Establishment of tretments for patients with atopic dermatitis based on the immunological background

重症特应性皮炎(AD)患者表现出嗜酸性粒细胞相关的晚期皮肤反应和高水平的IgE，尽管有越来越多的证据揭示其发病机制，但其数量正在增加。非特异性免疫抑制剂已被用于AD的治疗。这些治疗药物有时会导致宿主免疫防御的恶化。AD与免疫反应向Th2表型倾斜有关。确实需要开发一种抗原特异性治疗方法来选择性地抑制Th2细胞介导的反应。含有CpG基序的寡核苷酸(ODN)被认为是一种免疫调节剂，通过使T细胞反应偏向Th1显性表型来减少Th2介导的反应。为了证实CpG ODN在Th2介导的皮肤炎症中的作用，我们引入了一种独特的皮肤模型，该模型由蛋白-Ag诱导的嗜酸性粒细胞炎症，并通过三次腹腔注射使BALB/c的血清IgE水平升高。用卵清蛋白(OVA)/明矾预涂，然后进行一周的OVA皮肤贴片。皮内注射CpG ODN可减少嗜酸性粒细胞的渗入和IgE系统反应。有趣的是，位于OVA贴片部位的皮内CpG ODN显著增强了对嗜酸性粒细胞浸润和IgE水平的抑制作用，并且在给予Ag时效果更好。我们的数据表明，CpG ODN与Ag一起经皮给药可以作为一种新的Ag特异性免疫调节剂治疗AD患者的皮肤嗜酸性炎症。

The number of patients with severe atopic dermatitis (AD), who show an eosinophil-related late phase skin reaction and high levels of IgE, is increasing, although there is accumulating evidence revealing its pathomechanism. Ag-nonspecific immunosuppressants have been used for the treatment of AD. These therapeutic agents sometime cause the deterioration of the host immunologic defense. AD is associated with skewing of immune response towards Th2 phenotype. There is a real need for developing an antigen-specific treatment to selectively suppress Th2 cell-mediated responses. Oligodeoxynucleotides (ODN) containing CpG motifs have been highlighted as an immunomodulator that reduces Th2-mediated responses by biasing the T-cell response toward a Th1-dominant phenotype. To substantiate the effect of CpG ODN in the Th2-mediated skin inflammation, we introduced a unique cutaneous model of a protein-Ag-induced eosinophilic inflammation with increased levels of serum IgE in BALB/c by three-time i.p. priming with ovalbumin (OVA)/alum and following a week-OVA skin patching.. Intradermal administration of CpG ODN diminished the number of infiltrated eosinophils and IgE systemic response. Interestingly, intradermal CpG ODN at the site of OVA patching significantly augmented the inhibitory effects on both the eosinophil infiltration and IgE levels and more effective when administered with Ag. Our data suggest that a cutaneous administration of CpG ODN with Ag can work as a novel Ag-specific immunomodulator therapy to treat the cutaneous eosinophilic inflammation that can be found in patients with AD.