reactions and an increase of IgE (hussain, I. et al., Curr Drug Targets Inflamm Allergy., 2: 199-120, 2003). Meanwhile, other researchers have studied the effect of atopic dermatitis-related chemokines and receptors thereof upon skin barriers. As a result, it was reported that a great amount of TSLP (thymic stromal lymphopoietin) and MDC (macrophage-derived chemokine) are produced from keratinocytes of patients suffering from atopic dermatitis, and a great amount of RANTES, TARC and MDC are produced upon stimulation of IFN-γ (Giustizieri, M L., et al., J. Allergy Clin Immunol., 107:871-877, 2001).
In general, the immune system of the vertebrate have developed evolutionary in such a manner that immunoactivity arises rapidly in response to the attack of microorganisms through the recognition of several kinds of characteristic molecules in microorganisms. According to studies of many researchers, it was shown that bacterial DNA has various structural determining factors, which are not present in the DNA of the vertebrate, and such factors activates immune cells (Gillkeson, G S. et al., J. Clin. Invest., 95:1398-1402, 1995). The significant difference between the vertebrate DNA and the bacterial DNA is that genomes of the vertebrata have suppressed CpG dinucleotide and 70% of cytosine is methylated in the CpG motif (Krieg, A M. et al., Nature 374:546-549, 1995). Unlike mammals, unmethylated CpG motifs are abundant in bacteria. Oligodeoxynutleotides (ODNs) comprising CpG motifs activate the protection mechanism of a host, which ranges from the innate immune response to the acquired immune response (Akdis, C A. Curr Opin Immunol., 12:641-646, 2000). In general, CpG ODNs can activate B cells as well as NK cells. Additionally, the CpG sequence stimulates macrophage in order to secrete IL-12, which is a latent derivative for the production of IFN-γ from NK cells (Krieg, A M. Annual Review Immunol., 20: 709-760, 2002). In addition to the above, such cells secrete pro-inflammatory cytokines such as IL-1, IL-6, IL-18 and TNF-α, and cytokines such as IFN-γ and IL-12 which make a Th1-biased immunological environment or chemokines. Moreover, the CpG ODNs enhance humoral responses inducing IgG2a isotypes (Th1 type indicator), and increases activation of cytoxic T lymphocytes (CTL) (Warren, T L. et al., J. Immunol., 165:6244-6251, 2000). Use of the CpG ODNs for the treatment of allergic conditions and cancer in animal models is effective for the enhancement of direct or indirect immune responses. It is known that such CpG ODNs have different physiological activities depending on their nucleotide sequences, even if they have the same CpG motif.
Recently, CpG ODNs having a modified backbone have been developed in order to increase the availability of CpG ODNs. The CpG ODNs with a phosphodiester backbone, i.e. a basic backbone of DNA, are sensitive to nuclease, and thus is degraded in vivo. Therefore, there is little possibility for inducing in vivo toxicity. However, the above CpG ODNs have low activity compared to the CpG ODNs with other backbones (Kwon, H J. et al., Biochem. Biophys. Res. Commun, 311:129-138, 2003; and Lee, K W. et al., Mol. Immunol, 41:955-964, 2004). On the contrary, CpG ODNs with a phosphorothioate backbone is prepared by artificially modifying its structure so as to prevent its degradation by the nuclease in vivo. The CpG ODNs with a phosphorothioate backbone are more stable in vivo and shows more excellent effect of inducing B cells, compared to the CpG ODNs with a phosphodiester backbone. Therefore, the CpG ODNs that are modified to have a phosphorothioate backbone are widely used. However, the CPG ODNs with a phosphorothioate backbone increase non-specific ODN binding to various proteins, and are not degraded readily in vivo, thereby causing toxicity. Additionally, it is reported that the CpG ODNs with a phosphorothioate backbone cause arthritis and aggravate arthritis conditions (Deng G M et al., Arthritis & Rheumatisum, 43(2):356-364, 2000; Masayuki Miayta et al., Arthritis & Rheumatisum, 43(11):2578-2582, 2000), and also can cause autoimmune diseases such as SLE (systemic lupus erythematosis) (Tanaka, T. et al., J Exp. Med. 175:597-607, 1992; and Hans-Joachim Anders et al., The FASEB Journal express article 10. 1096/fj. 03-0646fje. published online Jan. 20, 2004). In addition to the above reports, many researchers reported side effects of the CpG ODNs with a phosphorothioate backbone (Tsunoda I. et al., Brain Pathol., 9(3):481-493, 1999; and Bachmaier K. et al., Science, 283(5406):1335-1339, 1999).
As described above, although there has been widely studied on a use of the CpG ODNs as immunoactivators, any disclosure of the CpG ODNs for use in the prevention and treatment of skin diseases cannot be found. Particularly, the use of the CpG ODNs with a phosphodiester backbone for the prevention and treatment of skin diseases has never been studied.